. Sodium channel blocking actions of the -opioid receptor agonist U50,488 contribute to its visceral antinociceptive effects. J Neurophysiol 87: 1271-1279, 2002; 10.1152/jn.00624.2001. The goal of the present study was to determine whether the -opioid receptor agonist (ORA) U50,488 attenuates behavioral and primary afferent nerve responses to noxious colorectal distension (CRD) by sodium channel blockade. We tested the analgesic -ORA (Ϯ)-trans U50,488, its enantiomers (Ϫ)-trans (1S,2S)-U50,488 and non -ORA (ϩ)-trans (1R,2R)-U50,488, and/or its diastereomer (Ϫ)-cis (1S,2R)-U50,488 for their ability to attenuate visceromotor and pelvic nerve afferent fiber responses to noxious CRD in vivo and voltage-activated sodium current in colon sensory neurons in vitro. In unanesthetized rats, subcutaneous administration of U50,488, (1S,2S)-U50,488, and (1R,2R)-U50,488 attenuated the behavioral visceromotor response to noxious CRD; the rank order of potency was: (1S,2S)-U50,488 Ͼ U50,488 Ͼ Ͼ (1R,2R)-U50,488. U50,488 and its stereoisomers also inhibited responses of decentralized pelvic nerve afferent fibers to noxious CRD in a dose-dependent manner. Cumulative doses of 16 mg/kg of (1S,2S)-U50,488, (1S,2R)-U50,488, and (1R,2R)-U50,488 reduced responses to a mean 29, 30, and 47% of control, respectively. The mean inhibitory doses of these drugs were not different (range: 6.6 -10.8 mg/kg). Sodium channel blockers mexiletine and carbamazepine mimicked the effect of U50,488. In contrast, the -ORAs dynorphin (1-13) and ICI 204,488 were ineffective in attenuating pelvic nerve activity. Perfusion of (1S,2S)-U50,488, (1S,2R)-U50,488, or (1R,2R)-U50,488 on colon sensory neurons in vitro decreased voltage-activated sodium currents. This inhibition by U50,488 and its stereoisomers was not opioid receptor-mediated because it could not be reversed by the opioid receptor antagonist naloxone and was also not a G protein-mediated effect. The results reported here suggest that the visceral antinociceptive effects of U50,488 and its stereoisomers are contributed to by their peripheral sodium channel blocking actions. I N T R O D U C T I O NThe mechanisms and modulation of visceral pain have been extensively examined using colorectal distension (CRD) as a noxious visceral stimulus. Previous studies employing CRD have documented the ability of -opioid receptor agonists (ORAs) like U50,488 to attenuate pseudaffective visceromotor and cardiovascular responses to noxious CRD following their systemic, but not intrathecal administration (Danzebrink et al. 1995; Harada et al. 1995a,b). A peripheral, visceral antinociceptive action of U50,488 has been demonstrated. U50,488 was shown to dose dependently inhibit responses of mechanosensitive pelvic nerve afferent fibers to noxious colorectal or urinary bladder distension in the rat Su et al. 1997a,b). This inhibition could not be completely antagonized by very high doses of naloxone or by two -opioid receptor-selective antagonists, nor-Binaltorphimine dihydrochloride (nor-BNI) and DIPPA. Furthermore, ...

No abstract

No abstract