Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain

Abstract

Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord. The levels of IGF-1 released by infiltrating macrophages into the injured ION and the TG were significantly increased. The IONI-induced the number of transient receptor potential vanilloid (TRPV) subfamily type 4 (TRPV4) upregulation in TRPV subfamily type 2 (TRPV2)-positive small-sized, and medium-sized TG neurons were inhibited by peripheral TRPV2 antagonism. Furthermore, the IONI-induced mechanical allodynia was suppressed by TRPV4 antagonism in the whisker pad skin. These results suggest that IGF-1 released by macrophages accumulating in the injured ION binds to TRPV2, which increases TRPV4 expression in TG neurons innervating the whisker pad skin, ultimately resulting in mechanical allodynia of the whisker pad skin.

Orofacial Neuropathic Pain-Basic Research and Their Clinical Relevancies

“…Trigeminal nerve injury results in pain hypersensitivity categorized as persistent orofacial pain, allodynia, and hyperalgesia ( Kaji et al, 2016 ; Batbold et al, 2017 ; Sugawara et al, 2019 ). When the peripheral nerves are damaged, the cellular response is induced by via various molecules at the site of nerve damage.…”

“…Via TRPV2, the signaling of IGF-1 that is released by macrophages which accumulate in the site of infraorbital nerve injury, increases TRPV4 expression in neurons of the TG, innervating the facial skin. This results in mechanical hypersensitivity in the facial skin ( Sugawara et al, 2019 ). Many molecules released from the injured axons, the infiltrating macrophages, and Schwann cells activate non-injured axons after peripheral nerve injury.…”

Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats

“…The interval between each mechanical stimulus was set at >3 min to avoid sensitization of the receptive field by frequent stimulus. The timing was based on previous studies [54][55][56]. Measurement of the PWT was performed under the same conditions and conducted in a randomized, experimenter-blinded design.…”

Visualization of trigeminal ganglion sensory neuronal signaling regulated by Cdk5

“…Pain affecting the face or oral cavity (orofacial pain) afflicts 5%-12% of the population worldwide and can severely decrease the quality of life (Crandall, 2018;Herrero Babiloni et al, 2018). It also contributes to other health and social problems such as the opioid crisis (Sugawara et al, 2019). Clinicians struggle to alleviate pain due to our current inadequate understanding of the detailed mechanisms.…”