QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wilson, S. G. Articles by Mogil, J. S. Search for Related Content PubMed PubMed Citation Articles by Wilson, S. G. Articles by Mogil, J. S. Pubmed/NCBI databases Medline Plus Health Information Pain

NEUROPHARMACOLOGY

The Heritability of Antinociception: Common Pharmacogenetic Mediation of Five Neurochemically Distinct Analgesics

Department of Psychology and Program in Neuroscience, University of Illinois at Urbana-Champaign, Champaign, Illinois (S.G.W., E.J.C., K.A.M., J.J.H., B.M., L.H., J.S.M.); Department of Psychology, McGill University, Montreal, Quebec, Canada (S.B.S., K.S., J.S.M.); and Department of Animal Sciences, University of Illinois at Urbana-Champaign, Champaign, Illinois (S.L.R.-Z.)

The heritability of nociception and antinociception has been well established in the mouse. The pharmacogenetics of morphine analgesia are fairly well characterized, but far less is known about other analgesics. The purpose of this work was to begin the systematic genetic study of non-µ-opioid analgesics. We tested mice of 12 inbred mouse strains for baseline nociceptive sensitivity (49°C tail-withdrawal assay) and subsequent antinociceptive sensitivity to systemic administration of (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate (U50,488; 10–150 mg/kg), a -opioid receptor agonist; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; 0.5–480 mg/kg), a synthetic cannabinoid receptor agonist; epibatidine (7.5–150 µg/kg), a nicotinic receptor agonist; clonidine (0.1–5 mg/kg), an ₂-adrenergic receptor agonist; and, for purposes of comparison, the prototypic µ-opioid receptor agonist, morphine (5–200 mg/kg). Robust interstrain variability was observed in nociceptive sensitivity and in the antinociceptive effects of each of the drugs, with extreme-responding strains exhibiting antinociceptive potencies differing up to 37-fold. Unexpectedly, we observed moderate-to-high genetic correlations of strain sensitivities to the five drugs (r = 0.39–0.77). We also found moderate-to-high correlations between baseline nociceptive sensitivity and subsequent analgesic response to each drug (r = 0.33–0.68). The generalizability of these findings was established in follow-up experiments investigating morphine and clonidine inhibition of formalin test nociception. Despite the fact that each drug activates a unique receptor, our results suggest that the potency of each drug is affected by a common set of genes. However, the genes in question may affect antinociception indirectly, via a primary action on baseline nociceptive sensitivity.

Address correspondence to: Dr. Jeffrey S. Mogil, Dept. of Psychology, McGill University, 1205 Dr. Penfield Ave., Montreal, QC H3A 1B1, Canada. E-mail: jeff{at}hebb.psych.mcgill.ca

This article has been cited by other articles:

				R. W. Hurley and M. C. B. Adams Sex, Gender, and Pain: An Overview of a Complex Field Anesth. Analg., July 1, 2008; 107(1): 309 - 317. [Abstract] [Full Text] [PDF]

				M. L. Chanda and J. S. Mogil Sex differences in the effects of amiloride on formalin test nociception in mice Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R335 - R342. [Abstract] [Full Text] [PDF]

				W. R. Lariviere, M. A. Sattar, and R. Melzack Inflammation-Susceptible Lewis Rats Show Less Sensitivity Than Resistant Fischer Rats in the Formalin Inflammatory Pain Test and With Repeated Thermal Testing J Neurophysiol, May 1, 2006; 95(5): 2889 - 2897. [Abstract] [Full Text] [PDF]

				R. R. Edwards Individual differences in endogenous pain modulation as a risk factor for chronic pain Neurology, August 9, 2005; 65(3): 437 - 443. [Abstract] [Full Text] [PDF]

				S. G. Wilson, C. D. Bryant, W. R. Lariviere, M. S. Olsen, B. E. Giles, E. J. Chesler, and J. S. Mogil The Heritability of Antinociception II: Pharmacogenetic Mediation of Three Over-the-Counter Analgesics in Mice J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 755 - 764. [Abstract] [Full Text] [PDF]