Cholinergic Neurotransmission in the Posterior Insular Cortex Is Altered in Preclinical Models of Neuropathic Pain: Key Role of Muscarinic M2 Receptors in Donepezil-Induced Antinociception

Abstract

Neuropathic pain is one of the most debilitating pain conditions, yet no therapeutic strategy has been really effective for its treatment. Hence, a better understanding of its pathophysiological mechanisms is necessary to identify new pharmacological targets. Here, we report important metabolic variations in brain areas involved in pain processing in a rat model of oxaliplatin-induced neuropathy using HRMAS 1 H-NMR spectroscopy. An increased concentration of choline has been evidenced in the posterior insular cortex (pIC) of neuropathic animal, which was significantly correlated with animals' pain thresholds. The screening of 34 genes mRNA involved in the pIC cholinergic system showed an increased expression of the high-affinity choline transporter and especially the muscarinic M2 receptors, which was confirmed by Western blot analysis in oxaliplatin-treated rats and the spared nerve injury model (SNI). Furthermore, pharmacological activation of M2 receptors in the pIC using oxotremorine completely reversed oxaliplatin-induced mechanical allodynia. Consistently, systemic treatment with donepezil, a centrally active acetylcholinesterase inhibitor, prevented and reversed oxaliplatin-induced cold and mechanical allodynia as well as social interaction impairment. Intracerebral microdialysis revealed a lower level of acetylcholine in the pIC of oxaliplatin-treated rats, which was significantly increased by donepezil. Finally, the analgesic effect of donepezil was markedly reduced by a microinjection of the M2 antagonist, methoctramine, within the pIC, in both oxaliplatin-treated rats and spared nerve injury rats. These findings highlight the crucial role of cortical cholinergic neurotransmission as a critical mechanism of neuropathic pain, and suggest that targeting insular M2 receptors using central cholinomimetics could be used for neuropathic pain treatment.

The Analgesic Effects of (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] Octane on a Mouse Model of Neuropathic Pain

“…Consequently, the level of acetylcholine (ACh) may be lower in the pain-related brain regions, which was observed in the poster insular cortex of oxaliplatin-treated rats. 7 The basal release of ACh was significantly lower in rats with partial ligation of the sciatic nerve. 34 Our data further showed that the expression levels of both M1 and M2 were decreased in the VTA, PFC, and striatum, suggesting that the regulation of the mAChRs system by the reward system was downregulated under the chronic pain condition.…”

“…3 Different subtypes of mAChRs are expressed in the sensory pathway, including at the terminal of the primary afferent nerve, 4,5 the spinal cord, 6 and the superspinal cord brain regions. 7 Both genetic and pharmacologic approaches have been used to study the involvement of mAChRs in the modulation of nociception. 8 Significant antinociceptive effects were observed after the administration of cholinesterase inhibitors or agonists of mAChRs in basic research studies.…”

Structural and Functional Alterations in Hemodialysis Patients: A Voxel-Based Morphometry and Functional Connectivity Study

“…The insular mainly accepts pain perception and it can relieve pain (Brooks and Tracey, 2007). In addition, more than 50% of hemodialysis patients experience pain, approximately 69% of hemodialysis patients present with joint pain, and almost all of the patients with hemodialysis therapy exhibit non-specific symptoms, such as cramps or headaches (Davison, 2003), resulting from alterations in the concentration of metabolic substances, such as dopamine receptors in the insular (Ferrier et al, 2015). Therefore, decreased thalamo-insular connection may be an important mechanism of pain in hemodialysis patients, suggesting that insular is a key brain region in pain perception.…”

The Analgesic Effects of (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] Octane on a Mouse Model of Neuropathic Pain: Erratum

“…Consequently, the level of acetylcholine (ACh) may be lower in the pain-related brain regions, which was observed in the poster insular cortex of oxaliplatintreated rats. 7 The basal release of ACh was significantly lower in rats with partial ligation of the sciatic nerve. 34 Our data further showed that the expression levels of both M1 and M2 were decreased in the VTA, PFC, and striatum, suggesting that the regulation of the mAChRs system by the reward system was downregulated under the chronic pain condition.…”