The antinociceptive effect of the mu-opioid fentanyl is reduced in the presence of the alpha(2)-adrenergic antagonist idazoxan in inflammation.
Interactions between alpha(2)-adrenergic and mu-opioid systems play an important role in the modulation of hyperalgesic states. The antinociceptive effects of alpha(2)-adrenergic agonists and mu-opioids are potentiated when co-administered; however, attempts to induce cross reversal of the antinociceptive effects of alpha(2)-adrenergic and mu-opioid systems have produced contradictory results. We have studied the possible endogenous tonic control of the alpha(2)-adrenergic systems in the modulation of pain in inflammation, and the interactions between the two antinociceptive systems in rat spinal cord nociceptive reflexes activated by both natural and electrical stimulation. The facilitatory actions of the alpha(2)-adrenergic antagonist idazoxan were compared in control rats and in animals with carrageenan-induced paw inflammation. The antinociceptive effect of the mu-opioid fentanyl was tested alone and in the presence of idazoxan. In agreement with some previous observations, idazoxan i.v. produced no change in responses to natural and electrical stimulation in normal animals. In animals with inflammation, idazoxan only induced facilitation of responses evoked by noxious thermal stimulation but not by mechanical or electrical stimulation. Fentanyl reduced the responses to either stimuli with lower potency in the presence of idazoxan, but only in animals with inflammation. Its dose-response curve was shifted to the right between 1.8- and 3. 5-fold depending on the stimulus used. It is concluded that the increase of thermal responses by idazoxan in animals with inflammation is probably due to changes in the peripheral blood flow. Nevertheless, since an interaction with mu-opioids is clear in inflammation, endogenous alpha(2)-adrenergic systems play an important role in the modulation of the effectiveness of opioids during inflammation.
Herrero
J F
JF
Departamento de Fisiología, Facultad de Medicina, Universidad de Alcalá, Campus Univ. Alcala en Henares, Madrid, Spain. ffjfhg@alcala.es
Solano
R E
RE
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005283:Fentanyl / Q000494:pharmacology*; D006614:Hindlimb; D019329:Idazoxan / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009619:Nociceptors / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012016:Reference Values
D000317:Adrenergic alpha-Antagonists; D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D002351:Carrageenan; D005283:Fentanyl; D019329:Idazoxan