Disparate cholinergic currents in rat principal trigeminal sensory nucleus neurons mediated by M1 and M2 receptors: a possible mechanism for selective gating of afferent sensory neurotransmission

Abstract

Neurons situated in the principal sensory trigeminal nucleus (PSTN) convey orofacial sensory inputs to thalamic relay regions and higher brain centres, and the excitability of these ascending tract cells is modulated across sleep/wakefulness states and during pain conditions. Moreover, acetylcholine release changes profoundly across sleep/wakefulness states and ascending sensory neurotransmission is altered by cholinergic agonists. An intriguing possibility is, therefore, that cholinergic mechanisms mediate such state-dependent modulation of PSTN tract neurons. We tested the hypotheses that cholinergic agonists can modulate PSTN cell excitability and that such effects are mediated by muscarinic receptor subtypes, using patch-clamp methods in rat and mouse. In all examined cells, carbachol elicited an electrophysiological response that was independent of action potential generation as it persisted in the presence of tetrodotoxin. Responses were of three types: depolarization, hyperpolarization or a biphasic response consisting of hyperpolarization followed by depolarization. In voltage-clamp mode, carbachol evoked corresponding inward, outward or biphasic currents. Moreover, immunostaining for the vesicle-associated choline transporter showed cholinergic innervation of the PSTN. Using muscarinic receptor antagonists, we found that carbachol-elicited PSTN neuron hyperpolarization was mediated by M2 receptors and depolarization, in large part, by M1 receptors. These data suggest that acetylcholine acting on M1 and M2 receptors may contribute to selective excitability enhancement or depression in individual, rostrally projecting sensory neurons. Such selective gating effects via cholinergic input may play a functional role in modulation of ascending sensory transmission, including across behavioral states typified by distinct cholinergic tone, e.g. sleep/wakefulness arousal levels or neuropathic pain conditions.

Sleep, activity, temperature and arousal responses of mice deficient for muscarinic receptor M2 or M4

“…Consistent with this model, greater startle in the KO strains would result from their reduced or absent inhibitory central muscarinic tone. In addition, acetylcholine acting on M2R in the sensory trigeminal nucleus could contribute to selective gating of ascending sensory transmission, potentially influencing characteristics of sleep, arousal, and pain perception (Kohlmeier et al 2006). However, peripheral administration of M2R antagonists, in contrast with M4R antagonists, does not disrupt PPI in mice (Ukai et al 2004), suggesting a more prominent role for M4R.…”

Genetic Association of Objective Sleep Phenotypes with a Functional Polymorphism in the Neuropeptide S Receptor Gene

“…The highest concentration of NPS precursor mRNA has been found in brainstem neurons adjacent to the locus coeruleus, in the parabrachial nucleus and in the principle sensory trigeminal nucleus [2], [4]. Both the locus coeruleus area and the parabrachial nucleus are known for their contribution in the ascending arousal network, and the sensory trigeminal nucleus is also strongly modulated by the sleep/wake cycle [6], [7]. Compared to the NPS expression pattern, the NPSR1 precursor mRNA is distributed more widely in the brain.…”

Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain

“…During carbachol application, the role of nAChRs could be masked by simultaneous activation of multiple mAChRs often producing functionally opposite effects on nociceptive neurotransmission (38–40). Therefore, to investigate directly a contribution of nAChRs to the nociceptive signaling in meninges, we used the specific nAChRs agonist nicotine.…”