Somatosensory input strength can be modulated by primary afferent depolarization (PAD) generated via presynaptic GABAA receptors on afferent terminals. We investigated whether acetylcholine (ACh) also provides modulatory actions on PAD via nicotinic acetylcholine receptors (nAChRs) using in vitro murine spinal cord nerve-attached models. Primary afferent stimulation-evoked dorsal root potentials (DRPs) were used as an indirect measure of PAD while evoked afferent transmission was recorded in the deep dorsal horn as extracellular field potentials (EFPs). Changes in afferent membrane excitability were inferred from DC-shifts in recorded dorsal roots or peripheral nerves. Of nAChR antagonists tested, D-tubocurarine (D-TC) depressed DRP amplitude the most (43% of control) and actions were restricted to the A-fiber-evoked DRP and selective depression of Aδ-evoked synaptic EFPs (36% of control). These actions occurred centrally as afferent excitability was unchanged. In comparison, ACh depressed evoked responses by different mechanisms. ACh produced coincident depolarizing DC-shifts in peripheral axons and intraspinally that corresponded temporally with reductions in the DRP and all afferent-evoked synaptic actions (31-37% of control). DC-shifts were produced via nAChRs on primary afferents: they were also seen with nAChR agonists (epibatidine and nicotine), blocked with D-TC but not GABAA receptor blockers, and retained after block of voltage-gated Na+ channels. Notably, prominent actions on evoked responses were comparably altered between two mouse strains, in rat, and when performed in different labs. Thus, nAChRs can regulate afferent excitability via two distinct mechanisms: by modulating central Aδ-afferent actions, and by broadly changing membrane polarization of all classes of primary afferents.

Somatosensory information can be modulated at the spinal cord level by primary afferent depolarization (PAD), known to produce presynaptic inhibition (PSI) by decreasing neurotransmitter release through the activation of presynaptic ionotropic receptors. Descending monoaminergic systems also modulate somatosensory processing. We investigated the role of D 1like and D 2 -like receptors on pathways mediating PAD in the hemisected spinal cord of neonatal mice. We recorded low-threshold evoked dorsal root potentials (DRPs) and population monosynaptic responses as extracellular field potentials (EFPs). We used a paired-pulse conditioning-test protocol to assess homosynaptic and heterosynaptic depression of evoked EFPs to discriminate between dopaminergic effects on afferent synaptic efficacy and/or on pathways mediating PAD, respectively. DA (10 μM) depressed low-threshold evoked DRPs by 43%, with no effect on EFPs. These depressant effects on DRPs were mimicked by the D 2 -like receptor agonist quinpirole (35%). Moreover, by using selective antagonists at D 2 -like receptors (encompassing the D 2 , D 3 , and D 4 subtypes), we found that the D 2 and D 3 receptor subtypes participate in the quinpirole depressant inhibitory effects of pathways mediating PAD.

These data indicate a direct inhibitory effect of clobenpropit on catecholamine transport.

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