I. Yalcin, A. Charlet, M. Cordero-Erausquin, L.-H. Tessier, M. Picciotto et al.
Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.
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 _(2)-subunit-containing nicotinic acetylcholine receptors in the control of nociceptive thresholds. We show that mechanical and thermal nociceptive thresholds are significantly lowered in _(2)(_)-knockout (KO) mice. Using nicotinic antagonists in these mice, we demonstrate that _(2)(_)-nAChRs are responsible for tonic inhibitory control of mechanical thresholds at the spinal level. We further hypothesized that tonic _(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 _(2)(_)-KO mice, and the agonist muscimol restored basal mechanical threshold in _(2)(_)-KO mice. Thus, _(2)(_)-nAChRs appeared to be necessary for GABAergic control of nociceptive information. As a consequence of this defective inhibitory control, _(2)(_)-KO mice were also hyperresponsive to capsaicin-induced C-fiber stimulation. Our results indicate that _(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 _(2)(_)-KO mice. As high-frequency TENS induces analgesia through A_-fiber recruitment, these data suggest that _(2)(_)-nAChRs may be critical for the gate control of nociceptive information by non-nociceptive sensory inputs. In conclusion, acetylcholine signaling through _(2)(_)-nAChRs seems to be essential for setting nociceptive thresholds by controlling GABAergic inhibition in the spinal cord.
BIOSEB Instruments Used:
Von Frey Filaments (Bio-VF-M)