Spinal nociceptive hypersensitivity induced by intramuscular capsaicin in rats subjected to multiple continuous stress

Persistent physical and psychological stress is highly relevant to the development of chronic muscle pain; however, the neural mechanisms underlying stress-induced hyperalgesia remain largely unknown. This study aimed to elucidate the peripheral and spinal mechanisms of stress-induced muscle hyperalgesia using a rat model developed under multiple continuous stress (MCS) by keeping rats in a cage filled with shallow water (1.5 cm in depth) for 5 or 6 days. In the MCS rats, intramuscular injection of capsaicin (300 μM, 50 μL), which activates TRPV1-positive muscular C-fiber nociceptors, increased pain-related facial expressions scored using a rat grimace scale. Intramuscular capsaicin injections induced significant c-Fos expression throughout the ipsilateral spinal dorsal horn (laminae I–VI) at segments L3–L5 in rats exposed to MCS, when compared to naïve control rats. Increased c-Fos expression was also observed on the contralateral side in the MCS group. Single-fiber electrophysiological recordings using ex vivo muscle-nerve preparations revealed that neither the general characteristics nor the responsiveness of muscular C-fibers to noxious stimuli were altered in the MCS group. These results indicate that spinal nociceptive hypersensitivity is associated with muscle pain induced by MCS. However, it is unlikely to be mediated by altered responses to muscular C-fiber nociceptors.