An isobolographic analysis of the adrenergic modulation of diclofenac antinociception.
We evaluated the noradrenergic modulation of the antinociceptive activity of diclofenac in mice using the acetic acid writhing test. Dose-response curves were obtained for the antinociceptive effect of diclofenac, phenylephrine, clonidine, desipramine, prazosin, and yohimbine administered both systemically and intrathecally, and ED(50)s were calculated. Noradrenergic modulation was evaluated by performing an isobolographic analysis of the systemic or intrathecal coadministration of fixed-ratio combinations of diclofenac with each adrenergic drug. The systemic, but not the intrathecal, combinations of diclofenac with phenylephrine or clonidine showed supraadditivity, suggesting that the activation of alpha(1) and alpha(2) adrenoceptors interfered with the nociceptive transmission at spinal and supraspinal levels. Supraadditive effects were not demonstrated for the intrathecal injection of diclofenac combined with phenylephrine, clonidine and a selective norepinephrine uptake inhibitor (desipramine) or adrenergic antagonists. We conclude that interaction between adrenoceptors and diclofenac can modulate antinociception by activating common or different mechanisms. Diclofenac has an antinociceptive activity that, in addition to cyclooxygenase inhibition, can be modulated by additive and supraadditive interactions with adrenergic drugs.


CONCLUSIONS
Diclofenac analgesia in mice can be modulated by interaction with adrenergic drugs. The systemic but not the intrathecal administration of phenylephrine and clonidine produced supraadditive interactions. For desipramine, prazosin, and yohimbine, supraadditive interactions were not statistically demonstrated. The coadministration of drugs inducing supraadditive effects could be clinically relevant for the treatment of chronic pain because of reduction of doses and side effects.
Miranda
H F
HF
Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago 7, Chile. hmiranda@machi.med.uchile.cl
Sierralta
F
F
Pinardi
G
G
D018663:Adrenergic Agents / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D051379:Mice; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D018663:Adrenergic Agents; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D010656:Phenylephrine; D015016:Yohimbine; D003000:Clonidine; D011224:Prazosin