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The Journal of Neuroscience, July 15, 1998, 18(14):5426-5432

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

R. Scott Bitner, Arthur L. Nikkel, Peter Curzon, Stephen P. Arneric, Anthony W. Bannon, and Michael W. Decker

Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500

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 4-containing nAChRs in the NRM. The 4 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 4 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 4-containing nAChRs are expressed by serotonergic neurons.

Key words: ABT-594; nucleus raphe magnus; c-fos expression; nicotinic antagonism; serotonin; 4-containing nicotinic acetylcholine receptor; antinociception

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18145426-07$05.00/0

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