Opioids in chronic pain

The advance in our understanding of the biogenesis of various endogenous op ioid peptides, their anatomical distribution, and the characteristics of th e multiple receptors with which they interact open a new avenue for underst anding the role of opioid peptide systems in chronic pain. The main groups of opioid peptides: enkephalins, dynorphins and beta -endorphin derive from proenkephalin, prodynorphin and proopiomelanocortin, respectively. Recentl y, a novel group of peptides has been discovered in the brain and named end omorphins, endomorphin-1 and -2. They are unique in comparison with other o pioid peptides by atypical structure and high selectivity towards the mu -o pioid receptor. Another group, which joined the endogenous opioid peptide f amily in the last few years is the pronociceptin system comprising the pept ides derived from this prohormone, acting at ORL1 receptors. Three members of the opioid receptor family were cloned in the early 1990s, beginning wit h the mouse delta -opioid receptor (DOR1) and followed by cloning of mu -op ioid receptor (MOR1) and kappa -opioid receptor (KOR1). These three recepto rs belong to the family of seven transmembrane G-protein coupled receptors, and share extensive structural homologies. These opioid receptor and pepti de systems are significantly implicated in antinociceptive processes. They were found to be represented in the regions involved in nociception. and pa in. The effects of opioids in animal models of inflammatory pain have been studied in great detail. Inflammation in the periphery influences the centr al sites and changes the opioid action. Inflammation increased spinal poten cy of various opioid receptor agonists. In general, the antinociceptive pot ency of opioids is greater against various noxious stimuli in animals with peripheral inflammation than in control animals. Inflammation-induced enhan cement of opioid antinociceptive potency is characteristic predominantly fo r mu opioid receptors, since morphine elicits a greater increase in spinal potency of mu- than of delta- and kappa -opioid receptor agonists. Enhancem ent of the potency of mu -opioid receptor agonists during inflammation coul d arise from the changes occurring in opioid receptors, predominantly in af finity or number of the mu -opioid receptors. Inflammation has been shown t o alter the expression of several genes in the spinal cord dorsal hom. Seve ral studies have demonstrated profound alterations in the spinal PDYN syste m when there is peripheral inflammation or chronic arthritis. Endogenous dy norphin biosynthesis also increases under various conditions associated wit h neuropathic pain following damage to the spinal cord and injury of periph eral nerves. Interestingly, morphine lacks potent analgesic efficacy in neu ropathic pain. A vast body of clinical evidence suggests that neuropathic p ain is not opioid-resistant but only that reduced sensitivity to systemic o pioids is observed in this condition, and an increase in their dose is nece ssary in order to obtain adequate analgesia, Reduction of morphine antinoci ceptive potency was postulated to be due to the fact that nerve injury redu ced the activity of spinal opioid receptors or opioid signal transduction. Our recent study with endogenous Ligands of the mu -opioid receptor, endomo rphins, further complicates the issue, since endomorphins appear to be effe ctive in neuropathic pain. Identification of the involved differences may b e of importance to the understanding of the molecular mechanism of opioid a ction in neuropathic pain, as well as to the development of better and more effective drugs for the treatment of neuropathic pain in humans. (C) 2001 Elsevier Science B.V. All rights reserved.