EFFECTS OF KAPPA-OPIOID RECEPTOR-SELECTIVE AGONISTS ON RESPONSES OF PELVIC NERVE AFFERENTS TO NOXIOUS COLORECTAL DISTENSION

The aim of this study was to examine the effects of K-opioid receptor selective agonists on responses of mechanosensitive afferent fibers in the pelvic nerve. Single-fiber recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root of the rat. A total of 572 afferent fibers in the S1 dorsal root were identified by electrica l stimulation of the pelvic nerve; 252 (44%) responded to noxious colo rectal distension (CRD; 80 mmHg). Of these 252 fibers that responded t o CRD, 100 were studied further. All 100 fibers gave monotonic increas es in firing to increasing pressures of CRD. Eighty-eight fibers had l ow thresholds for response (mean: 3 mmHg) and 12 fibers had high-thres holds for response (mean: 28 mmHg). Responses of 17 fibers also were t ested after instillation of 5% mustard oil (MO) into the colon. The re sting activity of 16/17 fibers significantly increased after MO instil lation; 13 (77%) also exhibited sensitization of responses to graded C RD when tested 30 min after intracolonic MO instillation. The effects of kappa(1)-opioid receptor preferring agonists (U50,488H, U69,593 and U62,066), the K-2-opioid receptor preferring agonist bremazocine, and the kappa(3)-opioid receptor preferring agonist naloxone benzoylhydra zone (nalBzoH) were tested on responses of 64 mechanosensitive afferen t fibers to noxious CRD. All five agonists dose-dependently inhibited afferent fiber responses to noxious CRD. Doses producing inhibition to 50% of the control response to CRD did not differ among the five agon ists, ranging from similar to 4 to 15 mg/kg. The effects of kappa(1), kappa(2), and kappa(3) receptor agonists were attenuated by naloxone; two kappa-opioid receptor-selective antagonists were ineffective. Ther e were no differences in the dose-response relationships of these drug s for fibers recorded from untreated and irritant-treated colons. Cond uction velocities of the fibers remained unaffected after high doses o f all tested agonists. In an in vitro study, U50,488 (10(-4) M) did no t produce any significant change in the tension of colonic smooth musc le. These results document that responses of mechanosensitive pelvic n erve afferent fibers innervating the colon are inhibited by kappa-opio id receptor agonists having varying affinities for putative kappa-opio id receptor subtypes. The inhibitory effects of these drugs likely are mediated by an action at receptors associated with the afferent fiber s. The receptor at which these effects are produced is K-opioid-like b ut clearly different from the kappa-opioid receptor characterized in t he CNS and is perhaps an orphan receptor.