A leptin-mediated central mechanism in analgesia-enhanced opioid reward in rats

J Neurosci. 2014 Jul 16;34(29):9779-88. doi: 10.1523/JNEUROSCI.0386-14.2014.


Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1β in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management.

Keywords: conditioned place preference; leptin; nucleus accumbens; opioid; pain; reward.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / administration & dosage*
  • Animals
  • Animals, Newborn
  • Arthritis, Experimental / complications
  • Astrocytes / drug effects
  • Cerebral Cortex / cytology
  • Conditioning, Operant / drug effects
  • Conditioning, Operant / physiology
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Leptin / genetics
  • Leptin / pharmacology
  • Leptin / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Morphine / administration & dosage*
  • Mutation / genetics
  • Pain / drug therapy*
  • Pain / etiology
  • Pain Measurement / drug effects
  • Pain Threshold / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reward*


  • Analgesics, Opioid
  • Leptin
  • Morphine