An isobolographic analysis of the adrenergic modulation of diclofenac antinociception

We evaluated the noradrenergic modulation of the antinociceptive activity o f diclofenac in mice using the acetic acid writhing test. Dose-responsecurv es were obtained for the antinociceptive effect of diclofenac, phenylephrin e, clonidine, desipramine, prazosin, and yohimbine administered both system ically and intrathecally, and ED(50)s were calculated. Noradrenergic modula tion 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, combinati ons of diclofenac with phenylephrine or clonidine showed supraadditivity, s uggesting that the activation of a(1) and a, adrenoceptors interfered with the nociceptive transmission at spinal and supraspinal levels. Supraadditiv e effects were not demonstrated for the intrathecal injection of diclofenac combined wi th phenylephrine, clonidine and a selective norepinephrine upt ake inhibitor (desipramine) or adrenergic antagonists. We conclude that int eraction between adrenoceptors and diclofenac can modulate antinociception by activating common or different mechanisms. Diclofenac has an antinocicep tive activity that, in addition to cyclooxygenase inhibition, can be modula ted by additive and supraadditive interactions with adrenergic drugs.