Chronic arthritis down‐regulates peripheral μ‐opioid receptor expression with concomitant loss of endomorphin 1 antinociception

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Abstract
Objective: To determine whether peripheral administration of the endogenous μ‐opioid peptide endomorphin 1 could reduce knee joint pain, using animal models of acute and chronic arthritis.Methods: 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 μ‐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.Results: In normal knees, endomorphin 1 caused up to a 75% reduction in joint afferent nerve activity, which was blocked by the μ‐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 μ‐opioid receptor protein and gene expression compared with that in normal control animals.Conclusion: Taken together, these results provide the first electrophysiologic evidence that selective activation of peripheral μ‐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 μ‐opioid receptor expression in afferent nerve cell bodies. These findings begin to explain the ambiguous efficacy of peripherally administered μ‐opioid drugs in controlling chronic inflammatory joint pain.

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