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bioRxiv · 10.64898/2026.02.02.703408

Nociceptive activity enhances GABAA receptor mediated facilitation of proprioceptive afferent transmission to motoneurons, and is gated by serotonin.

Bennett, D. J.
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Abstract

Sensory transmission in the monosynaptic stretch reflex (MSR) from proprioceptive Ia afferents to motoneurons is markedly inhibited by serotonin, providing a mechanism by which the brain gates spinal cord function. However, the main serotonin receptor subtype that modulates the MSR is the 5-HT1D receptor that is expressed almost exclusively on nociceptive C-fibres, suggesting an unexpected gating of proprioceptive transmission by regulation of nociceptive pathways. We demonstrate here that activation of C-fibres (electrically or pharmacologically by TRPM8 agonists) increases action potential propagation in proprioceptive Ia afferents by producing a very long-lasting tonic depolarization in Ia afferents (tonic primary afferent depolarization, tonic PAD). This tonic PAD is produced indirectly by C-fibres augmenting axoaxonic GABAergic input onto Ia afferents (bicuculline sensitive), which activates nodal GABAA receptors that aid sodium spike initiation. In contrast, activation of 5-HT1D receptors with the anti-migraine drug zolmitriptan inhibits C-fibre activity, which in turn reduces the GABAA receptor-mediated tonic PAD on Ia afferents, and reduces spike propagation to motoneurons. Overall, these findings demonstrate a mechanism by which brainstem derived serotonin not only inhibits ongoing nociceptive C-fibres activity, but also indirectly inhibits GABAergic neurons and sensory transmission in large proprioceptive sensory afferents, leading to reduced motoneuron activity. Furthermore, these findings suggest that spontaneous nociceptive C-fibres activity may provide a general increase in proprioception, opposite to the classical gating of nociceptive pathways by low threshold afferents, and impacting the clinical use of zolmitriptan.

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Bennett, D. J.. 2026-02-05. Nociceptive activity enhances GABAA receptor mediated facilitation of proprioceptive afferent transmission to motoneurons, and is gated by serotonin.. https://doi.org/10.64898/2026.02.02.703408

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