Sodium channel blocking actions of the kappa-opioid receptor agonist U50,488 contribute to its visceral antinociceptive effects - PubMed (original) (raw)

Sodium channel blocking actions of the kappa-opioid receptor agonist U50,488 contribute to its visceral antinociceptive effects

X Su et al. J Neurophysiol. 2002 Mar.

Free article

Abstract

The goal of the present study was to determine whether the kappa-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 kappa-ORA (+/-)-trans U50,488, its enantiomers (-)-trans (1S,2S)-U50,488 and non kappa-ORA (+)-trans (1R,2R)-U50,488, and/or its diastereomer (-)-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 > U50,488 angle quotation mark, right (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 kappa-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.

PubMed Disclaimer

Cited by

Citronellol, a monoterpene alcohol, reduces nociceptive and inflammatory activities in rodents.
Brito RG, Guimarães AG, Quintans JS, Santos MR, De Sousa DP, Badaue-Passos D Jr, de Lucca W Jr, Brito FA, Barreto EO, Oliveira AP, Quintans LJ Jr. Brito RG, et al. J Nat Med. 2012 Oct;66(4):637-44. doi: 10.1007/s11418-012-0632-4. Epub 2012 Feb 21. J Nat Med. 2012. PMID: 22350215
Ionic storm in hypoxic/ischemic stress: can opioid receptors subside it?
Chao D, Xia Y. Chao D, et al. Prog Neurobiol. 2010 Apr;90(4):439-70. doi: 10.1016/j.pneurobio.2009.12.007. Epub 2009 Dec 28. Prog Neurobiol. 2010. PMID: 20036308 Free PMC article. Review.
The κ-opioid receptor agonist U-50488 blocks Ca2+ channels in a voltage- and G protein-independent manner in sensory neurons.
Hassan B, Ruiz-Velasco V. Hassan B, et al. Reg Anesth Pain Med. 2013 Jan-Feb;38(1):21-7. doi: 10.1097/AAP.0b013e318274a8a1. Reg Anesth Pain Med. 2013. PMID: 23222359 Free PMC article.
Peripheral kappa-opioid agonists for visceral pain.
Rivière PJ. Rivière PJ. Br J Pharmacol. 2004 Apr;141(8):1331-4. doi: 10.1038/sj.bjp.0705763. Epub 2004 Mar 29. Br J Pharmacol. 2004. PMID: 15051626 Free PMC article. Review.
Asimadoline and its potential for the treatment of diarrhea-predominant irritable bowel syndrome: a review.
Mangel AW, Hicks GA. Mangel AW, et al. Clin Exp Gastroenterol. 2012;5:1-10. doi: 10.2147/CEG.S23274. Epub 2012 Jan 12. Clin Exp Gastroenterol. 2012. PMID: 22346361 Free PMC article.

Sodium channel blocking actions of the kappa-opioid receptor agonist U50,488 contribute to its visceral antinociceptive effects - PubMed (original) (raw)