Regulation of kappa Opioid Receptor (KOR) Responsiveness on Peripheral Sensory Neurons

We have examined the function of KOR in primary cultures of trigeminal ganglion (TG) sensory neurons and in an animal model of thermal allodynia. The KOR agonist, U50488, did not inhibit PGE2‐stimulated adenylyl cyclase (AC) activity in vitro and did not reduce PGE2‐stimulated thermal allodynia in vivo. However, after a 15 min treatment (priming) with the inflammatory mediator bradykinin (BK) quiescent KOR became functionally competent, capable of inhibiting AC activity and thermal allodynia. The effect of U50488 in BK‐primed tissue was blocked by the KOR antagonist nor‐BNI both in vitro and in vivo. The priming effect of BK was blocked by either indomethacin or bis‐indolylmaleimide, suggesting that an arachidonic acid (AA) metabolite and PKC activation mediate BK‐induced regulation of KOR. Further, KOR function in BK‐primed 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 also mediate regulation of KOR signaling. Interestingly, not all signaling elicited by KOR requires inflammatory mediator pretreatment. For example, U50488‐mediated increases in ERK activation occurred in the absence of BK and was not altered by BK pretreatment. We propose that peripheral nociceptor function can be regulated by KOR, especially under conditions of tissue inflammation.