Contribution of peripheral α1A-adrenoceptors to pain induced by formalin or by α-methyl-5-hydroxytryptamine plus noradrenaline

Abstract

We examined the peripheral adrenergic mechanisms involved in pain induced by α-methyl-5-hydroxytryptamine (α-methyl-5-HT) plus (±)-noradrenaline or prostaglandin E 2 and by intraplantar formalin. Agents were injected s.c. into the plantar surface of rats' paws, and the paw lifting and licking response scored. Pain produced by α-methyl-5-HT (10 μg) plus noradrenaline (10 μg) was blocked by pretreatment with the α-adrenoceptor antagonists, phentolamine (10 μg) and prazocin HCl ( α 1; 40 μg), but not by timolo (β; 10 μg) or idazoxan ( α 2; 40 μg). Phenylepherine, but not clonidine, substituted for noradrenaline to induce pain when combined with α-methyl-5-HT. The α 1A-adrenoceptor antagonist, WB-4101 (2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane HCl), but not the α 1B-adrenoceptor antagonist, chloroethylclonidine, also blocked the pain response produced by α-methyl-5-HT plus noradrenaline. Neither of these agents altered pain produced by α-methyl-5-HT plus prostaglandin E 2 (0.1 μg). Formalin-induced pain (1%, 50 μl) was biphasic, and timolol increased the first phase response. The second phase was attenuated by 40% by phentolamine (10 μg) injected 10 min before formalin or at the beginning of the second phase; 30 μg did not produce a larger effect. Prazosin and WP-4101, but not idazoxan or chloroethylclonidine, also attenuated the second phase. Thus, activation of α 1A-adrenoceptors can contribute to pain, but pain induced by α-methyl-5-HT plus prostaglandin E 2 is independent of adrenergic function, indicating that adrenergic function is not necessary for induction of pain by inflammatory mediators. α 1A-Adrenoceptor blockade attenuates pain when administered after development of pain, implying that peripheral adrenergic mechanisms contribute to ongoing maintenance of pain.