Stimulation-Produced Analgesia

The seminal observation pointing to selective pain-modulating systems was the discovery of “stimulation-produced analgesia,” which is a highly specific suppression of behavioral responses to noxious stimuli produced by electrical stimulation of the midbrain periaqueductal gray (PAG). During PAG stimulation, animals remained alert and active, and their responses to most environmental stimuli were unchanged. However, the expected responses to noxious stimuli, including orientation, vocalization, and escape, were absent. Stimulation-produced analgesia was also elicited from the rostral ventromedial medulla (RVM, Mayer and Price 1976).

A critical step was the demonstration that stimulation-produced analgesia can be induced in humans. As in animals, stimulation-produced analgesia in humans is elicited by electrical stimulation of the PAG and more rostral periventricular structures. Importantly, motor function is not affected, and patients report subjective analgesia (see reviews by Boivie and Meyerson 1982, Levy et al 2010). Although this procedure is rarely performed at present, the specificity of the analgesic effect and the fact that it is consistently elicited from discrete brain sites that are homologous in a variety of species, including humans, speak to the biological importance of pain modulation.

Discovery of the pain-modulating role of the PAG was a decisive advance in understanding brain mechanisms of pain processing. Subsequent research demonstrated that the PAG is part of a central circuit that controls nociceptive transmission at the level of the spinal cord dorsal horn via a relay in the RVM (Fig. 8-1, Fields and Heinricher 1985). In animals, simple noxious stimulus–evoked reflexes, considered to be organized primarily at the spinal level, are inhibited by stimulation of either the PAG or RVM. Furthermore, this inhibition is selective for nociceptive neurons in the spinal cord dorsal horn (Waters and Lumb 1997). In addition, lesions of the descending projections of the RVM through the dorsolateral funiculus of the spinal cord block inhibition of both nociceptive dorsal horn neurons and nocifensive reflex responses. Importantly, suppression of noxious evoked behavior is not motor inhibition since affective responses are also modulated by PAG and RVM manipulation (Borszcz et al 1996, Hirakawa et al 2000, Munn et al 2009, da Silva et al 2010a). Interest in this system was further heightened when it became clear that it is recruited by opioid analgesic drugs (Yaksh et al 1988).

Although other brain stem pain-modulating circuits will be mentioned (pontomedullary noradrenergic pathways, feedback via the nucleus reticularis dorsalis), this chapter emphasizes the PAG–RVM system. This focus is motivated by the demonstrated significance of this system in the actions of centrally acting analgesic drugs, its role in environmental analgesia, and evidence that it contributes to hyperalgesic states associated with inflammation, nerve injury, immune system activation, and stress.

PAG–RVM System and Facilitation of Pain Transmission

The seminal observation of stimulation-produced analgesia from the PAG and RVM and the recognition shortly thereafter that this network is recruited as part of the analgesic actions of opioids led to a widely held view of this circuit as an “analgesia system.” However, functional studies have clearly shown that brain stem modulatory systems exert bidirectional control and that pain facilitation is a major part of their function (for reviews see Porreca et al 2002, Ren and Dubner 2002, Heinricher et al 2009).

Functional studies have implicated the RVM in hyperalgesia and chronic pain triggered through both “bottom-up” and “top-down” mechanisms. Thus the RVM contributes to hyperalgesia and allodynia in inflammatory and neuropathic pain models (Porreca et al 2002, Heinricher et al 2003). Furthermore, facilitation of output from the RVM generates a tonic aversive state in rodents that can be demonstrated with place conditioning (King et al 2009). The RVM has also been implicated in deep muscle and visceral hypersensitivity and in headache-related pain (Vera-Portocarrero et al 2008, Edelmayer et al 2009, Da Silva et al 2010b, Sanoja et al 2010). It may be a factor in post-surgical hypersensitivity, although this is apparently relatively minor (Pogatzki et al 2002, Rivat et al 2009). The examples just listed illustrate that descending facilitation is engaged as part of a positive feedback loop stimulated by noxious input. Top-down facilitating modulation is also ubiquitous. The RVM is required for hyperalgesia associated with naloxone-precipitated withdrawal or prolonged opioid administration (Kaplan and Fields 1991, Vanderah et al 2001, Vera-Portocarrero et al 2011). The RVM is also engaged to produce hyperalgesia in models of mild or chronic stress (Martenson et al 2009, Imbe et al 2010, Rivat et al 2010) and as part of the sickness response triggered by systemic immune activation (Wiertelak et al 1997, Heinricher et al 2004). In these top-down examples, input from higher centers such as the amygdala and hypothalamus brings the PAG–RVM system into play to produce hyperalgesia.

Although relatively few studies have indicated a direct facilitating influence arising from the PAG, the observations outlined above indicate that the PAG–RVM system as a whole exerts true bidirectional control of nociceptive processing. Facilitation operates in parallel with descending inhibition, with differential control of input from various body regions or different modalities (Vanegas 2004, Vanegas and Schaible 2004, You et al 2010). Discovering how this system is recruited to either inhibit or facilitate nociception under different physiological conditions and in different behavioral contexts is an important challenge for future understanding of descending modulation.

Organization of the PAG–RVM System

The influence of the PAG on the dorsal horn is relayed through the RVM (see Fig. 8-1). However, both the PAG and RVM receive significant input from higher structures, thereby providing a pathway through which cognitive and emotional factors can control pain processing. The PAG–RVM system also receives somatosensory, including nociceptive, information via the spinomesencephalic and spinoreticular tracts. This system is thus positioned to integrate top-down and bottom-up influences on pain transmission.

Ascending projections from both the PAG and RVM, though not as well studied as the descending pathway, have the potential to influence cortical processing of nociceptive input (Morgan et al 1989, Munn et al 2009).

Pharmacology of the PAG–RVM Pain-Modulating Network

Opioid Actions in the Rostral Ventromedial Medulla: ON- and OFF-Cells

Supraspinal opioid administration activates descending antinociceptive controls. How do opioids produce this effect? Morphine and other μ-opioid receptor agonists produce direct post-synaptic hyperpolarization of a subpopulation of neurons in the PAG and RVM (referred to as “secondary cells”). This hyperpolarization is mediated by increased K⁺ conductance (Pan et al 1990, Chieng and Christie 1994). μ-Opioid receptor agonists also act presynaptically to depress synaptic transmission. Presynaptic effects on GABAergic synaptic transmission are pronounced in the RVM, and neurons disinhibited by local μ-opioid action are referred to as “primary cells” (Pan et al 1990). (See Heinricher and Ingram 2008 for review.)

How are opioid effects at the membrane level translated into behaviorally measurable antinociception? Answering this question requires analysis at the circuit level, which is more advanced for the RVM than for the PAG. RVM OFF-cells are activated, ON-cells inhibited, and NEUTRAL-cells unaffected when morphine or μ-opioid receptor agonists are administered systemically, into the PAG or directly into the RVM (Fig. 8-3, Heinricher and Ingram 2008). Local iontophoretic application of morphine directly inhibits ON-cells but has no effect on OFF- or NEUTRAL-cells (Heinricher et al 1992). Thus, ON-cells are probably equivalent to the secondary cells that are directly hyperpolarized by μ-opioid receptor agonists, whereas the opioid activation of OFF-cells in vivo must be indirect, primarily via inhibition of GABAergic inhibitory input (Fig. 8-4).

Activation of OFF-cells is necessary and sufficient for the antinociceptive effects of opioids in acute pain. Selective blockade of OFF-cell activation prevents the antinociceptive effect of systemically or intraventricularly administered morphine (Heinricher et al 1997, 1999, 2001b, 2010). Inhibition of ON-cells is not by itself sufficient to account for the behavioral antinociception produced by μ-opioids under normal conditions (Heinricher et al 1999) but presumably complements and reinforces the activation of OFF-cells. However, direct opioid inhibition of RVM ON-cells may contribute significantly to antinociception in hyperalgesic states such as inflammation or opioid dependence, states characterized by increased ON-cell activity (Porreca et al 2002, Heinricher et al 2003, 2009).

As mentioned, an endogenous opioid acting on RVM neurons provides a significant link between the PAG and the RVM. Microinjecting opioid antagonists into the RVM blocks the antinociception produced by PAG manipulations, and the inhibition of RVM ON-cells by PAG morphine or bicuculline is reversed by local iontophoresis of naloxone (Pan and Fields 1996). Endogenous opioids could also act presynaptically to inhibit GABA release onto OFF-cells, again because opioid inhibition of ON-cells does not by itself produce a measurable antinociceptive effect. Figure 8-4 illustrates this opioid link in the RVM relay from the PAG to the spinal cord dorsal horn.

Insight into the role of the δ-opioid receptor in the RVM remains at an early stage, at least in comparison to our understanding of the μ-opioid receptor (see Heinricher and Fields 2003 for review). In general, δ-opioid receptor agonists produce effects that are similar to but weaker than those produced by μ-opioid receptor agonists. Microinfusion of δ-agonists into the RVM produces neuronal effects similar to those of μ-opioid receptor agonists: ON-cells are inhibited, OFF-cells are excited, and NEUTRAL-cells are unaffected. Tissue inflammation potentiates the effects mediated by the δ-opioid receptor in the RVM (Hurley and Hammond 2000), which synergizes with μ-opioid actions to enhance exogenous opioid analgesics (Hurley and Hammond 2001, Sykes et al 2007). There is also evidence that activation of the δ-opioid receptor contributes to opioid tolerance. Morphine tolerance is reduced in δ-opioid receptor–knockout mice (Zhu et al 1999). Furthermore, bivalent compounds that act as both μ-opioid receptor agonists and δ-opioid receptor antagonists show increased analgesia and reduced morphine tolerance (Daniels et al 2005).

κ-Opioid receptor actions in the RVM are superficially more complex than μ- or δ-receptor actions. Analgesia follows focal application of κ-agonists in the RVM, although some investigators report no effect. κ-Agonists in the RVM can also reduce the antinociceptive effect of morphine and interfere with stress-induced analgesia (Rossi et al 1994, Pan et al 1997, Foo and Helmstetter 2000, Ackley et al 2001). This apparent complexity is explained at the circuit level: U69593, a κ-opioid agonist, both reduces the ON-cell burst and suppresses opioid activation of OFF-cells (Meng et al 2005). The effect on ON-cells would presumably have a modest hypoalgesic effect, whereas the interference with OFF-cell activation would prevent opioid analgesia. This general schematic is confirmed by studies at the cellular level, where two inhibitory actions of κ-agonists have been demonstrated in the RVM: hyperpolarization of primary neurons (which presumably include OFF-cells) and presynaptic inhibition of glutamatergic excitation (Pan et al 1997, Ackley et al 2001, Bie and Pan 2003).

Role of Serotonin in the Descending Modulation of Nociceptive Transmission

Serotonergic neurons account for about 20% of the total RVM population (Moore 1981), and there is evidence of serotonin involvement in descending modulation of pain transmission (Le Bars 1988, Suzuki et al 2004, see also Chapter 28). Electrical stimulation of the RVM evokes the release of serotonin in spinal cord cerebrospinal fluid, and the analgesia produced by this stimulation is reduced by serotonin antagonists administered intrathecally (see Le Bars 1988 for review). Iontophoresis of serotonin inhibits the response of dorsal horn neurons to noxious stimulation (Headley et al 1978, Jordan et al 1978), and serotonin applied directly to the spinal cord inhibits nociceptive transmission (Yaksh and Wilson 1979). Furthermore, the analgesic action of systemically administered opiates can be reduced by depletion of serotonin or by neurotoxic destruction of spinal serotonin terminals.

The significance of serotonin for pain modulation has presented something of a dilemma since initial studies suggested that RVM serotonergic neurons were NEUTRAL-cells rather than ON- or OFF-cells (Mason 1997). However, a recent analysis of a large sample of RVM neurons labeled for serotonin following juxtacellular recording (Bernard et al 2010) found a substantial proportion of serotonergic neurons with ON- and OFF-cell response properties. The existence of serotonin-containing neurons with NEUTRAL-, ON-, and OFF-cell properties would, like the distribution of GABA across all three classes (Winkler et al 2006), argue against a 1:1 relationship between neurotransmitter content and physiological function.

In fact, serotonin, like the PAG–RVM system as a whole, has both anti- and pro-nociceptive roles at the level of the spinal cord. Inhibition is thought to be largely mediated via subtypes of G protein–linked 5-HT₁ and 5-HT₂ receptors (Millan 2002). Other evidence suggests that the inhibition is indirect and can be exerted by descending 5-HT₃–mediated excitation of GABAergic inhibitory interneurons (Alhaider et al 1991). The 5-HT₃ receptor is also thought to mediate the facilitatory actions of serotonin (Suzuki et al 2004). This facilitation is presumably mediated either by direct serotonin action on nociresponsive neurons that express the 5-HT₃ receptor or by enhancement of release of neurotransmitters from the terminals of primary afferent nociceptors that express presynaptic 5-HT₃ receptors. Suzuki and colleagues suggest that a positive feedback loop from nociceptors to the RVM and back to the dorsal horn leads to activation of spinal 5-HT₃ receptors. They reported that the loss of noxious stimulus–induced facilitation of the responses of deep dorsal horn neurons following destruction of NK1 receptor–expressing lamina I neurons by neurotoxin could be mimicked by antagonism of 5-HT₃ receptors at the level of the spinal cord (Suzuki et al 2002). These authors hypothesized that lamina I neurons activate descending facilitatory output from the RVM and that 5-HT₃ receptors in the dorsal horn mediate this positive feedback loop. Functional studies show that intrathecal injection of the 5-HT₃ antagonist ondansetron decreases pain behavior in the second phase of the formalin test (Oyama et al 1996, Zeitz et al 2002) and the hyperalgesia produced by activation of RVM ON-cells via microinjection of CCK (Dogrul et al 2009). However, Peters and colleagues (2010) failed to demonstrate an anti-allodynic effect of ondansetron following spinal nerve ligation, inconsistent with the proposal of Suzuki and colleagues (2004).

Pain-Modulating Systems in the Pontine Tegmentum: Noradrenergic Cell Groups

A second major brain stem pain-modulating system arises in the noradrenergic cell groups of the lateral pontine tegmentum (A5, A6 or locus coeruleus, and A7, see Fig. 8-1). α₂-Adrenergic agents administered at the spinal level produce clinically significant analgesia (Eisenach et al 1996). Just as opioid analgesics co-opt an endogenous opioid pain-modulating system, this effect of α₂-receptor agonists points to modulation of spinal nociception by endogenous noradrenergic systems. Stimulation directed at the noradrenergic cell groups produces antinociception mediated by spinal α₂-adrenergic receptors (for reviews see Proudfit 1992, Pertovaara 2006). Like the PAG–RVM system, noradrenergic pathways exert bidirectional control, with antinociception mediated by spinal α₂-adrenergic receptors and pro-nociception by α₁ receptors (Holden et al 1999, Nuseir and Proudfit 2000).

It is not clear whether noradrenergic tone has a significant impact on acute nociceptive responsiveness under basal conditions. Thus, pharmacological blockade of spinal α₁ or α₂ receptors and long-term depletion of norepinephrine have been reported by several groups to have little or no effect on responses in acute pain tests (Martin et al 1999, Nuseir and Proudfit 2000, Jasmin et al 2003a). By contrast, Howorth and co-authors (2009) reported thermal hyperalgesia when a viral vector–based approach was used to reduce the excitability of pontospinal noradrenergic neurons in normal animals. The mechanical threshold was not lowered. Disparate findings also arise when considering the formalin test, with no effect, reduced responses, and enhanced responses in animals subjected to long-term depletion of norepinephrine or suppression of noradrenergic neuron excitability (Martin et al 1999, Jasmin et al 2003a, Howorth et al 2009).

Data from studies involving chronic pain models are no more consistent. There are several reports that noradrenergic depletion or antagonism facilitates responses in neuropathic pain states, which suggests that descending noradrenergic inhibitory systems are recruited following nerve injury, thus limiting the hyperalgesia that would otherwise result (Xu et al 1999, Jasmin et al 2003a). However, reducing the excitability of pontine noradrenergic neurons did not enhance either tactile or cold allodynia in animals subjected to nerve injury (Howorth et al 2009), and several other groups reported attenuation of allodynia and hyperalgesia following depletion of spinal norepinephrine (Brightwell and Taylor 2009, Martins et al 2010).

These conflicting data indicate that a simple model in which activation of pontospinal noradrenergic neurons suppresses spinal nociceptive processing will be inadequate for understanding the role of this transmitter in descending control. The fact that norepinephrine has bidirectional effects is likely to be one important complicating factor (Holden et al 1999, Nuseir and Proudfit 2000). In addition, the noradrenergic cell groups have supraspinal targets as well as descending connections, which could contribute to changes in nociception following manipulation of noradrenergic cell bodies.

It seems likely that noradrenergic pathways in the pons can be engaged independently of the PAG–RVM system. However, the PAG projects to the dorsolateral pontine area where noradrenergic neurons are found and was shown to make direct connections with A7 noradrenergic neurons (Bajic and Proudfit 1999, Bajic et al 2000). The RVM is reciprocally linked with A7 (Yeomans and Proudfit 1990, Clark and Proudfit 1991). Furthermore, although no noradrenergic neurons are present in the RVM itself, electrical stimulation of the RVM evokes the release of noradrenaline at the spinal cord (Hammond et al 1985), and the inhibition of spinal withdrawal reflexes by activation of the RVM is attenuated by noradrenergic antagonists given intrathecally (Barbaro et al 1985). Iontophoresis of α₂-adrenergic antagonists onto nociceptive dorsal horn neurons blocks inhibition of these neurons by PAG stimulation (Budai et al 1998). These findings could most easily be explained by a circuit in which noradrenergic neurons are recruited by activation of the PAG or RVM. Consistent with this, RVM neurons projecting to the A7 region contain substance P, and focal application of substance P in the A7 region produces analgesia (Yeomans and Proudfit 1992). In addition, the antinociceptive effect of cholinergic stimulation in the RVM is substantially attenuated by inactivation of the A7 region (Nuseir et al 1999). Finally, spinal norepinephrine mediates the antinociceptive effect of activating RVM OFF-cells with neurotensin (Buhler et al 2008). Viewed collectively, these data indicate that the PAG–RVM system produces its antinociceptive effects at least in part by engaging the descending noradrenergic pathways. Whether this extends to pro-nociceptive output remains to be investigated.

Pontine noradrenergic systems may also mediate cortical control of spinal nociceptive transmission. Increasing GABA levels in the anterior insular cortex produces an analgesic effect that is blocked by intrathecal administration of α-adrenergic antagonists. Because this cortical region projects to the locus coeruleus, as well as the RVM, it was suggested that inhibition of insular outflow disinhibits noradrenergic neurons of the locus coeruleus (Jasmin et al 2003b). However, the possibility that the insula engages noradrenergic systems via the RVM cannot be ruled out from these data.

Plasticity of the RVM in Chronic Pain States

Physiological Function of Brain Stem Pain-Modulating Networks

Despite our extensive knowledge of the circuit properties and pharmacological responsiveness of descending modulatory networks, knowledge of their physiological function and clinical significance is tentative. Adding to the complexity of this analysis, several pain-modulating networks are operating in parallel, and understanding the net behavioral effect of their combined actions requires parsing the contribution of each under a variety of conditions. Nevertheless, there is evidence of recruitment of modulatory systems as part of counterirritation, sickness, fear, and anxiety, based on cognitive variables, including attention and expectation.

Attention

That attentional factors can reliably alter perceived pain intensity is well established (Villemure and Bushnell 2002). In a typical experimental paradigm, human subjects are trained in a task to make either a visual or a noxious thermal discrimination. Attending to the painful stimulus generally increases its perceived intensity, and distraction largely reduces it.

There is evidence that attentional modulation of pain involves descending pathways. In monkeys, the responses of some nociceptive dorsal horn neurons to a noxious thermal stimulus were found to be greater when the monkey was required to discriminate the intensity of the stimulus than when required to carry out a distracting visual task (Hayes et al 1981). Furthermore, under conditions of correct cueing of a thermal discrimination task, monkeys displayed shorter response latencies for signaling their detection of the increase in skin temperature. From this it was inferred that they perceive the stimulus as more intense (Bushnell et al 1985). These studies suggest that attentional shifts lead to a centrally generated component in the response of dorsal horn neurons to noxious thermal stimulation and that this centrally generated increment alters the perceived intensity of pain.

Although it is uncertain what neural circuits are involved in the attentional modulation of dorsal horn neurons, human functional imaging studies implicate the PAG–RVM system. Tracey and colleagues (2002) studied brain stem regions during a task in which normal human subjects rated thermal pain in the presence or absence of a visual distractor. During distraction, pain intensities were rated as significantly lower, and there was a concomitant increase in activity in the PAG. In an extension of this work, Bantick and co-workers (2002) studied subjective pain reports and forebrain functional magnetic resonance imaging signals when noxious stimuli were applied with or without a distraction task. Pain reaction times were increased and intensity ratings were predictably lowered during distraction. This was associated with activation of the rostral anterior cingulate cortex during distraction and a decrease in other areas, including the contralateral thalamus, insular cortex, and mid-cingulate region (an area activated by noxious stimuli). The authors attributed this pattern of reduced activation during distraction to reduced input via nociceptor-activated sensory pathways. These imaging results indicate that both the PAG and the anterior cingulate cortex are activated when pain intensity is reduced by distraction and point to a possible mechanism for attentional regulation of afferent pathways.

Expectations and Pain-Predictive Cues: Anterior Cingulate and Anterior Insular Cortex (See Chapter 27)

With learning, neutral contextual cues acquire the power to either increase or decrease the activity of nociceptive dorsal horn neurons in the absence of a noxious stimulus. In situations in which subjects are conditioned with specific cues that predict either painful or neutral stimuli, the cues come to have a significant effect on the pain experience (Sawamoto et al 2000, Ploghaus et al 2003). When pain-predictive cues are presented just before non-painful warm stimuli, human subjects are more likely to report the warm stimuli as being painful. In these same subjects, concomitant functional imaging demonstrates activation of the rostral anterior cingulate cortex and anterior insular cortex by cues predicting pain. Consistent with the functional imaging data, single-unit recordings in awake primates have revealed activation of a population of anterior cingulate cortex neurons specifically during pain avoidance behavior (Koyama et al 2001), and lesions of the rostral anterior cingulate cortex prevent the development of pain avoidance behavior (e.g., Johansen et al 2001). These data tie the human sensory experience to the pain modulatory circuitry studied so extensively in animals.

Non-human primate studies indicate that at least part of the expectancy-related enhancement of pain perception is due to activation of descending pathways that alter nociceptive processing in the dorsal horn. Thus, Duncan and colleagues (1987) recorded the activity of nociceptive trigeminal dorsal horn neurons, including some that project to the thalamus. The primates were trained to press a button in response to a light cue. Pressing the button initiated a trial during which the animal had to discriminate between two noxious thermal stimuli. The activity of some neurons displayed abrupt increases or decreases that were time-locked to the light cue or the button press. Importantly, these task-related changes in activity occurred before onset of the thermal stimulus. These experiments show that the activity of dorsal horn nociceptive neurons can be increased or decreased by a context-specific modulatory signal that originates in the CNS. The presence of facilitatory modulation of dorsal horn nociresponsive neurons raises the intriguing possibility that pain can be produced by a centrally originating drive of dorsal horn nociceptive neurons, without activation of primary afferent nociceptors.

Can we link the evidence implicating the rostral anterior cingulate cortex and the anterior insula in expectancy-related modulation with the changes observed in the dorsal horn? There are several possible pathways through which cortical regions activated during expectancy could reach brain stem pain-modulating nuclei. These pathways include direct projections from the anterior cingulate cortex to the PAG (An et al 1998) and direct anterior insular connections to the RVM and pontine noradrenergic cell groups (Jasmin et al 2004). There is also a dense rostral anterior cingulate cortex projection to the NAc (Knishes and Haber 1994), which in turn projects to the hypothalamus and to the basolateral amygdala. Both of the latter have connections with PAG and RVM. Further research is needed to establish that expectancy-related cortical activation modulates pain through descending influences on dorsal horn nociceptive neurons. However, as described earlier, we know that the PAG–RVM system is engaged during placebo analgesia. We also know that placebo analgesia is mediated primarily by expectancy (see Chapter 27). These two lines of evidence strongly suggest that the PAG–RVM system mediates alterations in pain as a result of expectancy.

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