Melanocortin 4 receptor induces hyperalgesia and allodynia after chronic constriction injury by activation of p38 MAPK in DRG

Int J Neurosci. 2012 Feb;122(2):74-81. doi: 10.3109/00207454.2011.630542. Epub 2011 Nov 24.


Melanocortin 4 receptor (MC4R) is implicated in the initiation and maintenance of neuropathic pain. Although the effect of MC4R on neuropathic pain is known, it remains unclear how MC4R mediates neuropathic pain. In vitro MC4R activates mitogen-activated kinase (MAPK). Accordingly, we investigate whether MC4R activates the p38MAPK cascade in vivo to trigger pain behavior of Wistar rats after chronic constriction injury (CCI). Intrathecal injection of MC4R antagonist HS014 (5 μg/day) at the moment of CCI for seven days attenuated thermal hyperalgesia and mechanical allodynia. Similarly, intrathecal injection of a p38 inhibitor (SB203580, 10 mg/day) at the moment of CCI for seven days was also effective. To assess whether the effects of HS014 were mediated via increased p38MAPK activation, ipsilateral L4 and L5 dorsal root ganglion (DRG) were analyzed for MC4R and phosphorylated p38MAPK (p-p38MAPK) after CCI alone or CCI combined with HS014 treatment or SB203580 treatment. After CCI, DRG p-p38MAPK and MC4R were elevated by three, seven, and 14 days. Treatment with SB203580 blocked p38 activation. Both MC4R and phosphorylated p38 localized in DRG neurons. These data suggest a sequential role for MC4R and p38 in the induction and maintenance of neuropathic pain. MC4R plays an important role in the establishment of neuropathic pain following CCI, seemingly dependent on p38 activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enzyme Activation / drug effects
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism*
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / physiopathology
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use*
  • Injections, Spinal
  • Male
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Neuralgia / physiopathology
  • Peptides, Cyclic / administration & dosage
  • Peptides, Cyclic / therapeutic use*
  • Phosphorylation / drug effects
  • Pyridines / administration & dosage
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Rats
  • Rats, Wistar
  • Receptor, Melanocortin, Type 4 / antagonists & inhibitors
  • Receptor, Melanocortin, Type 4 / physiology*
  • Sciatic Nerve / injuries*
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • HS014 cyclic peptide
  • Imidazoles
  • Peptides, Cyclic
  • Pyridines
  • Receptor, Melanocortin, Type 4
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580