Intra-cerebral and intra-nasal melanocortin-4 receptor antagonist blocks withdrawal hyperalgesia in alcohol-dependent rats

Addict Biol. 2017 May;22(3):692-701. doi: 10.1111/adb.12360. Epub 2016 Jan 24.


Humans diagnosed with alcohol use disorder are more sensitive to painful stimuli during withdrawal, which suggests that excessive alcohol drinking worsens pain outcomes. Alcohol-dependent rats exhibit increases in nociceptive sensitivity during withdrawal. Data from animal models suggest that brain melanocortin-4 receptors (MC4Rs) mediate alcohol drinking and nociception. Here we tested: (1) the effect of alcohol dependence on thermal nociception in rats, and (2) the ability of acute alcohol and (3) MC4R antagonists to reverse hyperalgesia during withdrawal in alcohol-dependent rats. Rats were trained to self-administer operant alcohol and were tested for baseline thermal nociception. Half of the rats were made dependent on alcohol, then all rats were cannulated in the lateral ventricle. We tested the effects of acute alcohol drinking, acute fixed-dose alcohol, intra-ventricular agouti-related protein (endogenous MC4R antagonist), intra-ventricular HS014 (synthetic MC4R antagonist) and intra-nasal HS014 on hyperalgesia during withdrawal in alcohol-dependent rats, relative to non-dependent drinkers and alcohol-naïve controls. Alcohol-dependent rats exhibit thermal hyperalgesia that is abolished by alcohol drinking, bolus alcohol and intra-ventricular and intra-nasal MC4R antagonists. These manipulations did not affect thermal nociception in non-dependent drinkers and alcohol-naïve controls, suggesting that alcohol dependence produces neuroadaptations in brain MC4R systems. These results suggest that brain MC4R systems may be an effective therapeutic target for reducing nociception in the alcohol-dependent organism.

Keywords: alcohol dependence; hargreaves; hyperalgesia; intranasal; melanocortins; pain.

MeSH terms

  • Administration, Intranasal
  • Alcoholism / complications*
  • Animals
  • Brain / drug effects*
  • Disease Models, Animal
  • Hyperalgesia / complications
  • Hyperalgesia / drug therapy*
  • Male
  • Nociception / drug effects
  • Peptides, Cyclic / pharmacology*
  • Rats, Wistar
  • Receptor, Melanocortin, Type 4 / antagonists & inhibitors*
  • Substance Withdrawal Syndrome / drug therapy*


  • HS014 cyclic peptide
  • Peptides, Cyclic
  • Receptor, Melanocortin, Type 4