Hypothalamic paraventricular stimulation inhibits nociceptive WDR trigeminocervical complex cells via oxytocinergic transmission

Oxytocinergic transmission blocks nociception at the peripheral, spinal, and supraspinal levels through the oxytocin receptor (OTR). Indeed, a neuronal pathway from the hypothalamic paraventricular nucleus (PVN) to the spinal cord and trigeminal nucleus caudalis (Sp5c) has been described. Hence, although the trigeminocervical complex (TCC), an anatomical area spanning the Sp5c, C1, and C2 regions, plays a role in some pain disorders associated with craniofacial structures ( e.g. , migraine), the role of oxytocinergic transmission in modulating nociception at this level has been poorly explored. Hence, in vivo electrophysiological recordings of TCC wide dynamic range (WDR) cells sensitive to stimulation of the periorbital or meningeal region were performed in male Wistar rats. PVN electrical stimulation diminished the neuronal firing evoked by periorbital or meningeal electrical stimulation; this inhibition was reversed by OTR antagonists administered locally. Accordingly, neuronal projections (using fluoro-ruby) from the PVN to the WDR cells filled with neurobiotin were observed. Moreover, colocalization between OTR and CGRP or OTR and GABA was found near neurobiotin-filled WDR cells. Retrograde neuronal tracers deposited at the meningeal (true-blue) and infraorbital nerves (fluoro-gold) showed that at the trigeminal ganglion (TG), some cells were immunopositive to both fluorophores, suggesting that some TG cells send projections via the V1 and V2 trigeminal branches. Together, these data may imply that endogenous oxytocinergic transmission inhibits the nociceptive activity of second-order neurons via OTR activation in CGRPergic (primary afferent fibers) and GABAergic cells. Significance statement This study sheds light on the mechanisms involved in the regulation of trigeminal nociception, which is crucial for understanding the pathophysiology of primary headaches, such as migraine. Current evidence suggests that the hypothalamus plays a role in controlling the nociceptive activity at the trigeminal level. The present study found that electrical stimulation of the hypothalamic paraventricular nucleus (PVN) inhibited the nociceptive activity of trigeminal second-order WDR cells through oxytocinergic mechanisms. Furthermore, we found that oxytocin receptors are located in the primary peptidergic afferent fibers and GABAergic cells. These findings support the idea of a direct oxytocinergic pathway between the PVN and TCC and highlight the potential of oxytocin receptors as a target for migraine pain and other primary headaches.