Loss of vasomotor responsiveness to the mu-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.

• Authors: Jason J McDougall, A Kursat Barin, Chelsea M McDougall
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 286 Issue 4 Pg. R634-41 (Apr 2004) ISSN: 0363-6119 [Print] United States
• PMID: 14670807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oligopeptides
• Receptors, Opioid, mu
• endomorphin 1
• phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide
• Somatostatin

Topics

• Animals
• Arthritis, Experimental (pathology, physiopathology)
• Blotting, Western
• Dose-Response Relationship, Drug
• Immunohistochemistry
• Joints (blood supply, pathology, physiopathology)
• Male
• Muscle, Smooth, Vascular (drug effects, physiology)
• Oligopeptides (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Opioid, mu (antagonists & inhibitors, drug effects)
• Regional Blood Flow (physiology)
• Somatostatin (analogs & derivatives, pharmacology)
• Vascular Resistance