Cortical Cholinergic Modulation in Neuropathic Pain


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Cholinergic modulation of the brain cortex is critical for cognitive processes, and altered cholinergic modulation of the prefrontal cortex is emerging as an important mechanism of neuropathic pain. Despite the known sex differences in pain prevalence and perception, the precise nature of the mechanisms responsible for sexual dimorphism in chronic neuropathic pain are poorly understood. In my thesis, I investigated potential sex differences in cholinergic modulation of layer 5 commissural pyramidal neurons of the rat prelimbic cortex in control conditions and in the SNI model of neuropathic pain. I discovered quantitative differences between cholinergic modulation in cells from male and female rats, and that these differences are amplified by the neuropathic pain condition. Unexpectedly, in SNI, cholinergic modulation appeared more severely affected in males than in females. I also found large sex-dependent differences in the expression of the M1 subunit across different cortical areas in control and SNI animals. Finally, I show that selective pharmacological blockade of the muscarinic M1 subunit in the prefrontal cortex is sufficient to induce cold (but mot mechanical) allodynia in naïve animals of both sexes. These results identify impaired cholinergic modulation of the medial prefrontal cortex as a causal mechanism of allodynia and suggest that differences in cholinergic modulation of this brain area may contribute, at least in part, to the sexual dimorphism in pain mechanisms.

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