Orofacial neuropathic pain and enhanced excitability of non-nociceptive-like and nociceptive-like trigeminal Aβ-afferent neurons in mice following infraorbital nerve chronic constrictive injury

Orofacial neuropathic pain is a debilitating pain condition. It is poorly treated, partially due to an incomplete understanding of its underlying neurophysiological mechanisms. Orofacial neuropathic pain is often caused by injury or dysfunction of trigeminal nerve branches, including the infraorbital nerve (IoN). Clinically, a main symptom of orofacial neuropathic pain is mechanical allodynia, excruciating pain induced by gentle touch. While previous studies on neuropathic pain have mainly focused on the involvement of C- and Aδ-afferents, the potential contribution of Aβ-afferents to orofacial neuropathic pain has not been well explored. In the present study, we have established a mouse model of chronic constrictive injury of the IoN (IoN-CCI) and assessed orofacial pain behaviors and excitability of Aβ-afferent trigeminal ganglion (TG) neurons. Behavioral assessment using the von Frey test has revealed significantly increased mechanical sensitivity 3-4 weeks post-surgery in IoN-CCI mice compared with the sham group. Machine-learning-based eyelid distance measurement has demonstrated orbital tightening in IoN-CCI mice, suggesting spontaneous pain. Using ex vivo TG preparations and patch-clamp recordings, we have found that action potential (AP) thresholds are significantly reduced in both non-nociceptive-like and nociceptive-like Aβ-afferent TG neurons of IoN-CCI mice. Consistently, there is a significant increase in voltage-gated Na ⁺ currents in both non-nociceptive-like and nociceptive-like Aβ-afferent TG neurons following IoN-CCI. Our findings demonstrate that both non-nociceptive-like and nociceptive-like Aβ-afferent TG neurons undergo hyperexcitability following infraorbital nerve injury, raising the possibility that both types of Aβ-afferent TG neurons may contribute to orofacial neuropathic pain following infraorbital nerve injury.