Signaling Interaction between Facial and Meningeal Inputs of the Trigeminal System Mediates Peripheral Neurostimulation Analgesia in a Rat Model of Migraine

[Display omitted] •Bidirectional neurogenic inflammation appears in both facial tissues and meninges.•Bifurcated primary neurons partially mediate interactions of trigeminal territories.•Facial and dural nociceptive inputs interact in same WDR neurons in Sp5C.•Homotopic peripheral neurostimulation represents an effective treatment for migraine. Peripheral neurostimulation within the trigeminal nerve territory has been used for pain alleviation during migraine attacks, but the mechanistic basis of this non-invasive intervention is still poorly understood. In this study, we investigated the therapeutic role of peripheral stimulation of the trigeminal nerve, which provides homosegmental innervation to intracranial structures, by assessing analgesic effects in a nitroglycerin (NTG)-induced rat model of migraine. As a result of neurogenic inflammatory responses in the trigeminal nervous system, plasma protein extravasation was induced in facial skin by applying noxious stimulation to the dura mater. Noxious chemical stimulation of the dura mater led to protein extravasation in facial cutaneous tissues and caused mechanical sensitivity. Trigeminal ganglion (TG) neurons were double-labeled via retrograde tracing to detect bifurcated axons. Extracellular recordings of wide dynamic range (WDR) neurons in the spinal trigeminal nucleus caudalis (Sp5C) demonstrated the convergence and interaction of inputs from facial tissues and the dura mater. Peripheral neurostimulation of homotopic facial tissues represented segmental pain inhibition on cephalic cutaneous allodynia in the migraine model. The results indicated that facial territories and intracranial structures were directly connected with each other through bifurcated double-labeled neurons in the TG and through second-order WDR neurons. Homotopic stimulation at the C-fiber intensity threshold resulted in much stronger inhibition of analgesia than the same intensity of heterotopic stimulation. These results provide novel evidence for the neurological bases through which peripheral neurostimulation may be effective in treating migraine in clinical practice.