Peripheral nerve injury reduces analgesic effects of systemic morphine via spinal 5-hydroxytryptamine 3 receptors

Anesthesiology. 2014 Aug;121(2):362-71. doi: 10.1097/ALN.0000000000000324.


Background: Morphine produces powerful analgesic effects against acute pain, but it is not effective against neuropathic pain, and the mechanisms underlying this reduced efficacy remain unclear. Here, the authors compared the efficacy of systemic morphine between normal rats and rats with peripheral nerve injury, with a specific focus on descending serotonergic mechanisms.

Methods: After L5 spinal nerve ligation injury, male Sprague-Dawley rats were subjected to behavioral testing, in vivo microdialysis of the spinal dorsal horn to determine serotonin (5-hydroxytryptamine [5-HT]) and noradrenaline release, and immunohistochemistry (n = 6 in each group).

Results: Intraperitoneal administration of morphine (1, 3, or 10 mg/kg) produced analgesic effects in normal and spinal nerve ligation rats, but the effects were greater in normal rats (P < 0.001). Morphine increased 5-HT release (450 to 500% of the baseline), but not noradrenaline release, in the spinal dorsal horn via activation of serotonergic neurons in the rostral ventromedial medulla. Intrathecal pretreatment with ondansetron (3 μg), a 5-HT3 receptor antagonist, or 5,7-dihydroxytryptamine creatinine sulfate (100 μg), a selective neurotoxin for serotonergic terminals, attenuated the analgesic effect of morphine (10 mg/kg) in normal rats but increased the analgesic effect of morphine in spinal nerve ligation rats (both P < 0.05).

Conclusions: Systemic administration of morphine increases 5-HT levels in the spinal cord, and the increase in 5-HT contributes to morphine-induced analgesia in the normal state but attenuates that in neuropathic pain through spinal 5-HT3 receptors. The plasticity of the descending serotonergic system may contribute to the reduced efficacy of systemic morphine in neuropathic pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • Immunohistochemistry
  • Injections, Intraperitoneal
  • Injections, Spinal
  • Male
  • Microdialysis
  • Morphine / pharmacology*
  • Norepinephrine / metabolism
  • Ondansetron / administration & dosage
  • Ondansetron / pharmacology
  • Pain Measurement / drug effects
  • Pain Threshold / drug effects
  • Peripheral Nerve Injuries / physiopathology*
  • Posterior Horn Cells / drug effects
  • Posterior Horn Cells / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin, 5-HT3 / drug effects*
  • Serotonin / metabolism
  • Serotonin Antagonists / administration & dosage
  • Serotonin Antagonists / pharmacology
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / physiopathology*


  • Analgesics, Opioid
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • Serotonin
  • Ondansetron
  • Morphine
  • Norepinephrine