Thermal sensitivity as a measure of spontaneous morphine withdrawal in mice

J Pharmacol Toxicol Methods. May-Jun 2013;67(3):162-8. doi: 10.1016/j.vascn.2013.02.003. Epub 2013 Feb 14.


Introduction: Opioid withdrawal syndrome is a critical component of opioid abuse and consists of a wide array of symptoms including increases in pain sensitivity (hyperalgesia). A reliable preclinical model of hyperalgesia during opioid withdrawal is needed to evaluate possible interventions to alleviate withdrawal. The following study describes a method for assessing increases in thermal sensitivity on the hotplate in a mouse model of spontaneous morphine withdrawal.

Methods: C57BL/6J mice received 5.5days of 30, 56, or 100mg/kg morphine or saline (s.c., twice daily). In Experiment I, thermal sensitivity data were collected at baseline and at 8, 24, 32, 48h and 1week following the final injection. Thermal sensitivity was assessed by examining latency to respond on a hotplate across a range of temperatures (50, 52, 54, and 56°C). In Experiment II, 0.01mg/kg buprenorphine was administered 30min prior to each testing session during the withdrawal period. In Experiment III, jumping during a 30min period was assessed at baseline and at 0, 8, 24, 32, and 48h following the final morphine injection.

Results: During the withdrawal period, thermal sensitivity increased significantly in all morphine-treated mice as compared to saline-treated mice. Thermal sensitivity was greater in mice treated with 56mg/kg morphine compared to 30mg/kg and peaked earlier than in mice treated with 100mg/kg (32h v 1wk). The increase in thermal sensitivity following 56mg/kg morphine was attenuated by a dose of buprenorphine that did not produce antinociception alone (i.e., 0.01mg/kg). In general, the results of the jumping experiment paralleled those obtained in Experiment I.

Discussion: Response latency on the hotplate is a reliable and sensitive measure of spontaneous morphine withdrawal in mice, making it an ideal behavior for assessing the potential of medications and environmental interventions to alleviate opioid withdrawal.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Buprenorphine / pharmacology
  • Hot Temperature
  • Hyperalgesia / etiology*
  • Hyperalgesia / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morphine / toxicity*
  • Narcotic Antagonists / pharmacology
  • Pain Threshold / physiology
  • Substance Withdrawal Syndrome / complications*
  • Substance Withdrawal Syndrome / physiopathology*


  • Narcotic Antagonists
  • Buprenorphine
  • Morphine