The analgesic action of nitrous oxide is dependent on the release of norepinephrine in the dorsal horn of the spinal cord

Anesthesiology. 1999 Nov;91(5):1401-7. doi: 10.1097/00000542-199911000-00033.


Background: The authors and others have demonstrated that supraspinal opiate receptors and spinal alpha2 adrenoceptors are involved in the analgesic mechanism for nitrous oxide (N2O). The authors hypothesize that activation of opiate receptors in the periaqueductal gray results in the activation of a descending noradrenergic pathway that releases norepinephrine onto alpha2 adrenoceptors in the dorsal horn of the spinal cord.

Methods: The spinal cord was transected at the level of T3-T4 in rats and the analgesic response to 70% N2O in oxygen was determined by the tail flick latency test. In a separate experiment in rats a dialysis fiber was positioned transversely in the dorsal horn of the spinal cord at the T12 level. The following day, the dialysis fiber was infused with artificial cerebrospinal fluid at a rate of 1.3 microl/min, and the effluent was sampled at 30-min intervals. After a 60-min equilibration period, the animals were exposed to 70% N2O in oxygen. The dialysis experiment was repeated in animals that were pretreated with naltrexone (10 mg/kg, intraperitoneally) before N2O. In a third series, spinal norepinephrine was depleted with n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine (DSP-4), and the analgesic response to 70% N2O in oxygen was determined.

Results: The analgesic effect of N2O was prevented by spinal cord transection. After exposure to N2O, there was a fourfold increase in norepinephrine released in the first 30-min period, and norepinephrine was still significantly elevated after 1 h of exposure. The increased norepinephrine release was prevented by previous administration of naltrexone. Depletion of norepinephrine in the spinal cord blocked the analgesic response to N2O.

Conclusions: A descending noradrenergic pathway in the spinal cord links N2O-induced activation of opiate receptors in the periaqueductal gray, with activation of alpha2 adrenoceptors in the spinal cord. N2O-induced release of norepinephrine in the dorsal horn of the spinal cord is blocked by naltrexone, as is the analgesic response. Spinal norepinephrine is necessary for the analgesic response to the N2O.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Non-Narcotic / antagonists & inhibitors
  • Analgesics, Non-Narcotic / pharmacology*
  • Animals
  • Benzylamines / administration & dosage
  • Benzylamines / pharmacology
  • Chromatography, Ion Exchange
  • Cordotomy
  • Injections, Spinal
  • Male
  • Microdialysis
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Neurotransmitter Uptake Inhibitors / administration & dosage
  • Neurotransmitter Uptake Inhibitors / pharmacology
  • Nitrous Oxide / antagonists & inhibitors
  • Nitrous Oxide / pharmacology*
  • Norepinephrine / metabolism*
  • Pain Measurement
  • Posterior Horn Cells / drug effects
  • Posterior Horn Cells / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-2 / drug effects
  • Receptors, Opioid / drug effects
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism*


  • Analgesics, Non-Narcotic
  • Benzylamines
  • Narcotic Antagonists
  • Neurotransmitter Uptake Inhibitors
  • Receptors, Adrenergic, alpha-2
  • Receptors, Opioid
  • Naltrexone
  • Nitrous Oxide
  • DSP 4
  • Norepinephrine