INDUCTION AND SUPPRESSION OF IMMEDIATE-EARLY GENES IN THE RAT-BRAIN BY A SELECTIVE ALPHA-2-ADRENOCEPTOR AGONIST AND ANTAGONIST FOLLOWING NOXIOUS PERIPHERAL STIMULATION

The effect of medetomidine, a highly selective alpha-2-adrenoceptor agonist, on noxious stimulation-induced expression of immediate-early genes was studied in the central nervous system of the rat. The expressions of c-JUN, JUN B, c-FOS FOS B and KROX-24 proteins were investigated by immunocytochemistry following the application of formalin (5%, 50 mul) into the plantar skin of one hindpaw. Medetomidine (100 or 300 mug/kg i.p.) was administered 12 min or 5 min before the application of formalin. Atipamezole (1.5 mg/kg i.p.), and alpha-2-adrenoceptor antagonist, administered simultaneously with medetomidine (300 mug/kg), was used to reverse the alpha-2-adrenergic effects. The rats were killed and perfused 90 min after formalin injection. Formalin induced expression of all studied proteins in the ipsilateral spinal dorsal horn and the contralateral parabrachial nucleus, and in the medial thalamus bilaterally. Both medetomidine doses administered 12 min before formalin strongly suppressed the expression of c-FOS in the spinal dorsal horn; the suppression was stronger in the deep (III-VI) than in the superficial (I and II) laminae of the dorsal horn (76% and 86% for 100 mug/kg dose vs 97% and 99% for 300 mug/kg dose, respectively). However, application of medetomidine 5 min before formalin did not reduce the expression of immediate early genes. In the parabrachial nucleus, both medetomidine doses also produced a significant suppression of c-FOS expression (68%). In contrast, medetomidine at the dose of 100 mug/kg was ineffective in the medial thalamus. Only the higher dose of medetomidine (300 mug/kg) produced a suppression by 29% and 46% in centromedian and paraventricular nuclei, respectively. Atipamezole produced a significant attenuation in spinal cord and a complete reversal in parabrachial nucleus of the medetomidine-induced suppression. However, in the medial thalamus, atipamezole produced a dramatic increase of formalin-induced c-FOS expression when compared with formalin injection alone. The expression of c-JUN, JUN B, FOS B and KROX-24 proteins paralleled that of c-FOS. It is concluded that the expression of immediate-early gene encoded proteins is more strongly suppressed by alpha-2-adrenoceptor agonists in spinal and parabrachial than in medial thalamic neurons. The increased expression of immediate-early genes in medial thalamus following atipamezole treatment may be explained by increased release of noradrenaline and the consequent activation of alpha-1- and beta-adrenoceptors. Compared with the previously reported effects of behaviorally equipotent doses of morphine, the suppression of c-FOS expression in the spinal cord was stronger following medetomidine than that following morphine. The expression of immediate-early gene encoded proteins dissociates from recent behavioral and electrophysiological findings which had reported that in the medial thalamus the 100 mug/kg dose, but at the spinal level only the 300 mug/kg dose, of medetomidine produced a suppression of responses to noxious stimulation.