NSAIDs induce peripheral antinociception by interaction with the adrenergic system

Aims: We evaluated the role of adrenergic systems on the peripheral antinociception induced by dipyrone and diclofenac. Main methods: The rat paw pressure test, in which sensitivity is increased by intraplantar injection of prostaglandin E-2, was used to examine the peripheral effects of locally administered drugs. Key findings: Dipyrone (10,20 and 40 mu g) and diclofenac (5,10 and 20 mu g) administered locally into the right paw elicited a dose-dependent antinociceptive effect, which was demonstrated to be local; the injection of drugs into the ipsilateral and contralateral hindpaws demonstrated an effect only in the ipsilateral paw because only the treated paw produced an antinociceptive effect. To test the adrenergic system, we used guanethidine (30 mg/kg) to deplete noradrenalin from noradrenergic vesicles. Guanethidine antagonized the peripheral antinociception induced by diclofenac and dipyrone. Yohimbine (2.5, 5, 10, or 20 mu g/paw) a nonselective alpha(2)-adrenergic receptor antagonist antagonized the peripheral antinociception induced by diclofenac (20 mu g/paw) and dipyrone (40 mu g/paw). Rauwolscine (Rau; 10, 15,20 mu g), a selective alpha(2C)-adrenoreceptor, was able to block the peripheral antinociception induced by NSAIDs. The other specific alpha 2A,B and D-adrenoreceptor antagonists (BRL 44480, imiloxan and RX 821002, respectively) did not modify the peripheral antinociception. However, prazosin (0.5, 1, and 2 mu g/paw), an alpha(1) receptor antagonist, and propranolol (0.3, 0.6 or 1.2 mu g/paw), a beta-adrenoreceptor antagonist, antagonized the antinociception induced by diclofenac (20 mu g/paw) and dipyrone (40 mu g/paw). Significance: Dipyrone and diclofenac produce peripheral antinociception, which involves the release of NA and interaction with alpha(1), alpha(2C) and beta-adrenoreceptors. (c) 2015 Elsevier Inc. All rights reserved.