5-HT1D receptors inhibit the monosynaptic stretch reflex by modulating C fibre activity.

The monosynaptic stretch reflex (MSR) plays an important role in feedback control of movement and posture, but can also lead to unstable oscillations associated with tremor and clonus, especially when increased with spinal cord injury (SCI). To control the MSR and clonus after SCI we examined how serotonin regulates the MSR in the sacrocaudal spinal cord of rats with and without a chronic spinal transection. In chronic spinal rats, numerous 5-HT receptor agonists, including zolmitriptan, methylergonovine and 5-HT, inhibited the MSR with a potency highly correlated to their binding affinity to 5-HT1D receptors and not other 5-HT receptors. Selective 5-HT1D receptor antagonists blocked this agonist induced inhibition, though antagonists alone had no action, indicating a lack of endogenous or constitutive receptor activity. In normal uninjured rats, the MSR was likewise inhibited by 5-HT, but at much higher doses, indicating a supersensitivity after SCI. This supersensitivity resulted from the loss of the serotonin transporter SERT with spinal transection, since normal and injured rats were equally sensitive to 5-HT after blocking SERT, or to agonists not transported by SERT (zolmitriptan). Immunolabelling revealed that the 5-HT1D receptor was confined to superficial lamina of the dorsal horn, colocalized with CGRP positive C fibres, and eliminated by dorsal rhizotomy. 5-HT1D receptor labelling was not found on large proprioceptive afferents or alpha-motoneurons of the MSR. Thus, serotonergic inhibition of the MSR must act indirectly by modulating C fibre activity, opening up new possibilities for modulating reflex function and clonus via pain related pathways.