title: Nociceptive thresholds are controlled through spinal β2-subunit-containing nicotinic acetylcholine receptors.
abstract: Although cholinergic drugs are known to modulate nociception, the role of endogenous acetylcholine in nociceptive processing remains unclear. In the current study, we evaluated the role of cholinergic transmission through spinal β(2)-subunit-containing nicotinic acetylcholine receptors in the control of nociceptive thresholds. We show that mechanical and thermal nociceptive thresholds are significantly lowered in β(2)(∗)-knockout (KO) mice. Using nicotinic antagonists in these mice, we demonstrate that β(2)(∗)-nAChRs are responsible for tonic inhibitory control of mechanical thresholds at the spinal level. We further hypothesized that tonic β(2)(∗)-nAChR control of mechanical nociceptive thresholds might implicate GABAergic transmission since spinal nAChR stimulation can enhance inhibitory transmission. Indeed, the GABA(A) receptor antagonist bicuculline decreased the mechanical threshold in wild-type but not β(2)(∗)-KO mice, and the agonist muscimol restored basal mechanical threshold in β(2)(∗)-KO mice. Thus, β(2)(∗)-nAChRs appeared to be necessary for GABAergic control of nociceptive information. As a consequence of this defective inhibitory control, β(2)(∗)-KO mice were also hyperresponsive to capsaicin-induced C-fiber stimulation. Our results indicate that β(2)(∗)-nAChRs are implicated in the recruitment of inhibitory control of nociception, as shown by delayed recovery from capsaicin-induced allodynia, potentiated nociceptive response to inflammation and neuropathy, and by the loss of high-frequency transcutaneous electrical nerve stimulation (TENS)-induced analgesia in β(2)(∗)-KO mice. As high-frequency TENS induces analgesia through Aβ-fiber recruitment, these data suggest that β(2)(∗)-nAChRs may be critical for the gate control of nociceptive information by non-nociceptive sensory inputs. In conclusion, acetylcholine signaling through β(2)(∗)-nAChRs seems to be essential for setting nociceptive thresholds by controlling GABAergic inhibition in the spinal cord.
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France Faculté des Sciences de la Vie, Université de Strasbourg, Strasbourg, France Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Ipek
authors.initials: I
authors.lastname: Yalcin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Charlet
authors.forename: Matilde
authors.initials: M
authors.lastname: Cordero-Erausquin
authors.forename: Luc-Henri
authors.initials: LH
authors.lastname: Tessier
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
authors.forename: Rémy
authors.initials: R
authors.lastname: Schlichter
authors.forename: Pierrick
authors.initials: P
authors.lastname: Poisbeau
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Freund-Mercier
authors.forename: Michel
authors.initials: M
authors.lastname: Barrot
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D018733:Nicotinic Antagonists / Q000494:pharmacology; D059225:Nociception / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*
chemical_list: D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic