Spinal and Supra Spinal Modulation of Pain Perception

Working with rats and using simple withdrawal reflexes as pain measures, Reynolds (31) showed that stimulation of a specific region of the midbrain periaqueductal gray (PAG) inhibited behavioral responses to noxious stimulation, giving rise to the term "stimulation produced analgesia.'' Stimulation of these sites inhibited responses of spinal neurons to noxious stimuli suggesting that the brain could modulate spinal activity. The PAG receives direct inputs from the hypothalamus and from the limbic forebrain, including several regions of the frontal neocortex and the central nucleus of the amygdala (Fig. 3). The PAG controls nocicep-tive transmission by means of connections through neurons in the rostral ventromedial medulla (RVM) and the dorsolateral pontine tegmentum (DLPT). These two regions project through the spinal cord dorsolateral funiculus and selectively target the dorsal horn laminae that accommodate nociceptive relay neurons. This circuit can therefore selectively modulate nociceptive transmission by its anatomical proximity to primary afferent nociceptor terminals and dorsal horn neurons that respond to noxious stimulation.

Some neurons in the dorsal horn of the spinal cord are strongly inhibited when a noxious stimulus is applied to any part of the body, distinct from their excitatory receptive fields. This phenomenon was termed "diffuse noxious inhibitory controls'' (DNIC) (33). DNIC refers to a neurophysiological mechanism that underlies the long-established clinical phenomenon of counter-irritation, in which application of an acute aversive stimulus provides temporary

Descending Pain Modulatory System

Figure 3 (See color insert) The principal components of descending pain modulatory pathways, which are activated in response to a painful visceral stimulus such as noxious balloon distension of the colon. Ponto-medullary networks including the pag, rostral ventral medulla, and the raphe nuclei are modulated by inputs from the ACC, amygdala, and other cortical regions. The major descending pain inhibitory pathways are mediated via the opioidergic, serotonergic, and noradrenergic systems. These pathways modulate pain transmission at the level of the dorsal horn of the spinal cord. Abbreviations: PAG, periaqueductal gray; ACC, anterior cingulate cortex. Source: From the AGA gastroenterology teaching project (GTP). Source: American Gastroenterological Association, Baltimore, Maryland, U.S.A.

Figure 3 (See color insert) The principal components of descending pain modulatory pathways, which are activated in response to a painful visceral stimulus such as noxious balloon distension of the colon. Ponto-medullary networks including the pag, rostral ventral medulla, and the raphe nuclei are modulated by inputs from the ACC, amygdala, and other cortical regions. The major descending pain inhibitory pathways are mediated via the opioidergic, serotonergic, and noradrenergic systems. These pathways modulate pain transmission at the level of the dorsal horn of the spinal cord. Abbreviations: PAG, periaqueductal gray; ACC, anterior cingulate cortex. Source: From the AGA gastroenterology teaching project (GTP). Source: American Gastroenterological Association, Baltimore, Maryland, U.S.A.

relief of chronic and recurrent pain (34). DNIC paradigms typically involve measurement of the nociceptive threshold for a "test" stimulus before, during, and after application of a second noxious "conditioning" stimulus to an anatomically remote area of the body. The RIII reflex is one such paradigm, and is a polysynaptic spinal reflex elicited by electrical stimulation of a sensory nerve and recorded from a flexor muscle in the ipsilateral limb. The threshold and amplitude of the RIII reflex are closely related to those of the concomitant cutaneous sensations evoked by electrical stimulation (35).

DNIC are not observed in patients with complete transection of the spinal cord (36), or specific medullary lesions, but are observed in patients with thalamic lesions (37). It has therefore been proposed that DNIC are triggered by ascending spinoreticular fibers, with the medullary reticular formation playing a crucial role in the subsequent descending modulation of spinal pain transmission (37).

Several neurotransmitters and their receptors are known to be involved in descending pain-inhibitory and pain-facilitatory pathways. The opioid system has been extensively described and investigations have largely focused on the m-opioid receptor due to the powerful analgesic action of its widely used ligand morphine. This receptor is ubiquitous in the central nervous system (CNS) sites involved in pain modulation, such as the hypothalamus, amygdala, insular cortex, PAG, DLPT, RVM, and spinal cord dorsal horn (38,39). Behavioral responses to noxious stimulation can be attenuated by the administration of m-opioid receptor agonists at these sites and disruption of RVM neurons that project to the spinal cord dorsal horn reduces the analgesic effects of morphine. There is evidence that opioid-mediated pain modulatory mechanisms operate in humans as naloxone has been reported to enhance experimental and postoperative pain in humans who have not received exogenous opioids (40,41).

Apart from opioid systems of pain modulation, norepinephrine (NE)-mediated and 5-hydroxytryptamine (5-HT)-mediated mechanisms of spinal and supraspinal pain modulation also exist and have been extensively described (42). The RVM contains the nucleus raphe magnus (NRM), and serotonergic neurons in this site demonstrate immunohistochemical FOS reactivity (a marker of noxious activity) following formalin injection and noxious heat stimulation of the hindpaw in the rat (43). Furthermore, Oatway et al. (44) recently demonstrated that ondansetron significantly attenuated mechanical allodynia in a rat model of spinal cord injury, whereas administration of a 5-HT3 receptor agonist exacerbated pain behavior.

In addition, treatment with 5,7-dihydroxytryptamine (which depletes endogenous 5-HT) eliminated the antiallodynic effect of ondansetron in spinal cord injury rats, further supporting the role of endogenous 5-HT in these pain behaviors through activation of 5-HT3 receptors.

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