We examined the peripheral
adrenergic mechanisms involved in
pain induced by
alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT) plus (+/-)-
noradrenaline or
prostaglandin E2 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
alpha-methyl-5-HT (10 micrograms) plus
noradrenaline (10 micrograms) was blocked by pretreatment with the alpha-
adrenoceptor antagonists,
phentolamine (10 micrograms) and prazocin HCl (alpha 1; 40 micrograms), but not by
timolol (beta; 10 micrograms) or
idazoxan (alpha 2; 40 micrograms). Phenylepherine, but not
clonidine, substituted for
noradrenaline to induce
pain when combined with
alpha-methyl-5-HT. The alpha 1A-adrenoceptor antagonist,
WB-4101 (2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane HCl), but not the alpha 1B-
adrenoceptor antagonist,
chloroethylclonidine, also blocked the
pain response produced by
alpha-methyl-5-HT plus
noradrenaline. Neither of these agents altered
pain produced by
alpha-methyl-5-HT plus
prostaglandin E2 (0.1 microgram).
Formalin-induced
pain (1%, 50 microliters) was biphasic, and
timolol increased the first phase response. The second phase was attenuated by 40% by
phentolamine (10 micrograms) injected 10 min before
formalin or at the beginning of the second phase; 30 micrograms did not produce a larger effect.
Prazosin and WP-4101, but not
idazoxan or
chloroethylclonidine, also attenuated the second phase. Thus, activation of alpha 1A-adrenoceptors can contribute to
pain, but
pain induced by
alpha-methyl-5-HT plus
prostaglandin E2 is independent of
adrenergic function, indicating that
adrenergic function is not necessary for induction of
pain by inflammatory mediators. alpha 1A-Adrenoceptor blockade attenuates
pain when administered after development of
pain, implying that peripheral
adrenergic mechanisms contribute to ongoing maintenance of
pain.