The heritability of antinociception: Common pharmacogenetic mediation of five neurochemically distinct analgesics

Sonya G. Wilson, Shad B. Smith, Elissa J. Chesler, Kimberly A. Melton, Jeremiah J. Haas, Bryan Mitton, Kate Strasburg, Lawrence Hubert, Sandra L. Rodriguez-Zas, Jeffrey S. Mogil

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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] benzene-acetamide methane-sulfonate hydrate (U50,488; 10-150 mg/kg), a κ-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 α2adrenergic 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.

Original languageEnglish (US)
Pages (from-to)547-559
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Feb 1 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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