An important contribution to our understanding of pain has been the discovery of a neuronal analgesia system that can be activated by the administration of opiates or by naturally occurring brain substances that share the properties of opiates. This endogenous system was first demonstrated by Reynolds, who found that stimulation of the ventrolateral periaqueductal gray matter in the rat produced a profound analgesia without altering behavior or motor activity. Subsequently, stimulation of other discrete sites in the medial and caudal regions of the diencephalon and rostral bulbar nuclei (notably raphe magnus and paragigantocellularis) was shown to have the same effect. Under the influence of such electrical stimulation, the animal could be operated on without anesthesia and move around in an undisturbed manner despite the administration of noxious stimuli. Investigation disclosed that the effect of stimulation-produced analgesia (SPA) is inhibition of the neurons of Rexed laminae I, II, and V of the dorsal horn, which are the neurons activated by noxious stimuli. In human subjects, stimulation of the midbrain periaqueductal gray matter through stereotactically implanted electrodes can also produced a state of analgesia. Other sites in which electrical stimulation is effective in suppressing nociceptive responses are the rostroventral medulla (nucleus raphe magnus and adjacent reticular formation) and the dorsolateral pontine tegmentum. These effects are relayed to the dorsal horn gray matter via a pathway in the dorsolateral funiculus of the spinal cord. Ascending pathways from the dorsal horn, conveying noxious somatic impulses, are also important in activating the modulatory network.
Opiates act preand postsynaptically on the neurons of laminae I and V of the dorsal horn, suppressing afferent pain impulses from both the A-d and C fibers as previously discussed. Furthermore, these effects can be reversed by the opioid antagonist naloxone. Interestingly, naloxone can reduce some forms of stimulation-produced analgesia. Levine and colleagues have demonstrated that not only does naloxone enhance clinical pain, but it also interferes with the pain relief produced by placebos. These observations suggest that the heretofore poorly understood beneficial effects of placebos may partly result from activation of an endogenous system that mutes pain through the release of endogenous opioids, or endorphins (see below). Prolonged pain and fear are the most powerful activators of this endogenous opioid-mediated modulating system. The same system is probably operative under a variety of other stressful conditions; for example, some soldiers, wounded in battle, require little or no analgesic medication (“stress-induced analgesia”). The opiates also act at several loci in the brainstem, at sites corresponding with those producing analgesia when stimulated electrically and generally conforming to areas in which neurons with endorphin receptors are localized.
Soon after the discovery of specific opiate receptors in the central nervous system, several naturally occurring peptides that bind specifically to these receptors and have a potent analgesic effects were identified. These endogenous, morphine-like compounds are generically referred to as endorphins, meaning “the morphines within.” The most widely studied are b-endorphin, a peptide sequence of the pituitary hormone b-lipotropin, and two other peptides, enkephalin and dynorphin. They and their receptors are found in greatest concentration in the midbrain. At the level of the spinal cord, exclusively enkephalin receptors are found. Figure 7-4 illustrates a theoretical construct of the roles of enkephalin (and substance P) at the point of entry of pain fibers into the spinal cord. Different elements of the sensory system produce and release each of these peptides. A subgroup of dorsal horn interneurons that are in contact with spinothalamic tract neurons also contains enkephalin. Much of the seminal early work in this field was summarized by Snyder.