Receptors and Effectors

Sensory nerves express a variety of receptors for inflammatory mediators. Different classes of nociceptors express distinct patterns of receptors. The receptors fall into three main classes: G protein–coupled receptors (GPCRs), ligand-gated ion channels, and the cytokine receptors or receptor tyrosine kinases (Fig. 3-1).

Intracellular Signaling Pathways

Sensory nerves are activated and sensitized by inflammatory mediators in several ways (see Fig. 3-1B). Some mediators directly activate cation channels and thus depolarize neurons toward the voltage for initiation of an action potential. Other receptors activate intracellular pathways and influence neuronal sensitivity and excitability indirectly. These mechanisms include GPCR-mediated production of the second-messenger molecules NO, COX, and lipoxygenase products of arachidonic acid. Phosphorylation or dephosphorylation of membrane proteins often regulates the transduction and transmission of sensory signals (Fig. 3-1C), and this can occur via PKA-, PKC-, mitogen-activated protein kinase (MAPK)-, or phosphatidylinositol-3′-kinase/Akt-mediated phosphorylation or by dephosphorylation via protein phosphatases such as calcineurin. In addition to phosphorylation, some of the mediators that act on nociceptors can stimulate biochemical processes such as methylation and lipid modification of proteins, and these pathways may be important in nociceptive neurons.

In general, the effect of sensitization is to increase the probability that a given stimulus (ligand or voltage) will activate the target receptor or ion channel or increase the probability that the neuron will be excited. Protein phosphorylation is a well-known mechanism for controlling the activity of ion channels. For example, activity of the heat-sensitive ion channel TRPV1 is modified by both PKC- and PKA-mediated phosphorylation (Bhave et al 2003, Mohaptra and Nau 2005), and the level of membrane expression is regulated by src-mediated phosphorylation (Zhang et al 2005b). Control of transduction channel activity can also be regulated by hydrolysis of PIP₂ and removal of the tonic inhibition caused by PIP₂ binding to the ion channel (see, e.g., Dai et al 2007). Ion channels that control the excitability and firing frequency of sensory neurons are also substrates for regulation by PIP₂ (Suh and Hille 2008) and phosphorylation (Gold 1999, Baker 2005, Beyak and Vanner 2005, Stamboulian et al 2010, Emery et al 2011).

Neuronal sensitization can occur through changes in the level of protein expression, either by transcriptional control altering the production of proteins or by changing the trafficking such that an altered amount of the protein is functionally expressed. Transcriptional control is an important long-term mechanism underlying the effects of neurotrophin receptor activation. In some cases, sensitization has been associated with the de novo expression of molecules important for nociception in neurons that do not normally express the protein (Hudson et al 2001, Vellani et al 2004).

Bradykinin

There is a considerable body of evidence that kinins contribute to the pathophysiological processes accompanying both acute and chronic inflammation. Bradykinin and the related peptide kallidin (Lys⁰-bradykinin) are formed from kininogen precursor proteins following the activation of plasma or tissue kallikrein enzymes during inflammation, tissue damage, or anoxia. The activity of these kinins is terminated by several degradative enzymes. Kininase I liberates the biologically active metabolites des-Arg⁹-bradykinin and des-Arg¹⁰-kallidin, whereas kininase II and endopeptidases form inactive metabolites (Calixto et al 2000, Marceau and Regoli 2004). The biologically active kinins activate two distinct types of G protein–linked receptors. Bradykinin and kallidin act preferentially at the B₂ receptor, whereas des-Arg⁹-bradykinin and des-Arg¹⁰-kallidin act with much higher affinity at the B₁ receptor than at the B₂ receptor.

B₂ receptors are expressed constitutively on a wide range of cell types, including nociceptive sensory nerves, and administration of bradykinin evokes pain and sensitizes polymodal nociceptors (see Mizumura et al 2009). Bradykinin acts directly on sensory nerves and can also act indirectly by evoking the release of other inflammatory mediators from non-neuronal cells. There is good pharmacological evidence that the acute and some of the long-term effects of bradykinin are mediated via the B₂ receptor. For example, peptide and non-peptide B₂ receptor antagonists have analgesic and anti-hyperalgesic actions in animal models of inflammatory pain (Dray and Perkins 1993; Perkins and Kelly 1993, 1994; Asano et al 1997; Burgess et al 2000; Cuhna et al 2007; Valenti et al 2010), as well as in some neuropathic pain models (Werner et al 2007, Luiz et al 2010). Interestingly, thermal hypersensitivity is still evoked by complete Freund’s adjuvant (CFA)-induced inflammation in mice lacking the B₂ receptor (Boyce et al 1996, Rupniak et al 1997, Ferreira et al 2001), but carrageenan-evoked thermal hypersensitivity is reduced (Boyce et al 1996, Rupniak et al 1997).

In contrast to B₂ receptors, B₁ receptors are not normally expressed at significant levels in normal tissue, except in some vascular beds, but their expression is induced by tissue injury and infection. This up-regulation of B₁ receptors requires de novo protein synthesis (Regoli et al 1978, Bouthillier et al 1987, DeBlois et al 1991), and there is evidence that the induction is stimulated by the release of cytokines such as IL-1β and TNF-α from immunocompetent cells in the damaged tissue (Calixto et al 2004, Cuhna et al 2007). Some effects of B₁ agonists are mediated via non-neuronal cells, where activation of the B₁ receptor evokes the release of PGE₂ and PGI₂, NO, and various cytokines (Leeb-Lundberg et al 2005, Kuhr et al 2010). There is also immunocytochemical and autoradiographic evidence that the B₁ receptor is expressed in a subset of sensory neurons (Wotherspoon and Winter 2000, Ma 2001, Petcu et al 2008) and that the level of expression is increased during inflammation (Fox et al 2003). The mechanisms regulating expression of the B₁ receptor in sensory neurons are not well understood but are likely to involve cytokines, as found in other cell types, and neurotrophins. Functional expression of sensory neuron B₁ receptors is up-regulated by exposure to the neurotrophins GDNF and neurturin. Under such conditions, B₁ receptor activation evokes sustained enhancement of the heat-gated current mediated by TRPV1 (Vellani et al 2004).

There is good pharmacological evidence that B₁ receptors have an important role in the hyperalgesia associated with persistent inflammation. Although B₁ agonists do not normally affect nociceptive thresholds in animals, they evoke hyperalgesia following inflammation (Davis and Perkins 1994, Perkins and Kelly 1994, Fox et al 2003). Furthermore, peptide B₁ antagonists such as des-Arg¹⁰-HOE140 and des-Arg⁸Leu⁹-bradykinin (Perkins and Kelly 1993, Perkins et al 1993, Campos and Calixto 1995, Rupniak et al 1997, Fox et al 2003), as well as non-peptide B₁ antagonists (Fox et al 2005, Hawkinson et al 2007), inhibit thermal or mechanical hyperalgesia in models of joint, paw, or tail inflammation. These data are consistent with the finding that mice lacking the B₁ receptor show reduced thermal (Ferreira et al 2001) and mechanical (Fox et al 2005) hyperalgesia after CFA treatment.

The relative importance of the changes in subtypes of bradykinin receptors is variable and depends on the inflammatory condition, with evidence of a shift toward a dominant role of B₁ receptors in chronic conditions in which B₁ receptor expression is up-regulated (see, e.g., Cuhna et al 2007). Although many studies have focused on the peripheral role of kinin receptors, there is also evidence from studies involving selective antagonists and knockout mice that B₁ and B₂ receptors expressed in the spinal cord influence spinal processing of nociceptive signals in inflammatory conditions (Pesquero et al 2000; Ferriera et al 2001, 2002).

Arachidonic Acid Metabolites

The enzymatic breakdown of arachidonic acid yields a variety of bioactive lipid molecules that have diverse physiological roles, including important actions in inflammation and pain. These molecules are not stored but are synthesized de novo from membrane lipids. The first step is release of arachidonic acid from phospholipids by the action of PLA₂ enzymes. Arachidonic acid is then metabolized to prostaglandins via the COX enzymes; to leukotrienes, 5-HPETE, and 5-hydroxyeicosatetraenoic acid (HETE) via 5-lipoxygenase; to 12-HPETE and 12-HETE via 12-lipoxygenase; to lipoxins via 15-lipoxygenase; and to epoxyeicosatetraenoic acids via the action of cytochrome P450.

Protease-Activated Receptors

Four types of G protein–coupled protease-activated receptors (PARs) have been identified (PAR1–4). These receptors are activated by a unique mechanism whereby extracellular, soluble, or surface-associated proteases cleave at specific residues in the extracellular N-terminal domain of the G protein to expose a novel N-terminal sequence that acts as a tethered ligand and activates the receptor by binding to other regions of the protein. These agonist effects can be mimicked by short synthetic peptides based on the sequence of the tethered ligands of the different PARs. PAR1, PAR3, and PAR4 are activated by thrombin produced during the blood-clotting cascade, whereas PAR2 activation is triggered by tryptase, which is known to be released from mast cells in inflammatory conditions, as well as by the blood-clotting factors VIIa and Xa and the cysteine protease cathepsin S (Soh et al 2010, Cattaruzza et al 2011). In this way PARs are activated as a result of tissue damage and inflammation. Because activation involves an irreversible enzymatic cleavage, restoration of PAR sensitivity requires internalization of the receptors and insertion of new receptor into the plasma membrane.

Serotonin

Serotonin is one of many mediators released from platelets (rats and humans) and mast cells (rats) in injured and inflamed tissues. In humans, intradermal dialysis of 5-hydroxytryptamine (5-HT) evokes burning pain (Lischetski et al 2001), and intramuscular injection of 5-HT elicits pain and sensitization to pressure stimuli (Ernberg et al 2000, Ernberg et al 2006). In situ hybridization studies have shown that DRG neurons normally express mRNA for 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2B, 5-HT_3B, and 5-HT₄ receptors (Nicholson et al 2003), with other evidence for the expression of 5-HT₇ receptors (Amaya-Castellanos et al 2011). Expression of some of these receptor subtypes (5-HT_2A, 5-HT₃, 5-HT₄, and 5-HT₇) is increased with inflammation (Wu et al 2001, Liu et al 2005).

Some of the excitatory actions of serotonin have been ascribed to activation of the 5-HT₃ receptor/ion channel. 5-HT₃ receptor agonists enhance the excitability of unmyelinated C-fibers (Moalem et al 2005, Lang et al 2006), and relatively selective 5-HT₃ antagonists reduce the pain evoked by peripheral administration of serotonin or carrageenan in rats (Eschalier et al 1985, Richardson et al 1985, Sufka et al 1992).

Serotonin can also activate and sensitize nociceptors by actions on G protein–coupled 5-HT receptors. 5-HT_2A receptors are expressed mainly in small-diameter (Aq- and C-fiber) peptidergic and non-peptidergic sensory neurons, and there is significant overlap with TRPV1 expression (Okamoto et al 2002, van Steenwinckel et al 2009). 5-HT_2A receptors play a significant role in inflammatory thermal hypersensitivity. Intraplantar administration of 5-HT_2A agonists into rats produces thermal hyperalgesia (Abbott et al 1996, Tokunaga et al 1998), and activation of peripheral 5-HT_2A receptors induces Fos expression in dorsal horn neurons, indicative of sensory neuron excitation (Doi-Saika et al 1997). Conversely, peripheral administration of 5-HT_2A receptor antagonists reduces the thermal hyperalgesia induced by either CFA or carrageenan (Okamoto et al 2002, Wei et al 2005, Huang et al 2009). In addition to the strong evidence for a role of 5-HT_2A receptors, there is also pharmacological evidence that 5-HT_2B receptors play a role in inflammatory mechanical hypersensitivity but not in thermal hyperalgesia (Lin et al 2011). The cellular mechanisms responsible for these effects are unclear. 5-HT₂ receptors are usually linked to the PLC pathway, and the sensitization mechanism or mechanisms may be attributable to PKC-mediated modulation of ion channels.

Relatively few data are available on the roles of peripheral 5-HT₄ and 5-HT₇ receptors in inflammatory conditions, although some pharmacological evidence indicates that these receptor subtypes have roles in the longer-term (days) mechanical allodynia following intraplantar administration of formalin (Godinez-Chapiro et al 2011). These receptors are positively coupled to adenylate cyclase, and receptor activation stimulates cAMP production. An increase in cAMP can result in a PKA-mediated modification of ion channel function, notably, increased activity of tetrodotoxin (TTX)-resistant sodium channels (Cardenas et al 2001, Scroggs 2011).

Nitric Oxide

Although the actions of NO on nociceptive processes are primarily spinal and evident after intrathecal administration of drugs, there is controversial evidence of a peripheral action of NO. The cellular source of NO is unclear, and both neuronal and non-neuronal sources are likely. NO is produced in the periphery during inflammation (see Toriyabe et al 2004). nNOS appears to be responsible for synthesis in the early phase of inflammation and nNOS and iNOS at later phases (Omote et al 2001). Experimentally, intradermal and intravascular injection of NO evokes a concentration-dependent pain in human volunteers (Holthusen and Arndt 1994, 1995), whereas topical administration of NO donors is antinociceptive. The site of action appears to be important. Studies in rats have shown that intradermal administration of the NO precursor L-arginine or an NO donor (3-[4-morphinolinyl]-sydnonimine hydrochloride [SIN-1]) evokes mechanical hypersensitivity. In contrast, subcutaneous injection of these agents had little effect on baseline mechanical thresholds but reversed PGE₂-induced hypersensitivity (Vivancos et al 2003) via an NO/cGMP pathway (Sachs et al 2004). A pro-nociceptive action of NO in inflammatory conditions is supported by the finding that local administration of the NOS inhibitor N^ω-nitro-L-arginine methyl ester (L-NAME) reduces both mechanical and thermal hyperalgesia, as well as the inflammation induced by carrageenan (Lawand et al 1997, Nakamura et al 1996). Similarly, co-injection of another NOS inhibitor, N^G-methyl-L-arginine (L-NMA), inhibited PGE₂-induced mechanical hyperalgesia, whereas intradermal injection of the NOS substrate L-arginine or the NO donor SIN-1 evoked mechanical hyperalgesia (Aley et al 1998). In peripheral nerves the NO-sensitive (soluble) guanylate cyclase is expressed by non-neuronal cells and not by sensory neurons (Schmidtko et al 2007), so the sensory neuron effects of activating the NO/cGMP pathway are likely to be indirect. NO can also nitrosylate ion channels, and this may be a more important mechanism for any direct pro- or antinociceptive NO effects. NO can stimulate DRG neurons by activation of both TRPA1 and TRPV1, and studies of genetically modified mice show that the thermal hyperalgesia elicited by injection of an NO donor is largely dependent on TRPV1 expression. In addition, both TRPA1 and TRPV1 appear to play roles in the acute nociceptive behavioral response to NO donor injection after pre-activation of the PLC/PKA pathways (Miyamoto et al 2009). Conversely NO activates ATP-sensitive K⁺ channels (Kawano et al 2009) and inhibits voltage-gated sodium channels (Renganathan et al 2002) in DRG neurons; both actions will inhibit neuronal firing and could contribute to antinociception. Many of the peripheral effects of NO or NOS inhibition are likely to involve other cells and mediators, including alterations in cytokine levels (Chen et al 2010b).

ATP and Adenosine

Low pH

The pH of the extracellular environment is known to fall in a number of pathophysiological conditions, such as hypoxia and anoxia, as well as with inflammation and tumors. Acidic conditions can have direct effects on sensory nerves. Low-pH solutions evoke prolonged activation of sensory nerves and produce a sharp stinging pain in humans (Lindahl 1962, Steen and Reeh 1993, Jones et al 2004). Several mechanisms are thought to underlie the neuronal excitation observed. One key effect of acid solutions is activation and sensitization of the thermosensitive ion channel TRPV1 (Tominaga et al 1998, McLatchie and Bevan 2001, Leffler et al 2006). A second mechanism is direct activation of ASICs (see Deval et al 2010), notably ASIC3, which is expressed in the sensory innervation of the heart and activated by modest reductions in extracellular pH (to about pH 7). ASIC3 has been proposed to be the sensor in cardiac nociceptors that triggers cardiac pain in response to myocardial acidity (Sutherland et al 2001) and may play a role in sensing acidic conditions in other tissues such as skin (Deval et al 2008) and skeletal muscle (Sluka et al 2003). Finally, low pH can augment or stimulate neuronal firing by inhibiting K⁺ channel activity (Baumann et al 2004).

Mast Cells

Mast cells are found in areas of the body that interact with the external environment, such as the skin and mucosal layers, and these cells are normally situated in close proximity to blood vessels and nerves. Mast cell granules contain numerous chemicals, including histamine, and they can also synthesize and release many cytokines and chemokines (Metcalfe et al 1997).

Mast cells can be degranulated by the compound 48/80, which when applied to human skin causes thermal hyperalgesia, thus indicating that chemicals in the granules of mast cells are pro-algesic (Drummond 2004). Chronic treatment with this compound prevents re-granulation of these cells, and in this state some common models of inflammatory pain, including those precipitated by injection of acetic acid or zymosan and the second phase of the formalin test, show reduced pain-like behavior (Ribeiro et al 2000, Parada et al 2001). Treatment with 48/80 to deplete mast cell granules also reduces both the thermal and mechanical hyperalgesia produced by CFA (Woolf et al 1996). One of the mechanisms by which NGF induces thermal hyperalgesia (see below) is thought to be mediated via its action on mast cells (Lewin et al 1994). Thus, NGF was not able to sensitize nociceptors to thermal stimuli in mice deficient in these cells (Rueff and Mendell 1996), and these mice do not fully develop pain-like symptoms in a model of cystitis, which also seems to be strongly dependent on the release of mast cell mediators (Rudick et al 2008).

Mast cells are also present in the sciatic nerve. Following partial sciatic nerve ligation (PSNL, a model of neuropathic pain), very few intact mast cells remain at the site of injury or directly distal to it, thus suggesting that the majority have released the contents of their granules. Stabilization of these cells increases the presence of intact mast cells and reduces the development of both mechanical and thermal hyperalgesia (Theodosiou et al 1999, Zuo et al 2003). Although the chemicals released by mast cells may act directly to sensitize nociceptors, such agents may also act to recruit and activate other immune cells within the injured nerve. Histamine is one of the mediators released by mast cells. However, the analgesic effect of antihistamine treatment is modest, and in some neuropathic pain models such agents have limited effects on mechanical pain–related hypersensitivity. Stabilization of mast cells with cromoglycate can reduce neuropathic hypersensitivity. Some of this action is likely to be indirect since such treatment also reduced both neutrophil and macrophage infiltration into the injured nerve (Zuo et al 2003). Mast cells can produce NGF (Leon et al 1994), and this might also contribute to the pro-algesic action of these cells.

Neutrophils

Neutrophils are PMN granulocytes and make up around 60% of the circulating white blood cells, which puts them in an ideal position to react, in large numbers, to pathogens or tissue injury. Rodent models of inflammatory pain are commonly induced by the local injection of an antigen, such as zymosan, LPS, or carrageenan, and subsequent activation of the innate and adaptive immune system (Cunha et al 2008a, 2008b; Guerrero et al 2008; Ting et al 2008). Accumulation of neutrophils occurs in all these models and can be reduced by blocking receptors that mediate the rolling, attachment, and transmigration of these cells from blood into tissue. Complement component 5a (C5a), a complement activation product, is a potent chemotactic factor for neutrophils (Shin et al 1968). Following injection of zymosan into the paw, pharmacological inhibition of the C5a receptor attenuated both mechanical hypersensitivity and neutrophil influx (Ting et al 2008). The chemokine receptors CXCR1 and CXCR2 are both important in neutrophil migration and activation in numerous inflammatory states (Bizzarri et al 2006). Dual inhibition of these receptors was able to significantly reduce the accumulation of neutrophils and abnormal sensory behavior induced by zymosan, carrageenan, and LPS (Cunha et al 2008a). More recently, specific antagonism of the CXCR2 receptor via the small molecule SB225002 reduced both pain-related hypersensitivity and neutrophil accumulation in the carrageenan model (Manjavachi et al 2010). Other factors with strong chemotactic effects on neutrophils include the lipoxygenase product LTB₄ (Ford-Hutchinson et al 1980). Both pharmacological and genetic inhibition of the action of LTB₄ reduced the hypersensitivity produced by joint inflammation (Guerrero et al 2008). In agreement with these data, chemical depletion of neutrophils decreased their accumulation in skin after both zymosan and carrageenan treatment and prevented full development of the abnormal sensory behavior in these models (Ting et al 2008). Although recruitment of these cells is important, blockade of the C5a receptor in the LPS and carrageenan models did not affect neutrophil recruitment but did attenuate pain-like behavior, thus suggesting that certain molecules such as C5a may, in some instances of inflammation, be more important for activation than for direct recruitment of these cells (Ting et al 2008). In naïve animals, intradermal injection of neutrophil chemotactic factors such as LTB₄, N-formylmethionyl-leucyl-phenylalanine (fMLP), C5a, and chemokine C-X-C motif ligand 1 (CXCL1) induces pain-related hypersensitivity (Levine et al 1985, 1986a; Cunha et al 2008a). Interestingly the prominent pro-algesic properties of NGF are also reported to depend on neutrophil recruitment (Bennett et al 1998b). Recently, IL-17 has been shown to be a pro-nociceptive cytokine, particularly in the setting of antigen-induced arthritis, where neutralization of its effect reduced pain-related hypersensitivity and neutrophil recruitment in a TNF-α–dependent manner (Pinto et al 2010). In addition, intraplantar injection of this cytokine produces both thermal and mechanical hypersensitivity associated with the accumulation of neutrophils in the dermis (Kim and Moalem-Taylor 2011b, McNamee et al 2011). However, it must be stated that neutrophil attraction alone may not be sufficient to cause pain-like behavior because the activation status of these cells is also likely to be important. The chemotactic factor glycogen results in neutrophil recruitment but does not cause any significant pain-like hypersensitivity (Levine et al 1985). Nevertheless, systemic depletion of neutrophils significantly reduced the pain-like behavior elicited by LTB₄, C5a, fMLP, and NGF administration, thus suggesting that activated neutrophils are crucial in the pro-algesic properties of these and other factors (Levine et al 1985, 1986a; Bennett et al 1998b; Ting et al 2008). In vitro experiments have shown that in a co-cultured system, dissociated DRG neurons increase their excitability following neutrophil activation, which suggests that neutrophils do release factors that can act directly on nociceptive neurons (Shaw et al 2008). Clinically, it seems that neutrophils play an important role in inflammatory diseases; in particular, they are present in the joint fluid and synovial membrane of patients with rheumatoid arthritis (RA) (Wright et al 2010). Interestingly, therapies used to treat RA, such as antibodies against TNF-α, reduce pain scores in these patients and decrease the influx of neutrophils into the joint (den Broeder et al 2003).

Neutrophils are normally completely absent from the naïve sciatic nerve. However, in animals in which the nerve has been injured to induce neuropathic pain–like behavior, substantial neutrophil infiltration takes place (Perkins and Tracey 2000, Zuo et al 2003, Kim and Moalem-Taylor 2011a). In addition, cytokine recruitment of neutrophils into the non-injured nerve can recapitulate this pain-like behavior (Kim and Moalem-Taylor 2011b). Some of the strongest evidence for a role of these cells in the development of neuropathic pain–like behavior comes from depletion studies. Systemic depletion of neutrophils before injury reduced the development of thermal hypersensitivity (Perkins and Tracey 2000). However, an attempt to deplete neutrophils 8 days after injury had no effect on pain behavior (Perkins and Tracey 2000), a finding suggestive of an important role in the initiation rather than the maintenance of neuropathic pain. Neutrophils can release numerous chemokines (Scapini et al 2000), and it is likely that their algogenic effects, like those of mast cells, may partly be due to the subsequent recruitment and activation of other immune cells such as macrophages.

Macrophages

Macrophages are leukocytes and represent a heterogeneous group of cells resident in the majority of tissues. They are continually being replenished from a circulating peripheral blood mononuclear cell population, which itself originates from bone marrow. These cells have homeostatic actions in their tissue of residence, such as clearing cell debris, as well as repairing and remodeling tissue following damage and inflammation. Macrophages derive from monocytes, which also generate a range of other specialized cells contributing to innate immunity, including microglia in the CNS, alveolar macrophages in the lung, Langerhans cells in the skin, osteoclasts in bone, Kupffer cells in the liver, and histocytes in connective tissue, as well as resident cells in the spleen, gastrointestinal tract, and the peritoneum (Gordon and Taylor 2005). Following tissue damage or infection, the macrophage population is augmented by blood-derived monocytes. The resident as well as the infiltrating macrophages react to endogenous danger signals released by necrotic cells or exogenous signals such as factors produced by microorganisms and appropriately release cytokines to orchestrate the innate and adaptive immune response. A strong body of evidence suggests a role of macrophages in the development of both inflammatory and neuropathic pain.

Intraperitoneal injection of acetic acid or zymosan is used as a model of visceral pain and induces overt pain-like behavior in rodents in the form of a writhing response. This behavior can be exacerbated by increasing the macrophage population (Ribeiro et al 2000). Inhibiting the production of inflammatory mediators by macrophages through treatment with either anti-inflammatory cytokines or pentoxifylline (which reduces activation of these cells via a poorly defined mechanism) has been shown to reduce inflammatory pain (Vale et al 2003, 2004). Mice deficient in the purinergic receptor P2X₄ demonstrate reduced mechanical hyperalgesia following either CFA or carrageenan application. This effect is attributed to a reduction in the release of PGE₂ from tissue-resident macrophages, which would normally occur in a P2X₄-dependent manner, and in agreement, injection of ATP-stimulated macrophages from wild-type mice into P2X₄-deficient mice was able to induce mechanical hyperalgesia (Ulmann et al 2010).

Macrophages have an important role in the development and maintenance of neuropathic pain. Traumatic injury to a peripheral nerve results in degeneration of axons separated from their cell bodies and breakdown of the associated myelin sheath in a process termed wallerian degeneration. Macrophages have an important role in phagocytosing and clearing myelin debris; because such debris is inhibitory to axon regeneration, clearance is vital for effective nerve repair. Chronic constriction injury (CCI) of the sciatic nerve in mice results in an increase in macrophage infiltration over a 28-day period that is strongly associated with neuropathic pain–like behavior (Myers et al 1996). Naturally occurring mutant mice that exhibit slow wallerian degeneration display delayed macrophage recruitment and reduced cytokine production in injured nerves (Sommer and Schafers 1998). Consistent with this attenuated inflammatory response, such mice also show delayed onset/reduced mechanical and thermal pain–related hypersensitivity (Myers et al 1996, Ramer et al 1997). Systemic depletion of macrophages also reduced both thermal and mechanical hyperalgesia in the PSNL model of neuropathic pain (Liu et al 2000, Barclay et al 2007).

Another means of inhibiting the pro-algesic actions of macrophages is to reduce their recruitment from the circulation to the injured nerve. An important molecule for macrophage chemotaxis is CCL3, blockade of which reduces macrophage infiltration, as well as thermal and mechanical pain–related hypersensitivity (Kiguchi et al 2010). The toll-like receptors (TLRs) are pattern recognition receptors that respond to structural motifs on pathogens and the products of tissue injury. They have an important role in macrophage recruitment and activation. Mice lacking TLR2 demonstrate absent macrophage recruitment and reduced neuropathic pain–like behavior (Shi et al 2011).

Another option for modulating the functional properties of these cells is to alter their functional status and thereby reduce the production of pro-inflammatory cytokines (Kiguchi et al 2010). This can be achieved by treatment with anti-inflammatory cytokines such as IL-10 (Wagner et al 1998). Trying to change the phenotype of macrophages from a pro- to an anti-inflammatory state may be a better therapeutic option than trying to globally inhibit their recruitment to or function within the injured nerve because they are essential for effective nerve repair (Barrette et al 2008).

Dendritic Cells

Dendritic cells (DCs) are closely related to macrophages; they are primarily antigen-presenting cells but also have phagocytic capabilities and can release cytokines and chemokines. Some of the pro-nociceptive effects of IL-17 may be mediated by these cells (Ruts et al 2010, Kim and Moalem-Taylor 2011b). In the epidermis these cells are referred to as Langerhans cells (LCs). Following traumatic nerve injury, epidermal nerve fiber density is decreased. However, spared fibers that intermingle with degenerating axons share innervation territories, and these spared axons have an important role in the generation of neuropathic pain. The endings of these spared axons show increased association with LCs after nerve injury (Lin et al 2001, Lindenlaub and Sommer 2002). In chemotherapy-induced neuropathic pain–like states these LCs express OX-6, a marker of activation associated with pro-inflammatory cytokine production (Siau et al 2006). This same phenomenon has been seen in skin biopsy samples taken from patients with complex regional pain syndrome (Calder et al 1998), and in diabetic patients with small-fiber neuropathy, the number of LCs is increased in the skin in comparison to control samples (Casanova-Molla et al 2012). DCs also infiltrate the injured sciatic nerve distal to and at the site of injury. This infiltration is delayed and occurs 1 week after the initial injury when a robust thermal and mechanical pain–related hypersensitivity takes place (Kim and Moalem-Taylor 2011a). Although these cells respond to a number of different types of tissue injury, there is as yet no direct evidence that they contribute to persistent pain states.

T Cells

T cells are lymphocytes activated by the presentation of antigens. They mediate cellular immunity either by directing the immune response via the release of cytokines to activate innate immune cells or through the destruction of infected cells. More than most, T cells represent a heterologous group of immune cells loosely divided into CD4⁺ (helper) and CD8⁺ (cytotoxic) with type 1 and type 2 subsets. Th1 cells release pro-inflammatory cytokines that activate neutrophils, macrophages, and natural killer (NK) cells, whereas Th2 cells release anti-inflammatory cytokines that activate humoral immunity and strongly deactivate macrophages (O’Garra and Arai 2000).

T cells have a pivotal role in autoimmune diseases. RA represents one such disease that is commonly associated with persistent pain, T-cell infiltration, and cytokine production (Toh and Miossec 2007). Abatacept is a fusion protein that prevents the activation of T cells and decreases pain in patients with RA. In models of neuropathic pain induced by either CCI or PSNL, the number of T cells is significantly increased in the injured nerve in comparison to controls (Cui et al 2000, Kim and Moalem-Taylor 2011a). This increase is associated with both thermal and mechanical pain–related hypersensitivity (Cui et al., 2000). Neuropathic pain–related behavior is reduced in T cell–deficient mice or in mice that lack the ability to produce mature T cells (Moalem et al 2004, Kleinschnitz et al 2006, Cao and Deleo 2008, Costigan et al 2009). Passive transfer of Th1 cells into mature T cell–deficient mice is able to restore full neuropathic pain–like behavior, and this pain behavior can be attenuated by Th2 cells in immune-competent mice (Moalem et al 2004). Guillain-Barré syndrome is an autoimmune disorder affecting the peripheral nervous system. The syndrome is a form of peripheral neuropathy and is commonly associated with abnormal pain (Ruts et al 2010). Rats with experimental autoimmune neuritis model this syndrome, and these animals display robust neuropathic pain–like behavior and significant expression of T cells in the affected nerves (Moalem-Taylor et al 2007, Ruts et al 2010).

Other Immune Cells

Many other cells have immune functions and orchestrate both innate and adaptive immunity. NK cells are lymphocytes and constitute up to 20% of the mononuclear cells found in the blood and spleen. They target and kill infected or “stressed” cells, thereby playing a major role in tumor rejection, and can release many pro-inflammatory cytokines. NK cell activity is not altered in the CCI model of neuropathic pain (Tsai and Won 2001), and although their numbers do increase in some nerve injuries, this is not associated with the development of hyperalgesia (Cui et al 2000). B lymphocytes mediate the humoral arm of the adaptive immune response and produce specific antibodies against presented antigens. A recent study looking at immune cell infiltration into the sciatic nerve found a significant increase in the number of B cells 3–14 days after injury, particularly at the site of damage (Kim and Moalem-Taylo, 2011a). However, there does not seem to be any direct evidence linking B cells to the development or maintenance of persistent pain. In fact, full neuropathic pain–like behavior develops in B cell–deficient mice following nerve injury (Costigan et al 2009). Eosinophils and basophils are, like neutrophils, PMN cells that play a role in both parasitic infection and the body’s response to allergens. There is little evidence linking these cells to pain modulation. Both these cell types can release a variety of pro-algesic factors, and further study is required to elucidate any possible role in pain pathophysiology.

Production of Immune Mediators by Non-immune Cells

Many immune cells in their quiescent state do not appear to interact with nociceptive systems. However, following tissue injury some cells undergo a profound phenotypic change that results in the release of cytokines and chemokines. These factors can recruit more immune cells and may also act as pain mediators. Non-immune cells can play an important role in initiating this process. An example is keratinocytes found within the epidermis, an important innervation target in which the naked endings of nociceptors terminate. Following injury or disease, keratinocytes can release an array of cytokines, chemokines, and growth factors (Pastore et al 2006, Li et al 2011), which can have sensitizing actions on nociceptors, as well as endogenous opioids, which can have an analgesic action (Khodorova et al 2003). A further example is Schwann cells, which in normal nerves are intimately associated with axons: myelinating Schwann cells wrap around peripheral axons to form the myelin sheaths that facilitate axonal conduction. There are also non-myelinating Schwann cells, which in nerve fibers ensheathe small-diameter unmyelinated axons, usually in groups called Remak bundles (Griffin and Thompson 2008). In the process of wallerian degeneration these cells de-differentiate and proliferate. They produce a variety of pro-algesic factors such as NGF (Bandtlow et al 1987, Heumann et al 1987, Matsuoka et al 1991); cytokines such as TNF-α, IL-1β, and IL-6 (Bolin et al 1995, Shamash et al 2002, Wagner and Myers 1996); and chemokines such as CCL2 (Fu et al 2010). Such factors may act directly by sensitizing the remaining intact axons within injured nerves (Sorkin et al 1997) and may also have a role in the recruitment of immune cells (Tofaris et al 2002, Perrin et al 2005), thereby contributing to the development of neuropathic pain.

Clearly, then, there is a large body of evidence showing that immune cells are important contributors to the development of multiple types of persistent pain. Immunosuppressive strategies, however, are in general not useful in treating pain because, of course, many aspects of inflammation are of use in promoting tissue repair. A more productive strategy is likely to be the identification of mediators produced by immune cells that lead to activation and sensitization of nociceptors. Below we consider the evidence for such specific mediators.

Cytokines

One well-recognized consequence of inflammation is the production of various prostanoids, but the limited efficacy of NSAIDs that target COX enzymes—and therefore prostanoid production—strongly suggests a role for other inflammatory mediators. The inflammatory process, triggered by the recruitment of immunocompetent cells and the generation of free radicals, leads to the release of several other algogenic mediators. NGF is one such mediator, and the biology of this factor is discussed at some length below since anti-NGF therapies are now being tested in the clinic. TNF-α and IL-1β are two inflammatory cytokines that also contribute to inflammatory pain. Administration of small doses of TNF-α or IL-1β to adult animals and humans can produce pain and hyperalgesia that start within minutes in some cases and typically persist for several hours (see Watkins and Maier 2003, McMahon and Cafferty 2004, Sommer and Kress 2004). Both these factors are capable of activating and sensitizing peripheral nociceptive neurons and thereby contribute to ongoing pain and hyperalgesia. There is evidence demonstrating that neutralization or block of IL-1β and TNF-α is also effective in preventing abnormal pain behavior in some inflammatory pain models (see Sommer and Kress 2004). Antibodies against TNF-α and IL-1β are now in clinical use for the treatment of inflammatory arthritis and are proving very successful both in treating disease symptoms, including pain, and in modifying the course of the disease (Fleischmann et al 2004, Iannone et al 2007, Laas et al 2009). The analgesic effects of blocking TNF-α are also seen in patients with osteoarthritis (OA) of the hand, for which they have been shown to significantly reduce spontaneous as well as pressure-evoked pain (Fioravanti et al 2009).

Sensory neurons are known to express receptor components capable of transducing extracellular TNF-α (Pollock et al 2002) and IL-1β (Gardiner et al 2002). Intraneural injection of either TNF-α or IL-1β can induce both thermal and mechanical hyperalgesia (Zelenka et al 2005), and blocking either of these factors peripherally following nerve injury attenuates such pain behavior (Lindenlaub et al 2000, Schafers et al 2003, Kiguchi et al 2010). For TNF-α these effects seem to be mediated via TNFR1 and not TNFR2 (Sommer et al 1998). In addition, intraplantar injection of TNF-α (Cunha et al 1992, Perkins et al 1994) or IL-1β (Safieh-Garabedian et al 1995, Amaya et al 2006) can induce hypersensitivity to both thermal and mechanical stimuli. These effects can be mediated directly on nociceptors; both TNF-α and IL-1β have been shown to increase the excitability of nociceptive neurons by enhancing TTX-resistant sodium channel currents via the activation of intracellular cascades involving p38 MAPK (Jin and Gereau 2006, Binshtok et al 2008). TNF-α can also enhance the sensitivity of TRPV1 to contribute to thermal hypersensitivity (Nicol et al 1997, Jin and Gereau 2006). Intriguingly, trimers of TNF-α have been reported to insert into membranes and form functional voltage-dependent sodium channels (Kagan et al 1992), which may allow generalized sensitization of sensory neurons in the absence of functional TNF-α receptors. In addition to these direct actions on sensory neurons, it is clear that a large proportion of the algogenic effect of TNF-α and IL-1β is mediated via NGF. Neutralizing antisera or other molecules blocking NGF prevent the pain produced by these inflammatory cytokines. Mast cells also express trkA (Horigome et al 1993) and in response to NGF proliferate, degranulate, and release inflammatory mediators, including TNF-α (Woolf et al 1996). Because mast cells also release NGF, there is the possibility of a vicious circle of events promoting pain.

Leukemia inhibitory factor (LIF) and IL-6 both belong to a family of neuropoietic cytokines defined by their binding to the common receptor gp130. Other members include IL-11, ciliary-derived neurotrophic factor, oncostatin M, and cardiotrophin-1. LIF signals via a receptor complex of the LIF receptor-β and gp130 and is retrogradely transported by a population of small-diameter DRG cells (Thompson et al 1997). Levels of LIF are normally very low. However, following nerve injury, LIF expression increases at the site of injury (Banner and Patterson 1994). Nerve injury also results in a large increase in expression of the neuropeptide galanin within sensory neurons. Evidence from both animals deficient in LIF (Sun and Zigmond 1996) and the administration of exogenous LIF (Thompson et al 1998) indicates that this cytokine is responsible for up-regulation of galanin. LIF may also be implicated in the sprouting of post-ganglionic sympathetic neurons that occurs around DRG cell bodies following nerve injury (Thompson and Majithia 1998).

The actions of LIF are not restricted to nerve injury but also extend to inflammatory conditions (Banner et al 1998). LIF levels increase during inflammation. LIF knockout mice have an enhanced inflammatory reaction. Conversely, administration of exogenous LIF can attenuate both the hyperalgesia and the increased NGF expression that normally occur during inflammation. Confusingly, the effects of exogenous LIF may be dose dependent in that another study has found that administration of this factor to naïve animals may itself produce hyperalgesia (Thompson et al 1996). Endogenous LIF, however, appears to have an interesting role as a mediator that suppresses the inflammatory reaction possibly at an early stage by negatively regulating the expression of IL-1β and NGF.

IL-6 can exert its biological effect through the binding of either a membrane-bound IL-6 receptor or a soluble receptor subunit, both of which need to form a complex with gp130 for signal transduction. Sensory neurons, which constitutively express gp130 (Gardiner et al 2002), lack the IL-6 membrane receptor, and it is therefore likely that direct actions of IL-6 on these cells involve it and the soluble form of the receptor binding to a cell. Intraplantar injection of IL-6 induces a dose-dependent mechanical hyperalgesia (Cunha et al 1992). Mice deficient in IL-6 show both reduced thermal and mechanical hyperalgesia following inflammation or nerve injury (Xu XJ et al 1997, Ramer et al 1998). By measuring release of CGRP, it seems that IL-6, in combination with its soluble receptor, can sensitize nociceptors in the skin to thermal stimuli (Obreja et al 2002), and electrophysiological experiments have also reported that this cytokine can sensitize joint afferents to mechanical stimulation (Brenn et al 2007). The effect of IL-6 on pain behavior could be direct since IL-6 can elicit calcium transients in around 33% of DRG neurons in vitro (von Banchet et al 2005). This evidence is suggestive of a role of IL-6 as a peripheral pain mediator, and this notion has been highlighted recently by a study using an antigen-induced arthritis model. Here, local neutralization of the IL-6/soluble IL-6 receptor complex with soluble gp130 in the knee joint significantly attenuated mechanical hyperalgesia to a greater extent than did repeated systemic delivery (Boetteger et al 2010). Like IL-1β and TNF-α, therapies that block IL-6 are used clinically and have been shown to reduce pain scores in RA patients (Smolen et al 2008, Burmester et al 2011).

These same immune-related factors and others can also act as pain mediators in the CNS, and such actions are discussed in Chapter 4.

Chemokines

Chemokines are chemotactic cytokines and have a key role in immune cell recruitment. They are small molecules (8–10 kDa) and are structurally related with four conserved cysteine residues. They signal via GPCRs, and a level of complexity is added by the fact that multiple chemokines may signal via one receptor. Like a number of cytokines, there is good preclinical evidence to suggest that some chemokines, particularly CCL2 and CX3CL1, are able to modulate pain processing at the level of the spinal cord. However, there is also evidence suggesting that this family of chemotactic cytokines can act as peripheral pain mediators. For example, inflammation or tissue injury can up-regulate numerous chemokine ligands, and the application of such factors can induce pain-related behavior (as highlighted in Table 3-2 and in Fig. 3-2A). These actions can be achieved either through direct actions on nociceptive neurons or through the recruitment of immune cells (as shown in Fig. 3-2B) and the subsequent release of other algogenic factors.

A number of chemokines have been shown to modulate peripheral pain pathways. This was first shown with the intraplantar injection of exogenous human CXCL8, also known as IL-8, which induced dose-dependent mechanical hyperalgesia in rats (Cunha et al 1991). Interestingly, there is no direct rodent ortholog of this chemokine, but CXCL1 seems to elicit similar effects when given to naïve rats, and antiserum against it attenuates carrageenan-induced mechanical hyperalgesia (Lorenzetti et al 2002, Qin et al 2005). In terms of the influence that chemokines have in persistent pain states, the majority of work suggests a prominent role for the CCL2/CCR2 axis. CCL2 is up-regulated in peripheral tissues in neuropathic (Perrin et al 2005, Fu et al 2010) and inflammatory pain states such as intraplantar CFA injection (Jeon et al 2008). Indeed, up-regulation in a number of different pain models was recently emphasized in a meta-analysis of micro-array studies (LaCroix-Fralish et al 2011). When injected into the paw, CCL2 is able to elicit both thermal and mechanical hyperalgesia (Abbadie et al 2003, Qin et al 2005, Bogen et al 2009). In addition to these findings, ablation of CCR2, the predominant receptor for CCL2, prevents the development of mechanical hyperalgesia following nerve injury (Abbadie et al 2003). CCL2 therefore acts as a peripheral pain mediator in the setting of nerve injury and/or inflammation. Another closely related chemokine, CCL3, can produce pain-related hypersensitivity when applied peripherally (Zhang et al 2005a, Eijkelkamp et al 2010) and is able to recapitulate neuropathic pain–like behavior when given intraneurally (Kiguchi et al 2010). One possible mechanism by which chemokines may influence the perception of nociceptive input is via direct interaction with sensory afferents. A number of chemokines can directly act on DRG neurons, as seen with calcium imaging (Oh et al 2001). These same chemokines were also able to induce pain-related behavior when injected into the paw. Subsequent to this work it was shown that CCL3 was capable of sensitizing TRPV1 on DRG neurons and that sodium currents in cultured sensory neurons could be enhanced by incubation with CXCL1 (Wang et al 2008). In addition, CCL3 might also be able to desensitize opioid receptors on sensory neurons, thereby preventing the analgesic effects of endogenous opioids released following tissue injury (Zhang et al 2004). The idea that chemokines can act directly on sensory neurons requires that appropriate receptors be expressed by these cells. Following nerve injury the chemokine receptors CCR2, CCR5, and CXCR4 can be expressed by DRG neurons, and cells in this condition have been shown to increase their responsiveness to a number of chemokine ligands, including CCL2, CCL5, CXCL10, and CXCL12 (White et al 2005; Sun et al 2006; Bhangoo et al 2007, 2009; Jung et al 2008). One study using in vivo electrophysiological techniques showed that after a chronic compression injury of the spinal nerve, DRG neurons were depolarized by CCL2 and lowered their threshold for activation with this ligand (Sun et al 2006). Although this effect was clear in DRG neurons from injured animals, some responses were also measured in neurons from uninjured ganglia (Sun et al 2006). Via an immunohistochemical approach in naïve rats, expression of both CCR1 and CXCR2 has been found in a high proportion of sensory neurons from naïve animals (Zhang et al 2005a, Wang et al 2008). In addition, Oh and colleagues (2001) detected mRNA for CXCR4, CX3CR1, CCR4, and CCR5 in DRGs, as well as staining for CXCR4 and CCR4 in vitro. Therefore, a range of chemokines released by either resident or infiltrating cells into damaged tissue could act directly on nociceptor nerve terminals to enhance pain perception.

Chemokines may also act indirectly to induce pain-related hypersensitivity. For example, the pro-algesic actions of both CXCL8 and CXCL1 have been attributed to their ability to induce the release of sympathetic amines from resident cells (Cunha et al 1991, 1992, 2005; Ben-Baruch et al 1995; Lorenzetti et al 2002), which can act to directly sensitize nociceptors. The majority of these indirect effects, however, are most likely to involve the recruitment of immune cells, cells that are known to infiltrate areas of damaged tissue. CXCL1-induced hyperalgesia is associated with neutrophil recruitment into the treated peripheral tissue (Cunha et al 2008a, 2008b). This chemokine attracts neutrophils predominantly through activation of the CXCR2 receptor. Systemic treatment with a CXCR1/2 inhibitor or specific antagonism of CXCR2 is able to attenuate the mechanical hyperalgesia induced by peripheral injection of carrageenan, zymosan, LPS, and CFA and that caused by nerve injury (Cunha et al 2008a, Manjavachi et al 2010). These analgesic effects are associated with reduced neutrophil infiltration. The ultraviolet B (UVB) model of inflammatory pain is associated with both neutrophil and macrophage infiltration and up-regulation of numerous chemokines at the peak of both thermal and mechanical hyperalgesia (Dawes et al 2011). Neutralization of one of the most overexpressed chemokines, CXCL5, which also acts via the CXCR2 receptor, was able to reduce the UVB-induced mechanical hyperalgesia and infiltration of immune cells. In addition, the pro-algesic properties of this chemokine in naïve animals involved the recruitment of both neutrophils and macrophages (Dawes et al 2011).

A number of chemokines are up-regulated in injured peripheral nerves. One of these, CCL2, is particularly pivotal in the recruitment of macrophages (Toews et al 1998)—cells that seem crucial for the full development of neuropathic pain (see the previous section on immune cells; Liu et al 2000, Barclay et al 2007). With the use of bi-transgenic reporter mice in a focal demyelination model of neuropathic pain it has been suggested that a large proportion of the pro-nociceptive effects of CCL2 occur in peripheral nerves because of its action on CCR2-expressing leukocytes (Jung et al 2009). In this same model, disruption of this interaction with a CCR2 antagonist significantly attenuates neuropathic pain–like behavior (Bhangoo et al 2007). CCL3 is also up-regulated in injured nerves (Perrin et al 2005, Kiguchi et al 2010). Local neutralization of CCL3 was able to attenuate both thermal and mechanical hyperalgesia following nerve damage, and this was associated with a reduction in the level of macrophages (Kiuchi et al 2010).

Resolution of Inflammation

The inflammatory cascade is under complex regulatory control, and regulatory factors include anti-inflammatory cytokines (IL-4, IL-10, IL-13, transforming growth factor [TGF-β]), promoters of resolution (lipoxins, neuroprotectins, maresins, resolvins), endocannabinoids, and inhibitors of pro-inflammatory signaling pathways (inhibitor of the nuclear factor NF-κB, complement inhibitors, IL-1R antagonist, co-stimulatory molecules, and MAPK phosphatases). These systems may be exploited to terminate inflammation, and a number of these mediators have been shown to have analgesic actions. An example is the resolvins, which are endogenous lipid mediators derived from ω-3 fatty acids. These factors promote resolution of inflammation through inhibition of leukocyte recruitment and can directly modulate sensory transduction and synaptic plasticity within the dorsal horn (Serhan et al 2002, Xu et al 2010, Park et al 2011). They have been shown to have potent analgesic actions in inflammatory pain states (Xu et al 2010, Park et al 2011).

Neurotrophic Factors

In 1996 a study was published on the genetic basis of the congenital insensitivity to pain observed in a single family (Indo et al 1996). A mutation was identified in the gene encoding a tyrosine kinase receptor known as trkA. This protein is the high-affinity receptor for a single trophic factor, NGF, and the mutation disrupts the normal signaling of NGF. This single example provides a startling example of the importance of trophic factors in general and NGF in particular for normal nociceptive functioning. Several clinical trials have indicated the analgesic efficacy of blocking NGF, and we now have a good understanding of the mechanisms by which NGF interacts with pain-signaling systems, which we review here.

Neurotrophic factors can be defined as factors that regulate the long-term survival, growth, or differentiated function of discrete populations of nerve cells. There are many neurotrophic factors, and multiple factors can affect a single population of neurons. However, trophic factors fall into a smaller number of families, with members being related by high levels of structural homology or by the common or related receptors that they use in exerting biological actions. The number of factors identified as affecting sensory processing is limited. Most data relate to just two families of factors: the neurotrophin family and the GDNF-related family. Here we primarily consider one member of the neurotrophin family—NGF. Other members of the neurotrophin family are BDNF, neurotrophin-3, and neurotrophin-4/5 (Gotz et al 1994, Lindsay 1996). In general, these members share around 50% of their amino acid sequence. At physiological concentrations, the neurotrophins exist as homodimers. The neurotrophins are initially expressed as pre-pro-precursors, which when processed, yield highly basic mature proteins of around 13 kDa (120 amino acids). These pre-pro-precursors themselves might be biologically active, and currently there is much discussion whether some of the pro-forms of neurotrophins are secreted and act on specific receptors (Teng et al 2010). Binding studies have demonstrated the presence of both high- and low-affinity binding sites for NGF on responsive cell lines (Bothwell 1995). Two different classes of neurotrophin receptor have now been characterized (for reviews see Barbacid 1995, Chao and Hempstead 1995). The first to be cloned was the p75 or low-affinity NGF receptor LNGFR, which binds all the neurotrophins more or less equally with relatively low affinity (Chao et al 1986). Additionally, there is a family of high-affinity receptors, trks, that are tyrosine kinase receptors (Kaplan et al 1991). The p75 receptor is thought to play several roles and may serve as the preferred receptor for pro-NGF. It can also interact with the trk receptors and modulate the specificity and sensitivity of neurotrophin interaction. There are three known members of the trk family of receptors, trkA, trkB, and trkC, and all show different specificities for the neurotrophins. NGF is the preferred ligand for trkA, BDNF and neurotrophin-4/5 are the preferred ligands for trkB, and neurotrophin-3 is the preferred ligand for trkC (Ip et al 1993).

A great deal of the information about signal transduction following trk activation comes from the study of events following activation of trk by NGF in PC12 cells. After NGF binding, receptor dimerization occurs, which is critical for receptor activation (Clary et al 1994). The tyrosine kinase domain of the receptor is activated and a number of substrates are phosphorylated; autophosphorylation of the receptor also occurs. There is now a large body of evidence demonstrating that neurotrophin receptors are expressed in specific populations of DRG cells. With double-labeling techniques it has been possible to relate receptor expression to different functional classes of DRG cells. Multiple approaches have demonstrated that approximately 40% of DRG cells express the NGF receptor trkA (Verge et al 1989, 1992; McMahon et al 1994; Averill et al 1995; Kashiba et al 1995; Molliver et al 1995; Wetmore and Olson 1995), and cells that express trkA are principally of small cell diameter. TrkA is expressed principally in the peptidergic population of small-diameter DRG cells, whereas very few non-peptidergic (isolectin B4-binding) small-diameter DRG cells express trkA (Averill et al 1995, Molliver et al 1995). Some of the myelinated DRG cells (i.e., those that express neurofilament 200) do express trkA (around 20%). TrkA-immunoreactive terminals within the spinal cord are present within laminae I and II_outer. TrkA is therefore expressed in small-diameter DRG cells that express CGRP and project to the superficial laminae of the spinal cord. These are all characteristic of nociceptive afferents. Thus, about half of the nociceptors in adult animals express both p75 and trkA and are therefore likely to be sensitive to NGF. The other half of the nociceptor population does not express any trk receptor, nor p75. Rather, they express receptors for members of the GDNF family of receptors. Interestingly, these two populations of C fibers have different central terminations, even though it is not yet clear whether they have distinct functional roles (although the receptors that they express do indicate that they can be activated by different putative pain mediators).

During development it appears that functionally distinct groups of sensory neurons depend on different neurotrophins for survival. Animals with a gene deletion of either NGF or trkA are born with DRGs lacking virtually all small-diameter primary sensory neurons, including the peptidergic neurons expressing CGRP and substance P (Crowley et al 1994). These animals are, as expected, profoundly hypo-algesic. In utero deprivation of NGF, achieved by antibody treatment, produces similar effects (Johnson et al 1980, Ruit et al 1992), and this phenotype is equivalent to that seen in patients with loss-of-function mutations in trkA, which also leads to loss of peripheral pain-signaling neurons.

The developmental dependence of nociceptors on NGF for survival is lost in the postnatal period, some time before the second week of life in the rat and presumably in the first few years of life in humans. However, NGF continues to exert profound effects on adult nociceptors. Adult DRG neurons can be cultured in the absence of added trophic factors (Lindsay 1988). If NGF is then added to these cultures, extensive neurite outgrowth of trkA-positive cells is promoted. NGF in these cultures also regulates expression of the neuropeptides substance P and CGRP (Lindsay and Harmar 1989). In addition, NGF regulates the chemical sensitivity of cultured sensory neurons. For example, the sensitivity of cultured sensory neurons to the potent algogen capsaicin is increased by NGF, as is their sensitivity to protons and to γ-aminobutyric acid (GABA) (Winter et al 1988, Bevan and Winter 1995). Expression of bradykinin binding sites in cultured sensory neurons has also been shown to be regulated by NGF (Petersen et al 1998), apparently in a p75 receptor–dependent manner. This marked regulation of the chemosensitivity of cultured sensory neurons by NGF is interesting in relation to the association between NGF and inflammatory pain, and the in vivo effects of NGF are discussed here.

The effects of NGF extend from the peripheral to the central terminals of sensory neurons, and many are mediated via altered gene expression in neurons expressing trkA. These effects are summarized in Figure 3-3.

Administration of small doses of NGF to adult animals and humans can produce pain and hyperalgesia. In rodents, thermal hyperalgesia is present within 30 minutes of systemic NGF administration and both thermal and mechanical hyperalgesia after a couple of hours (Lewin et al 1993). Subcutaneous injections of NGF also produce both thermal and mechanical hyperalgesia at the injection site. In humans, intravenous injections of very low doses of NGF produce widespread aching pain in deep tissues and hyperalgesia at the injection site (Petty et al 1994). Detailed quantitative sensory testing in human volunteers has demonstrated long-lasting mechanical and thermal hypersensitivity following the intradermal injection of NGF (Rukweid et al 2010). The rapid onset of some of these effects and their localization to the injection site strongly suggest that they arise, at least in part, from a local effect on the peripheral terminals of nociceptors. This has been substantiated by the observation that acute administration of NGF can sensitize nociceptive afferents to thermal and chemical stimuli (Rueff and Mendell 1996). Cutaneous nociceptors chronically exposed to elevated NGF levels (in an NGF-overexpressing mouse) show marked heat sensitization (Stucky et al 1998). Recordings of primary afferents innervating porcine skin following NGF application have demonstrated reduced activity-dependent slowing in mechanically insensitive afferents and increased ongoing activity, thus emphasizing the potential effects of NGF on axonal excitability (Obreja et al 2011).

NGF produces sensitization of nociceptors by several mechanisms. Some of these mechanisms are direct (that is, they follow activation of trkA on nociceptors), and some are indirect and mediated by NGF inducing the release of other algogens from a variety of peripheral cell types. The direct mechanisms involve both altered gene expression and post-translational regulation of receptors and ion channels. There are now multiple examples of post-translational changes induced by NGF that involve phosphorylation of receptors and ion channels, although other actions are possible, such as altered trafficking of receptors. The heat sensitization of nociceptors induced by NGF is prominent and rapid. Phosphorylation of particular residues on TRPV1 receptors appears to account for most of the effect. However, the intracellular cascades responsible are disputed, with published data supporting a critical role for PKA, PKC, MAPK ERK1/2, or a mechanism involving inhibition of PIP₂ (see Bonnington and McNaughton 2003). NGF has also been shown to enhance mechanically activated currents in cultured sensory neurons (Di Castro et al 2006). The post-translational modification of some ion channels, particularly TTX-resistant sodium channels, by NGF may likewise contribute to the sensitization of nociceptors by this agent (see Zhang et al 2002 and references therein).

Because cellular elements other than nociceptors in peripheral tissues express trkA, some of the sensitization of nociceptors by NGF may arise indirectly, and some of these elements have already been discussed. Mast cells contain a number of inflammatory mediators known to excite primary afferents, including histamine and serotonin (Leon et al 1994), and some types of mast cells express trkA receptors (Horigome et al 1994). NGF can produce mast cell degranulation (Mazurek et al 1986, Horigome et al 1994) and increase the proliferation of mast cells resident in tissue. In peritoneal mast cell cultures, NGF induces the expression of a number of cytokines (Bullock and Johnson 1996). Mast cell degranulators and serotonin antagonists have both been demonstrated to partially prevent the thermal but not the mechanical hyperalgesia (Lewin et al 1994, Woolf et al 1996) that occurs in response to NGF. These degranulators can significantly reduce hyperalgesia (both thermal and mechanical) and the up-regulation of NGF expression induced by CFA (Woolf et al 1996).

In skin, NGF may also affect keratinocytes, some of which express p75 receptors. NGF increases the proliferation of keratinocytes in culture (Paus et al 1994, Fantini et al 1995), and this process may contribute to tissue remodeling after inflammation. In addition, NGF may also target eosinophils and convert circulating eosinophils into tissue-type eosinophils (Hamada et al 1996), and it has been reported to increase B- and T-cell proliferation (Otten et al 1989), thus suggesting a role for NGF as an immunoregulatory factor.

There may be an interaction between NGF and sympathetic neurons during inflammation. Sympathetic efferents also possess the trkA receptor (Smeyne et al 1994). Surgical or chemical sympathectomy can reduce the short-latency thermal and mechanical hyperalgesia evoked by NGF (Andreev et al 1995, Woolf et al 1996). Production of eicosanoids by sympathetic efferents within the skin has been suggested to contribute to hyperalgesia in some inflammatory conditions (Levine et al 1986b). However, a role for eicosanoids in NGF-induced hyperalgesia is unlikely since it is unaffected by treatment with the NSAID indomethacin (Amann et al 1996).

Other Neurotrophic Factors As Peripheral Pain Mediators

In addition to NGF, preclinical data also suggest that other neurotrophic factors can act as peripheral pain mediators. The neurotrophins NT3 and BDNF both induce thermal hypersensitivity in rats when injected into the hindpaw, and following nerve injury, neutralization of BDNF in the periphery can reduce the increase in thermal hypersensitivity (Theodosiou et al 1999). In the adult system the non-peptidergic nociceptive fibers lack trkA but instead express c-Ret, the prominent receptor for GDNF (Snider and McMahon 1998). When injected into the paw of naïve animals, GDNF is reported to lower thermal pain–related thresholds (Malin et al 2006). However, this factor might not act as a pro-algesic mediator in persistent pain states since its application to nerve-injured rats is analgesic (Boucher et al 2000). Artemin, a member of the GDNF family of ligands, is also able elicit thermal hypersensitivity when given intradermally. In inflammation induced by CFA injection, artemin is greatly up-regulated at a transcriptional level in the skin in the first 24 hours (Malin et al 2007). It has also been observed that in genetically modified mice that overexpress artemin in the skin, sensitivity to both thermal and cold stimuli is increased (Elitt et al 2006).

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