An examination of the relationship between mu-opioid antinociceptive efficacy and G-protein coupling using pertussis and cholera toxins.
The hypothesis that mu-opioid agonists having low antinociceptive efficacy might be more susceptible to interference with G-protein coupling than mu-opioid agonists having higher antinociceptive efficacy was tested. Supraspinal antinociceptive efficacy for the three mu-opioid agonists morphine, [D-Ala2, NMePhe4, Gly5-ol]-enkephalin (DAMGO) and sufentanil in the mouse 55 degrees C warm-water tail-flick test was evaluated 18-24 h after intracerebroventricular (i.c.v.) administration of beta-funaltrexamine (beta-FNA). The beta-FNA pretreatment (0.2-2.0 nmol) attenuated antinociception in the order morphine > DAMGO > sufentanil, consistent with previous reports of their relative antinociceptive efficacy. The association of efficacy with G-protein coupling was then assessed by determining sensitivity to i.c.v. (0.1-3.0 micrograms) pertussis toxin (PTX) or cholera toxin (CTX). The effect of PTX on equiantinociceptive doses was in the inverse order of agonist efficacy. CTX augmented sufentanil-induced antinociception. Morphine- and DAMGO-induced antinociception were unaffected by CTX. These data suggest that: (i) highly efficacious mu agonists (viz., sufentanil) couple more efficiently to PTX-sensitive inhibitory Gi-proteins than do agonists of lower efficacy (viz., morphine, DAMGO) and (ii) highly efficacious mu agonists have greater capacity to utilize CTX-sensitive stimulatory Gs-proteins than do mu-agonists with lower efficacy.
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University Laboratory Animal Resources, University of Pennsylvania, Philadelphia, USA.
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D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000008:administration & dosage / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D037342:Pertussis Toxin; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D017409:Sufentanil / Q000008:administration & dosage / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D000700:Analgesics; D004745:Enkephalins; D017450:Receptors, Opioid, mu; D010566:Virulence Factors, Bordetella; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D002772:Cholera Toxin; D017409:Sufentanil; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins