There is considerable interest in understanding the regulation of peripheral opioid receptors to avoid central nervous system side effects associated with systemically administered opioid analgesics. Here we investigated the regulation of the kappa opioid receptor (KOR) on rat primary sensory neurons in vitro and in a rat model of thermal allodynia. Under basal conditions, application of the KOR agonist, U50488, did not inhibit adenylyl cyclase (AC) activity nor release of calcitonin gene-related peptide (CGRP) in vitro and did not inhibit thermal allodynia in vivo. However, following 15 min pre-treatment with bradykinin (BK), U50488 became capable of inhibiting AC activity, CGRP release and thermal allodynia. Inhibition of AC by 5 HT1 or neuropeptide Y1 receptor agonists and stimulation of ERK activity by U50488 did not require BK pre-treatment. The effect of U50488 in BK-primed tissue was blocked by the KOR antagonist nor-BNI both in vitro and in vivo. The effect of BK in vitro was blocked by either indomethacin or bis-indolylmaleimide, suggesting that an arachidonic acid (AA) metabolite and protein kinase C (PKC) activation mediate BK-induced regulation of KOR. Further, KOR function in BK-treated tissue was blocked by a soluble integrin-blocking peptide (GRGDSP), but not the inactive reverse sequence peptide (GDGRSP), suggesting that in addition to AA and PKC, RGD-binding integrins participate in the regulation of KOR signaling. Understanding of the mechanisms by which peripheral KOR agonist efficacy is regulated may lead to improved pharmacotherapy for treatment of pain with reduced adverse effects.
- Received November 22, 2010.
- Revision received March 31, 2011.
- Accepted April 5, 2011.
- The American Society for Pharmacology and Experimental Therapeutics