endomorphin-1 and Chronic-Disease

Endomorphin (EM)-1 and EM-2 are tetrapeptides located within the mammalian central nervous system and immune tissues, with high affinity and specificity for micro-opioid receptors. Most of the literature has focused on the analgesic properties of EM-1 and EM-2 in animal models of neuropathic or neurogenic pain, but there is persuasive evidence emerging that EMs can also exert potent anti-inflammatory effects in both acute and chronic peripheral inflammation. The purpose of this review is to present and evaluate the evidence for anti-inflammatory properties of EM-1 and EM-2 with a view to their potential for use in chronic human inflammatory disease. Distribution of EMs within the immune system and functional roles as immunomodulatory agents are summarized and discussed. Possible milestones to be met revolve around issues of peptide stability, biodegradability problems and optimal route and method of delivery. The potential for delivery of a low-cost drug with both peripheral anti-inflammatory and analgesic properties, effective in low doses, and targeted to the site of inflammation, should focus our attention on further development of EMs as potent therapeutic agents in chronic inflammation.

Topics: Animals; Chronic Disease; Humans; Inflammation; Oligopeptides; Receptors, Opioid, mu

To determine whether peripheral administration of the endogenous mu-opioid peptide endomorphin 1 could reduce knee joint pain, using animal models of acute and chronic arthritis.. Extracellular electrophysiologic recordings were made of rat knee joint primary afferent nerve activity in response to noxious hyperrotation of the joint. Neuronal activity was assessed before and following local injection of endomorphin 1. Comparisons were made between normal knees and knees with adjuvant-induced monarthritis, tested at 48 hours and 1 week posttreatment. Expression of mu-opioid receptors in the dorsal root ganglia ipsilateral to the chronically inflamed joints was determined by real-time polymerase chain reaction (PCR) and immunohistochemical analysis.. In normal knees, endomorphin 1 caused up to a 75% reduction in joint afferent nerve activity, which was blocked by the mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-amide. The inhibitory effect of endomorphin 1 was sustained in acutely inflamed knees. Conversely, in chronically inflamed joints, endomorphin 1 had no observable effect on the primary afferent nerve firing rate elicited by a noxious mechanical stimulus and, as such, was significantly different from the rate in normal joints. Immunohistochemical and real-time PCR analysis of the L3-L5 dorsal root ganglia ipsilateral to the chronic arthritis lesion revealed a reduction in mu-opioid receptor protein and gene expression compared with that in normal control animals.. Taken together, these results provide the first electrophysiologic evidence that selective activation of peripheral mu-opioid receptors reduces normal knee joint mechanosensitivity to a noxious stimulus. Furthermore, the analgesic effect of endomorphin 1 is lost during chronic inflammation due to down-regulation of mu-opioid receptor expression in afferent nerve cell bodies. These findings begin to explain the ambiguous efficacy of peripherally administered mu-opioid drugs in controlling chronic inflammatory joint pain.

Topics: Analgesics, Opioid; Animals; Arthritis, Experimental; Chronic Disease; Down-Regulation; Edema; Ganglia, Spinal; Joints; Neurons, Afferent; Nociceptors; Oligopeptides; Pain; Rats; Rats, Wistar; Receptors, Opioid, mu; RNA, Messenger