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


CONCLUSIONS
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.
Department of Anesthesiology, Affiliated Hospital of Medical College, Qingdao University, China. haichen0312@yahoo.com.cn
Haichen
H
Chu
Junzhi
J
Sun
Hongmei
H
Xu
Zejun
Z
Niu
Mei
M
Xu
D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D003250:Constriction; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008845:Microinjections; D009457:Neuroglia / Q000473:pathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*; D012585:Sciatica / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors
D054369:Agouti-Related Protein; D039481:CD11b Antigen; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; C116941:HS014 cyclic peptide; C470072:MC4R protein, human; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D011333:Pro-Opiomelanocortin