Ryanodine receptors are involved in muscarinic antinociception in mice

Abstract

The role of ryanodine receptors (RyRs) in the induction of muscarinic antinociception was investigated in a condition of acute thermal pain by means of the mouse hot-plate test. I.c.v. administration of non-hyperalgesic doses of ryanodine (0.001-0.06 nmol per mouse i.c.v.), an antagonist of ryanodine receptors (RyRs), dose-dependently prevented the antinociception induced by both physostigmine (100-150 g kg −1 s.c.) and oxotremorine (40-70 g kg −1 s.c.). A shift to the right of the dose-response curve of both cholinomimetic compounds was observed. Pretreatment with non-analgesic doses of 4-chloro-m-cresol (4-Cmc; 0.003-0.3 nmol per mouse i.c.v.), an agonist of RyRs, reversed in a dosedependent manner the antagonistic effect produced by ryanodine of muscarinic antinociception. The pharmacological treatments employed neither modified the animals' gross behavior nor produced any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate that a variation of intracellular calcium contents at the central nervous system level is involved in muscarinic antinociception. In particular, the stimulation of RyRs appears to play an important role in the increase of the pain threshold produced by physostigmine and oxotremorine in mice.

Expression of muscarinic M1 and M2 receptors in the anterior cingulate cortex associated with neuropathic pain

“…Cholinergic mediated analgesia can be prevented in knock-out mice for muscarinic receptors (MR), M2 and M4 (Duttaroy et al, 2002). Similar results were obtained with the supraspinal deactivation of the M1R which prevents the antinociception evoked by the activation of the muscarinic cholinergic system (Galeotti et al, 2003(Galeotti et al, , 2005. Furthermore, the use of a cholinergic agonist in the intralaminar parafasicular nucleus of the thalamus diminishes a nociceptive behaviour; this response is blocked by a muscarinic antagonist (Harte et al, 2004).…”

Type 1 and type 3 ryanodine receptors are selectively involved in muscarinic antinociception in mice: An antisense study

“…Recently, the involvement of RyRs in muscarinic antinociception has been hypothesized since the increase of pain threshold induced by cholinomimetics is prevented by pretreatment with the RyR antagonist ryanodine (Galeotti et al, 2005). The alkaloid ryanodine binds with high affinity to the RyR proteins inducing a complex change in single RyR channel function (Sutko et al, 1997).…”