Effect of periaqueductal gray melanocortin 4 receptor in pain facilitation and glial activation in rat model of chronic constriction injury

Objectives: Substantial evidence shows that spinal melanocortin 4 receptor (MC4R) may participate in regulation of central sensitization and chronic pain condition induced by peripheral nerve injury. Periaqueductal gray (PAG) is an important component of descending pain facilitatory system and takes part in spinal nociceptive information. This research will choose PAG to discuss the effect of MC4R in pain facilitation induced by chronic constriction injury (CCI) and further discuss its effect in glial activity and inflammatory factor levels in nerve injury. Methods: Behavior tests (von Frey test and hot-plate test), semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemistry were used in this research. Results: PAG injection of HS014 (a selective inhibitor of MC4R), not only significantly reduced the established mechanical allodynia and thermal hyperalgesia, but also delayed the development of pain facilitation. Semi-quantitative RT-PCR analysis revealed that MC4R and proopiomelanocortin (POMC) expression in PAG was significantly increased after CCI, but agouti-related protein (AgRP) expression decreased. Immunohistochemistry analysis showed that protein levels of astrocytic marker (GFAP), microglial marker (OX-42), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were significantly increased, but there was little change of the protein levels of IL-10 following CCI. Furthermore, blockade of MC4R decreased immunoreactivity of glia cells and protein levels of pro-inflammatory cytokines, and increased protein levels of anti-inflammatory cytokine IL-10 after CCI. Discussion: This research suggests that activation of MC4R in PAG after peripheral nerve injury participates in pain facilitation by regulating the glial activation and inflammatory cytokines secretion.