Endogenous opioid mechanisms partially mediate P2X3/P2X2/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain.
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.
McGaraughty
Steve
S
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.com
Honore
Prisca
P
Wismer
Carol T
CT
Mikusa
Joseph
J
Zhu
Chang Z
CZ
McDonald
Heath A
HA
Bianchi
Bruce
B
Faltynek
Connie R
CR
Jarvis
Michael F
MF
D000698:Analgesia; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000502:physiology*; D005557:Formaldehyde; D005620:Freund's Adjuvant; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology*; D010523:Peripheral Nervous System Diseases / Q000150:complications*; D010636:Phenols / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D013498:Suramin / Q000494:pharmacology
C470346:A-317491; D004723:Endorphins; D009292:Narcotic Antagonists; C546401:P2RX2 protein, human; C546407:P2RX3 protein, human; C546403:P2rx2 protein, rat; C546410:P2rx3 protein, rat; D010636:Phenols; D011083:Polycyclic Compounds; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D005557:Formaldehyde; D009270:Naloxone; D013498:Suramin; D005620:Freund's Adjuvant