Abstract
Persistent pain following orofacial surgery is not uncommon. High mobility group box 1 (HMGB1), an alarmin, is released by peripheral immune cells following nerve injury and could be related to pain associated with trigeminal nerve injury. Distal infraorbital nerve chronic constriction injury (dIoN-CCI) evokes pain-related behaviors including increased facial grooming and hyper-responsiveness to acetone (cutaneous cooling) after dIoN-CCI surgery in mice. In addition, dIoN-CCI mice developed conditioned place preference to mirogabalin, suggesting increased neuropathic pain-related aversion. Treatment of the infraorbital nerve with neutralizing antibody HMGB1 (anti-HMGB1 nAb) before dIoN-CCI prevented both facial grooming and hyper-responsiveness to cooling. Pretreatment with anti-HMGB1 nAb also blocked immune cell activation associated with trigeminal nerve injury including the accumulation of macrophage around the injured IoN and increased microglia activation in the ipsilateral spinal trigeminal nucleus caudalis. The current findings demonstrated that blocking of HMGB1 prior to nerve injury prevents the onset of pain-related behaviors, possibly through blocking the activation of immune cells associated with the nerve injury, both within the CNS and on peripheral nerves. The current findings further suggest that blocking HMGB1 before tissue injury could be a novel strategy to prevent the induction of chronic pain following orofacial surgeries.
Highlights
Posttraumatic trigeminal neuropathy (PTTN) is a chronic sensory disorder characterized by chronic orofacial numbness, paresthesia and pain [1]
Total facial grooming time was significantly greater in distal infraorbital nerve chronic constriction injury mice compared to that of sham mice (Figure 1A, Unpaired t test, Table S1), suggesting dIoN-CCI-induced spontaneous pain
Longer times were spent in the mirogabalin-paired side compared to that during the pretest session in dIoN-CCI mice, whereas no significant change in time spent in the mirogabalin-paired was observed in sham-operated mice. (Figure 2A; Two-way repeated measures (RM) analysis of variance (ANOVA), Sidak’s multiple comparisons test; Table S1)
Summary
Posttraumatic trigeminal neuropathy (PTTN) is a chronic sensory disorder characterized by chronic orofacial numbness, paresthesia and pain [1]. Around 3–7% of orofacial procedures, such as injection of local anesthesia, implant surgery, and third molar removal, result in PTTN [1]. Pain associated with PTTN is refractory to commonly used analgesics such as opioids and non-steroidal anti-inflammatory drugs [2]. It is believed that the risk of developing PTTN increases with the complexity of the surgical procedure [3]. Unlike other painful peripheral neuropathies, the potential of developing PTTN can be predicted based on preoperative assessment, such as X-ray of the trigeminal nerve tract or of the surgery site. The molecular mechanism of pain following PTTN has to be clarified
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