title: 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.
  
  
  CONCLUSIONS
  Our study describes a decrease in cholinergic neurotransmission in the posterior insular cortex in neuropathic pain condition and the involvement of M2 receptors. Targeting these cortical muscarinic M2 receptors using central cholinomimetics could be an effective therapy for neuropathic pain treatment.
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000 Clermont-Ferrand, France, Inserm, U1107 NEURO-DOL, F-63001 Clermont-Ferrand, France, Institut Analgesia, F-63000 Clermont-Ferrand, France.
authors.forename: Jérémy
authors.identifier: http://orcid.org/0000-0001-9755-3565
authors.initials: J
authors.lastname: Ferrier
authors.affiliation: Université Lyon, CNRS, ENS Lyon, UCB Lyon 1, Ctr RMN Très Hauts Champs, F-69100 Villeurbanne, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Bayet-Robert
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000 Clermont-Ferrand, France, Inserm, U1107 NEURO-DOL, F-63001 Clermont-Ferrand, France, Institut Analgesia, F-63000 Clermont-Ferrand, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Dalmann
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000 Clermont-Ferrand, France, Inserm, U1107 NEURO-DOL, F-63001 Clermont-Ferrand, France, Centre Jean Perrin, ERTICA EA4677 Université d'Auvergne, F-63001, Clermont-Ferrand, France.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: El Guerrab
authors.affiliation: Inserm, U1107 NEURO-DOL, F-63001 Clermont-Ferrand, France.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Aissouni
authors.affiliation: Université Lyon 1, Inserm U1044, CNRS UMR 5220, Laboratory CREATIS, F-69616 Villeurbanne, France, and.
authors.forename: Danielle
authors.initials: D
authors.lastname: Graveron-Demilly
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000 Clermont-Ferrand, France, Inserm, U1107 NEURO-DOL, F-63001 Clermont-Ferrand, France, Institut Analgesia, F-63000 Clermont-Ferrand, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Chalus
authors.affiliation: Institut Analgesia, F-63000 Clermont-Ferrand, France, CHU Clermont-Ferrand, F-63000 Clermont-Ferrand, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Pinguet
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000 Clermont-Ferrand, France, Inserm, U1107 NEURO-DOL, F-63001 Clermont-Ferrand, France, Institut Analgesia, F-63000 Clermont-Ferrand, France, CHU Clermont-Ferrand, F-63000 Clermont-Ferrand, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
authors.affiliation: Institut Analgesia, F-63000 Clermont-Ferrand, France, CHU Clermont-Ferrand, F-63000 Clermont-Ferrand, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Richard
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000 Clermont-Ferrand, France, Inserm, U1107 NEURO-DOL, F-63001 Clermont-Ferrand, France, Institut Analgesia, F-63000 Clermont-Ferrand, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Daulhac
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000 Clermont-Ferrand, France, Inserm, U1107 NEURO-DOL, F-63001 Clermont-Ferrand, France, Institut Analgesia, F-63000 Clermont-Ferrand, France, fabien.marchand@udamail.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Marchand
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000 Clermont-Ferrand, France, Inserm, U1107 NEURO-DOL, F-63001 Clermont-Ferrand, France, Institut Analgesia, F-63000 Clermont-Ferrand, France, CHU Clermont-Ferrand, F-63000 Clermont-Ferrand, France.
authors.forename: David
authors.initials: D
authors.lastname: Balayssac
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D015870:Gene Expression / Q000235:genetics; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007189:Indans / Q000494:pharmacology*; D007398:Interpersonal Relations; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009437:Neuralgia / Q000139:chemically induced / Q000503:physiopathology* / Q000523:psychology; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010275:Parasympathetic Nervous System / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000187:drug effects* / Q000235:genetics; D009435:Synaptic Transmission
chemical_list: D000700:Analgesics; D002800:Cholinesterase Inhibitors; D007189:Indans; D026901:Membrane Transport Proteins; D018727:Muscarinic Antagonists; D009944:Organoplatinum Compounds; D010880:Piperidines; D012333:RNA, Messenger; D043585:Receptor, Muscarinic M2; C065637:choline transporter; D000077150:Oxaliplatin; D000077265:Donepezil
keywords: acetylcholine; donepezil; insular cortex; metabolomics; neuropathy; oxaliplatin