Nociceptive thresholds are controlled through spinal β2-subunit-containing nicotinic acetylcholine receptors

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 β2-subunit-containing nicotinic acetylcholine receptors in the control of nociceptive thresholds. We show that mechanical and thermal nociceptive thresholds are significantly lowered in β2∗-knockout (KO) mice. Using nicotinic antagonists in these mice, we demonstrate that β2∗-nAChRs are responsible for tonic inhibitory control of mechanical thresholds at the spinal level. We further hypothesized that tonic β2∗-nAChR control of mechanical nociceptive thresholds might implicate GABAergic transmission since spinal nAChR stimulation can enhance inhibitory transmission. Indeed, the GABAA receptor antagonist bicuculline decreased the mechanical threshold in wild-type but not β2∗-KO mice, and the agonist muscimol restored basal mechanical threshold in β2∗-KO mice. Thus, β2∗-nAChRs appeared to be necessary for GABAergic control of nociceptive information. As a consequence of this defective inhibitory control, β2∗-KO mice were also hyperresponsive to capsaicin-induced C-fiber stimulation. Our results indicate that β2∗-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 β2∗-KO mice. As high-frequency TENS induces analgesia through Aβ-fiber recruitment, these data suggest that β2∗-nAChRs may be critical for the gate control of nociceptive information by non-nociceptive sensory inputs. In conclusion, acetylcholine signaling through β2∗-nAChRs seems to be essential for setting nociceptive thresholds by controlling GABAergic inhibition in the spinal cord.