Abstract
Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT), dopamine (DA) and noradrenaline (NA) on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs) or intracellular excitatory postsynaptic currents (EPSCs). The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs) recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75%) but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic transmission in the dorsal horn are broadly reduced by descending monoamine transmitters. These actions likely integrate with modulatory actions elsewhere to reconfigure spinal circuits during motor behaviors.
Highlights
Descending monoaminergic transmitter systems (5HT, NA and DA) play an integral role in modulating spinal sensory processing, capable of both depression and facilitation of sensory evoked actions
While the monoamines are involved in primary afferent depolarization (PAD) of predominantly pain/temperature encoding afferents (e.g. [7], [8], [9]), little is known about their modulation on PAD of proprioceptionencoding muscle afferents [10], [11], [12], [13] with no reported effects on myelinated cutaneous pathways [14], [15], [16]
All monoamines applied at 10 mM produced a pronounced reversible depression of Tib-evoked dorsal root potentials (DRPs) (Figure 2A–C)
Summary
Descending monoaminergic transmitter systems (5HT, NA and DA) play an integral role in modulating spinal sensory processing, capable of both depression and facilitation of sensory evoked actions (see [1], [2], [3], [4], [5]). An important question is the extent to which monoaminergic pathways regulate afferent activity by controlling PAD. [7], [8], [9]), little is known about their modulation on PAD of proprioceptionencoding muscle afferents [10], [11], [12], [13] with no reported effects on myelinated cutaneous pathways [14], [15], [16]. Stimulation of brainstem raphespinal pathways regulates PAD of group Ia muscle spindle and Ib Golgi tendon organ afferents [13], [17] but whether these actions are due to direct effects of 5HT is not known. Actions on afferent fibers are implicated in the monoaminergic depression of Ia muscle afferent-evoked monosynaptic reflexes [20], [21], [22], [23]
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