Cholinergic systems modulate synaptic transmission across the neuraxis and play an important role in higher brain function including cognition, arousal and nociception. The anterior cingulate cortex (ACC) is a fundamental brain region for nociception and
chronic pain, and receives
cholinergic projections mainly from basal forebrain. Recently, we found that the activation of
muscarinic M1 receptors in the ACC produced antinociceptive behavior in response to mechanical stimulation. However, it has not been tested whether stimulating
muscarinic receptors in the ACC can reduce mechanical
hypersensitivity in animal models of
chronic pain. Here, we tested whether the activation of
muscarinic M1 receptors in the ACC can alleviate mechanical
hypersensitivity in a nerve injury model. The activation of
muscarinic M1/M4 receptors by
McN-A-343 injected into the contralateral side of the ACC, but not into the ventral posterolateral nucleus, was found to dose-dependently reduce mechanical
hypersensitivity 7 days following partial sciatic nerve
ligation in rats. The reduction of mechanical
hypersensitivity by
McN-A-343, was blocked by a selective
muscarinic M1 antagonist, but not a M4 receptor antagonist. Importantly, the nerve injury model did not change the
protein expression of
muscarinic M1 receptors in the ACC. Additionally, a type A γ-
aminobutyric acid (GABAA) receptor agonist injected into the ACC reduced the mechanical
hypersensitivity in this injury model. Finally, a GABAA receptor antagonist blocked the reduction of mechanical
hypersensitivity by
McN-A-343 in the injury model. Collectively, these results suggest that activations of
muscarinic M1 receptors in the ACC reduce nerve injury-induced mechanical
hypersensitivity through GABAergic transmission via GABAA receptors.