Effect of a corticotropin-releasing factor 1 receptor antagonist on head withdrawal thresholds in mice with chronic constriction injury of the infraorbital nerve

Objectives Corticotropin-releasing factor (CRF)-1 receptors are involved in acute stress responses, pain enhancement under stressful conditions, activation of the hypothalamic-pituitary-adrenal system, and induction of anxiety and fear. In this study, the aim was to clarify the involvement of CRF-1 receptors in allodynia-like behavior in an animal model of trigeminal neuropathic pain.Methods Infraorbital nerve chronic constriction injury (IoN-CCI) was induced in mice by partial tight ligation of the left IoN fascicle. Head withdrawal thresholds (HWTs) were measured using mechanical and radiant-heat stimulation of the left whisker pad skin. The effects of a selective CRF-1 receptor antagonist (NBI 27914) were investigated on HWTs on Day 21 (D21) after nerve injury, and the effects of pre-injury administration of NBI on HWTs on Day 1 (D1) were examined to determine whether CRF-1 receptors are involved in the expression of allodynia-like behavior in neuropathy. The plasma corticosterone (PC) level was measured as an indicator of stress induced by trigeminal neuropathy.Results There was a high PC level and allodynia-like behavior after IoN-CCI. The elevated PC level suggests that the animals were under stress. Administration of NBI dose-dependently inhibited allodynia-like behavior, and it suppressed the PC level on D21 after nerve injury. Pre-administration of NBI also dose-dependently suppressed the increase in the PC level and the decrease in the HWT, although the effect on the HWT was short-lasting.Conclusions These findings suggest that nociceptive input acts as a stressor, and it contributes to the maintenance of allodynia-like behavior through CRF-1 receptors.