Melanocortin 4 Receptor Induces Hyperalgesia and Allodynia After Chronic Constriction Injury by Activation of p38 MAPK in DRG

Abstract

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.

Melanocortin type 4 receptor–mediated inhibition of A-type K+ current enhances sensory neuronal excitability and mechanical pain sensitivity in rats

“…As such, it is reasonable to infer that the nociceptive effects of MC4R activation are mediated, partially if not completely, through its inhibition of I A . Indeed, our present results are in line with previous in vivo studies indicating that antagonism of MC4R reduces the CCI-induced allodynia in rodents (9,55,56), whereas activation of MC4R causes hyperalgesia in various pain models (6 -8). Nevertheless, potential channel targets other than A-type channels can also be activated by the MC4R pathway.…”

Letter to the Editor: Melanocortin 4 Receptor Antagonists and Their Emerging Role in Pain Management

“…Richmond, Virginia, USA I read withgreat interest the recent article by Chu et al in a recent issue of your esteemed journal [1]. The article is highly thought provoking.…”

Motor Cortex-Periaqueductal Gray-Spinal Cord Neuronal Circuitry May Involve in Modulation of Nociception: A Virally Mediated Transsynaptic Tracing Study in Spinally Transected Transgenic Mouse Model

“…It is well known that MC4R exerts a wide variety of functions with paramount importance in brain physiology. Recent studies have shown that MC4R played an important role in nociceptive behavior induced by nerve injury[11], and spinal MC4R may participate in regulation of central sensitization and morphine tolerance[24], [25]. Substantial evidence shows that PAG and rostral ventromedial medulla (RVM) are the key areas in descending nociceptive modulation and takes part in the transmission of spinal nociceptive information[9], [26], [27].…”

“…A previous report considered that the main cause of motor cortex stimulation- induced antinociception was due to opioid participation in PAG[8]. However, recent evidence indicated that melanocortinergic signaling in spinal cord and PAG played an important role in neuropathic pain[9]–[11].…”