Long-term tactile hypersensitivity after nerve crush injury in mice is characterized by the persistence of intact sensory axons.

ABSTRACT: Traumatic peripheral nerve injuries are at high risk of neuropathic pain for which novel effective therapies are urgently needed. Preclinical models of neuropathic pain typically involve irreversible ligation and/or nerve transection (neurotmesis). However, translation of findings to the clinic has so far been unsuccessful, raising questions on injury model validity and clinically relevance. Traumatic nerve injuries seen in the clinic commonly result in axonotmesis (ie, crush), yet the neuropathic phenotype of "painful" nerve crush injuries remains poorly understood. We report the neuropathology and sensory symptoms of a focal nerve crush injury using custom-modified hemostats resulting in either complete ("full") or incomplete ("partial") axonotmesis in adult mice. Assays of thermal and mechanically evoked pain-like behavior were paralleled by transmission electron microscopy, immunohistochemistry, and anatomical tracing of the peripheral nerve. In both crush models, motor function was equally affected early after injury; by contrast, partial crush of the nerve resulted in the early return of pinprick sensitivity, followed by a transient thermal and chronic tactile hypersensitivity of the affected hind paw, which was not observed after a full crush injury. The partially crushed nerve was characterized by the sparing of small-diameter myelinated axons and intraepidermal nerve fibers, fewer dorsal root ganglia expressing the injury marker activating transcription factor 3, and lower serum levels of neurofilament light chain. By day 30, axons showed signs of reduced myelin thickness. In summary, the escape of small-diameter axons from Wallerian degeneration is likely a determinant of chronic pain pathophysiology distinct from the general response to complete nerve injury.

A Critical Involvement of Glutamatergic Neurons in the Anterior Insular Cortex for Subdiaphragmatic Vagotomy-induced Analgesia.

Subdiaphragmatic vagotomy (SDV) is known to produce analgesic effect in various pain conditions including not only visceral pain but also somatic pain. We aimed to determine brain mechanisms by which SDV induces analgesic effect in somatic pain condition by using formalin-induced acute inflammatory pain model. We identified brain regions that mediate SDV-induced analgesic effect on acute inflammatory pain by analyzing c-Fos expression in the whole brain. We found that c-Fos expression was specifically increased in the anterior insular cortex (aIC) among subregions of the insular cortex in acute inflammatory pain, which was reversed by SDV. These results were not mimicked in female mice, indicating sexual-dimorphism in SDV-induced analgesia. SDV decreased c-Fos expressions more preferentially in glutamatergic neurons rather than GABAergic neurons in the aIC, and pharmacological activation of glutamatergic neurons with NMDA in the aIC inhibited SDV-induced analgesic effect. Furthermore, chemogenetic activation of glutamatergic neurons in the aIC reversed SDV-induced analgesia. Taken together, our results suggest that the decrease in the neuronal activity of glutamatergic neurons in the aIC mediates SDV-induced analgesic effect, potentially serving as an important therapeutic target to treat inflammatory pain.

Anterior Insular-nucleus Accumbens Pathway Controls Refeeding-induced Analgesia under Chronic Inflammatory Pain Condition.

Feeding behaviors are closely associated with chronic pain in adult rodents. Our recent study revealed that 2 h refeeding after 24 h fasting (i.e., refeeding) attenuates pain behavior under chronic inflammatory pain conditions. However, while brain circuits mediating fasting-induced analgesia have been identified, the underlying mechanism of refeeding-induced analgesia is still elusive. Herein, we demonstrate that the neural activities in the nucleus accumbens shell (NAcS) and anterior insular cortex (aIC) were increased in a modified Complete Freund's Adjuvant (CFA)-induced chronic inflammatory pain condition, which was reversed by refeeding. We also found that refeeding reduced the enhanced excitability of aICCaMKII-NAcSD2R projecting neurons in this CFA model. Besides, chemogenetic inhibition of aICCaMKII-NAcSD2R neural circuit suppressed chronic pain behavior while activation of this circuit reversed refeeding-induced analgesia. Thus, the present study suggests that aICCaMKII-NAcSD2R neural circuit mediates refeeding-induced analgesia, thereby serving as a potential therapeutic target to manage chronic pain.