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Endogenous opioid mechanisms partially mediate P2X3/P2X2/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain.
Br J Pharmacol. 2005 Sep; 146(2):180-8.BJ

Abstract

P2X3/P2X2/3 receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X3/P2X2/3 receptor and that ultimately contribute to the ensuing antinociception. In order to determine if the endogenous opioid system is involved in this antinociception, naloxone was administered just prior to the injection of a selective P2X3/P2X2/3 receptor antagonist, A-317491, in rat models of neuropathic, chemogenic, and inflammatory pain. Naloxone (1-10 mg kg(-1), i.p.), dose-dependently reduced the antinociceptive effects of A-317491 (1-300 micromol kg(-1), s.c.) in the CFA model of thermal hyperalgesia and the formalin model of chemogenic pain (2nd phase), but not in the L5-L6 spinal nerve ligation model of neuropathic allodynia. In comparison experiments, the same doses of naloxone blocked or attenuated the actions of morphine (2 or 8 mg kg(-1), s.c.) in each of these behavioral models. Injection of a peripheral opioid antagonist, naloxone methiodide (10 mg kg(-1), i.p.), did not affect A-317491-induced antinociception in the CFA and formalin assays, suggesting that the opioid component of this antinociception occurred within the CNS. Furthermore, this utilization of the central opioid system could be initiated by antagonism of spinal P2X3/P2X2/3 receptors since the antinociceptive actions of intrathecally delivered A-317491 (30 nmol) in the formalin model were reduced by both intrathecally (10-50 nmol) and systemically (10 mg kg(-1), i.p.) administered naloxone. This utilization of the opioid system was not specific to A-317491 since suramin-, a nonselective P2X receptor antagonist, induced antinociception was also attenuated by naloxone. In in vitro studies, A-317491 (3-100 microM) did not produce any agonist response at delta opioid receptors expressed in NG108-15 cells. A-317491 had been previously shown to be inactive at the kappa and mu opioid receptors. Furthermore, naloxone, at concentrations up to 1 mM, did not compete for [3H] A-317491 binding in 1321N1 cells expressing human P2X3 receptors. Taken together, these results indicate that antagonism of spinal P2X3/P2X2/3 receptors results in an indirect activation of the opioid system to alleviate inflammatory hyperalgesia and chemogenic nociception.

Authors+Show Affiliations

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R4PM, AP9-1, 100 Abbott Park Road, Abbott Park, IL 60064, U.S.A. Steve.P.McGaraughty@abbott.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16041397

Citation

McGaraughty, Steve, et al. "Endogenous Opioid Mechanisms Partially Mediate P2X3/P2X2/3-related Antinociception in Rat Models of Inflammatory and Chemogenic Pain but Not Neuropathic Pain." British Journal of Pharmacology, vol. 146, no. 2, 2005, pp. 180-8.
McGaraughty S, Honore P, Wismer CT, et al. Endogenous opioid mechanisms partially mediate P2X3/P2X2/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain. Br J Pharmacol. 2005;146(2):180-8.
McGaraughty, S., Honore, P., Wismer, C. T., Mikusa, J., Zhu, C. Z., McDonald, H. A., Bianchi, B., Faltynek, C. R., & Jarvis, M. F. (2005). Endogenous opioid mechanisms partially mediate P2X3/P2X2/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain. British Journal of Pharmacology, 146(2), 180-8.
McGaraughty S, et al. Endogenous Opioid Mechanisms Partially Mediate P2X3/P2X2/3-related Antinociception in Rat Models of Inflammatory and Chemogenic Pain but Not Neuropathic Pain. Br J Pharmacol. 2005;146(2):180-8. PubMed PMID: 16041397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endogenous opioid mechanisms partially mediate P2X3/P2X2/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain. AU - McGaraughty,Steve, AU - Honore,Prisca, AU - Wismer,Carol T, AU - Mikusa,Joseph, AU - Zhu,Chang Z, AU - McDonald,Heath A, AU - Bianchi,Bruce, AU - Faltynek,Connie R, AU - Jarvis,Michael F, PY - 2005/7/26/pubmed PY - 2005/12/13/medline PY - 2005/7/26/entrez SP - 180 EP - 8 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 146 IS - 2 N2 - P2X3/P2X2/3 receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X3/P2X2/3 receptor and that ultimately contribute to the ensuing antinociception. In order to determine if the endogenous opioid system is involved in this antinociception, naloxone was administered just prior to the injection of a selective P2X3/P2X2/3 receptor antagonist, A-317491, in rat models of neuropathic, chemogenic, and inflammatory pain. Naloxone (1-10 mg kg(-1), i.p.), dose-dependently reduced the antinociceptive effects of A-317491 (1-300 micromol kg(-1), s.c.) in the CFA model of thermal hyperalgesia and the formalin model of chemogenic pain (2nd phase), but not in the L5-L6 spinal nerve ligation model of neuropathic allodynia. In comparison experiments, the same doses of naloxone blocked or attenuated the actions of morphine (2 or 8 mg kg(-1), s.c.) in each of these behavioral models. Injection of a peripheral opioid antagonist, naloxone methiodide (10 mg kg(-1), i.p.), did not affect A-317491-induced antinociception in the CFA and formalin assays, suggesting that the opioid component of this antinociception occurred within the CNS. Furthermore, this utilization of the central opioid system could be initiated by antagonism of spinal P2X3/P2X2/3 receptors since the antinociceptive actions of intrathecally delivered A-317491 (30 nmol) in the formalin model were reduced by both intrathecally (10-50 nmol) and systemically (10 mg kg(-1), i.p.) administered naloxone. This utilization of the opioid system was not specific to A-317491 since suramin-, a nonselective P2X receptor antagonist, induced antinociception was also attenuated by naloxone. In in vitro studies, A-317491 (3-100 microM) did not produce any agonist response at delta opioid receptors expressed in NG108-15 cells. A-317491 had been previously shown to be inactive at the kappa and mu opioid receptors. Furthermore, naloxone, at concentrations up to 1 mM, did not compete for [3H] A-317491 binding in 1321N1 cells expressing human P2X3 receptors. Taken together, these results indicate that antagonism of spinal P2X3/P2X2/3 receptors results in an indirect activation of the opioid system to alleviate inflammatory hyperalgesia and chemogenic nociception. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/16041397/Endogenous_opioid_mechanisms_partially_mediate_P2X3/P2X2/3_related_antinociception_in_rat_models_of_inflammatory_and_chemogenic_pain_but_not_neuropathic_pain_ L2 - https://doi.org/10.1038/sj.bjp.0706346 DB - PRIME DP - Unbound Medicine ER -