Kawamura_2026_J.Pharmacol.Sci_161_79

Acetylcholine-mediated modulation of pain-associated behaviors has been progressively well described. The mechanisms of cholinergic antinociception have been reported to involve the activation of nAChRs or mAChRs modulating GABAergic and/or glycinergic inhibitory transmissions. However, the functional activity of cholinesterase in pain signaling, which catabolizes ACh to choline, is not well established. We found that ACh increased the frequency and amplitude of spontaneous IPSCs in the presence of the cholinesterase inhibitor neostigmine in the rat substantia gelatinosa of the spinal trigeminal nucleus caudalis. In the absence of neostigmine, even a high concentration of ACh had no significant effect on the frequency of IPSCs. The non-hydrolysable agonist muscarine, but not nicotine, significantly increased IPSC frequency in the absence of neostigmine. The increase in IPSC frequency with ACh was blocked by strychnine, atropine, or tetrodotoxin. These results suggest that activation of the mAChR increases glycine receptor-mediated IPSC frequency in a manner dependent on an action potential generation, only when the activity of cholinesterase is inhibited by neostigmine in the substantia gelatinosa of the spinal trigeminal nucleus caudalis. The inhibition of ACh breakdown by a cholinesterase inhibitor might be important for producing analgesia through the cholinergic modulations of the nociceptive network. (200 words).