TY - JOUR T1 - 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 JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5426 LP - 5432 DO - 10.1523/JNEUROSCI.18-14-05426.1998 VL - 18 IS - 14 AU - R. Scott Bitner AU - Arthur L. Nikkel AU - Peter Curzon AU - Stephen P. Arneric AU - Anthony W. Bannon AU - Michael W. Decker Y1 - 1998/07/15 UR - http://www.jneurosci.org/content/18/14/5426.abstract N2 - Recently, a novel cholinergic channel modulator, (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), was shown to produce potent analgesia in a variety of rodent pain models when administered either systemically or centrally into the nucleus raphe magnus (NRM). The purpose of the present study was to investigate the possible supraspinal contribution of ABT-594 by assessing its ability to induce expression of the immediate early gene c-fos, a biochemical marker of neuronal activation, in the NRM of rats. Putative serotonergic neurons in the NRM, a medullary nucleus proposed to be involved in descending antinociceptive pathways, were identified immunohistochemically using a monoclonal antibody (mAb) against tryptophan hydroxylase. ABT-594 (0.03–0.3 μmol/kg, i.p.) produced a dose-dependent induction of Fos protein that was blocked by the central nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (5 μmol/kg, i.p.) but not by the peripheral nAChR antagonist hexamethonium (15 μmol/kg, i.p.). Immunohistological studies using mAb 299 revealed the expression of α4-containing nAChRs in the NRM. The α4 immunostaining was dramatically reduced by pretreating (30 d) animals with the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which was previously shown to substantially attenuate the antinociceptive actions of ABT-594. In a double immunohistochemical labeling experiment, coexpression of the serotonin marker tryptophan hxdroxylase and the α4 nAChR subunit in NRM neurons was observed. These results suggest that the analgesic mechanism of ABT-594 may in part involve the activation of the NRM, a site where α4-containing nAChRs are expressed by serotonergic neurons. ER -