ROLE OF THE NUCLEUS RAPHE MAGNUS IN ANTINOCICEPTION PRODUCED BY ABT-594 - IMMEDIATE-EARLY GENE RESPONSES POSSIBLY LINKED TO NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTORS ON SEROTONERGIC NEURONS

Recently, a novel cholinergic channel modulator, (R)-5-(2-azetidinylme thoxy)-2-chloropyridine (ABT-594), was shown to produce potent analges ia in a variety of rodent pain models when administered either systemi cally or centrally into the nucleus raphe magnus (NRM). The purpose of the present study was to investigate the possible supraspinal contrib ution of ABT-594 by assessing its ability to induce expression of the immediate early gene c-fos, a biochemical marker of neuronal activatio n, in the NRM of rats. Putative serotonergic neurons in the NRM, a med ullary nucleus proposed to be involved in descending antinociceptive p athways, were identified immunohistochemically using a monoclonal anti body (mAb) against tryptophan hydroxylase. ABT-594 (0.03-0.3 mu mol/kg , i.p.) produced a dose-dependent induction of Fos protein that was bl ocked by the central nicotinic acetylcholine receptor (nAChR) antagoni st mecamylamine (5 mu mol/kg, i.p.) but not by the peripheral nAChR an tagonist hexamethonium (15 mu mol/kg, i.p.). Immunohistological studie s using mAb 299 revealed the expression of alpha 4-containing nAChRs i n the NRM. The alpha 4 immunostaining was dramatically reduced by pret reating (30 d) animals with the serotonin neurotoxin 5,7-dihydroxytryp tamine (5,7-DHT), which was previously shown to substantially attenuat e the antinociceptive actions of ABT-594. In a double immunohistochemi cal labeling experiment, coexpression of the serotonin marker tryptoph an hydroxylase and the alpha 4 nAChR subunit in NRM neurons was observ ed, These results suggest that the analgesic mechanism of ABT-594 may in part involve the activation of the NRM, a site where alpha-containi ng nAChRs are expressed by serotonergic neurons.