Adrenergic, serotonergic and cholinergic components of nicotinic antinociception in rats

The present study was designed to determine the degree of participation of opioid, noradrenergic, serotonergic and cholinergic systems of the lumbar spinal cord in the antinociception produced by nicotinic stimulation of the pedunculopontine tegmental nucleus (PPTg) or nucleus raphe magnus (RMg). Adult, male Sprague-Dawley rats were implanted subcortically with 25-gauge cannulas into the PPTg or RMg. The animals were also implanted with intrathecal catheters terminating in the subarachnoid space just rostral to the lumbar enlargement. Seven days after surgery, animals were injected with 15 to 100 nmol of various receptor antagonists intrathecally 10 min before microinjections of 40 nmol of N-methylcarbachol (NMC) into the PPTg or RMg. Doses of antagonists were chosen which did not induce motor disturbances and did not alter hot-plate or tail-flick nociception when administered alone. NMC produced hot-plate and tail-flick antinociception for 20 to 25 min, peaking 5 to 10 min after either PPTg or RMg microinjection. Intrathecal administration of 50 nmol of idazoxan, 100 nmol of S-(-)-propranolol, 20 nmol of LY53857, 25 nmol of S-(-)-zacopride, 100 nmol of pirenzepine or 50 nmol of methoctramine each antagonized in part the antinociception produced by PPTg or RMg microinjections of 40 nmol of NMC. Intrathecal administration of 100 nmol of naloxone or 100 nmol of prazosin enhanced the antinociceptive effects of NMC. Intrathecal vehicle or 100 nmol of mecamylamine did not alter NMC-induced antinociception. Complete antagonism of PPTg-administered NMC antinociception was achieved only when animals were pretreated intrathecally with combinations of at least three of the following four antagonists, 20 nmol of S-(-)-zacopride, 15 nmol of LY53857, 25 nmol of idazoxan and 50 nmol of methoctramine. The data suggest that the antinociceptive responses produced by nicotinic stimulation of the PPTg or RMg have similar pharmacologic profiles, and are redundantly mediated via alpha-2 adrenergic, 5-HT1c/2 and 5-HT3 serotonergic, and M2 cholinergic receptor interactions in the lumbar spinal cord.