Loss of vasomotor responsiveness to the μ-opioid receptor ligand endomorphin-1 in adjuvant monoarthritic rat knee joints

Abstract

Endomorphin-1 is a short-chain neuropeptide with a high affinity fo the mu-opioid receptor and has recently been localized in acutely inflamed knee joints where it was found to reduce inflammation. The present study examined the propensity of endomorphin-1 to modulate synovial blood flow in normal and adjuvant-inflamed at knee joints. Under deep urethane anesthesia, endomorphin-1 was topically applied to exposed normal and 1 wk adjuvant monoarthritic knee joints (0.1 ml bolus; 10(-12)-10(-9) mol). Relative changes in articular blood flow were measured by laser Doppler perfusion imaging and vascular resistances in response to the opioid were calculated. In normal knees, endomorphin-1 caused a dose-dependent increase in synovial vascular resistance and this effect was significantly inhibited by the specific mu-opioid receptor antagonist d-Phe-Cys-Tyr-d-Trp-O n-Thr-Pen-Th amide (CTOP) (P < 0.0001, 2-factor ANOVA, n = 5-7). One week after adjuvant inflammation, the hypoaemic effect of endomorphin-1 was completely abolished (P < 0.0001, 2-factor ANOVA, n = 5-7). Immunohistochemical analysis of normal and adjuvant-inflamed joints showed a ninefold increase in endomorphin-1 levels in the monoarthritic knee compared with normal control. Western blotting and immunohistochemistry revealed a moderate number of mu-opioid receptors in normal knees; however, mu-opioid receptors were almost undetectable in arthritic joints. These findings demonstrate that peripheral administration of endomorphin-1 reduces knee joint blood flow and this effect is not sustainable during advanced inflammation. The loss of this hypoaemic response appears to be due to down regulation of mu-opioid receptors as a consequence of endomorphin-1 accumulation within the arthritic joint.

Role of peripheral μ‐opioid receptors in arthritis: Are they potential targets for therapy?

“…This finding supports the observation that endomorphin 1-evoked reduction in knee joint blood flow is attenuated after 1 week of inflammation, despite a 9-fold higher level of endomorphin 1 in the inflamed joint (24). Therefore, it is tempting to assume that endogenous endomorphin 1 accumulation downregulates opioid receptor expression on both the peripheral terminals and the cell bodies of primary sensory neurons.…”

“…This group of investigators previously showed almost complete absence of -opioid receptors on type IV afferent fibers in the synovium of arthritic joints in the same model, 1 week after intraarticular administration of CFA (24). This finding supports the observation that endomorphin 1-evoked reduction in knee joint blood flow is attenuated after 1 week of inflammation, despite a 9-fold higher level of endomorphin 1 in the inflamed joint (24).…”

“…The down-regulation of -opioid receptors in inflamed synovium (24) and unilateral dorsal root ganglia (9) might be characteristic of the chronic monarthritis model. Acute inflammation evoked by carrageenan or CFA injected intraplantarly into the rat hind paw increases receptor density in the inflamed tissue due to enhanced transport of -opioid receptors from the dorsal root ganglia to the periphery within the first 4 days (17,26), although receptor expression in the dorsal root ganglia remains unchanged.…”

“…16). Exogenous administration of endomorphin 1 into the rat knee joint has been shown to inhibit synovial blood flow and plasma protein extravasation after an acute inflammatory reaction (24,28). However, endomorphins did not show increased potency against inflammationrelated pain, and they appeared to be less potent and shorter acting than other -opioid receptor agonists such as morphine, in several experimental models of inflammation (16).…”

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

“…This was recently demonstrated in a model of adjuvant-induced monarthritis of 1 week duration, in which -opioid receptors were almost completely absent in the synovium of the diseased joints (19).…”