Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system

Eur J Neurosci. 2006 Oct;24(7):2011-20. doi: 10.1111/j.1460-9568.2006.05086.x. Epub 2006 Oct 16.


We used a model of neuropathic pain consisting of rats with chronic constriction injury (CCI) of the sciatic nerve, in order to investigate whether endocannabinoid levels are altered in the dorsal raphe (DR) and to assess the effect of repeated treatment with (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate, a synthetic cannabinoid agonist, or N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404), an inhibitor of endocannabinoid reuptake, on DR serotonergic neuronal activity and on behavioural hyperalgesia. CCI resulted in significantly elevated anandamide but not 2-arachidonoylglycerol levels in the DR. Furthermore, as well as thermal and mechanical hyperalgesia, CCI caused serotonergic hyperactivity (as shown by the increase of basal activity of serotonergic neurones, extracellular serotonin levels and expression of 5-HT1A receptor gene). Repeated treatment with either (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate or AM404 reverted the hyperalgesia and enhanced serotonergic activity induced by CCI in a way attenuated by N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide, a selective cannabinoid subtype 1 (CB1) receptor antagonist. Despite the elevated levels of anandamide following CCI, N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide did not produce hyperalgesia or any other effect on serotonergic neuronal activity when administered alone. Furthermore, the effects of AM404 were not accompanied by an increase in endocannabinoid levels in the DR. In conclusion, following CCI of the sciatic nerve, the endocannabinoid and serotonergic systems are activated in the DR, where repeated stimulation of CB1 receptors with exogenous compounds restores DR serotonergic activity, as well as thermal and mechanical nociceptive thresholds, to pre-surgery levels. However, an elevated level of endogenous anandamide in the DR does not necessarily contribute to the CB1-mediated tonic control of analgesia and serotonergic neuronal activity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Analysis of Variance
  • Animals
  • Arachidonic Acids / pharmacology
  • Behavior, Animal
  • Benzoxazines
  • Cannabinoid Receptor Modulators / agonists
  • Cannabinoid Receptor Modulators / antagonists & inhibitors
  • Cannabinoid Receptor Modulators / metabolism*
  • Disease Models, Animal
  • Drug Interactions
  • Endocannabinoids*
  • Hot Temperature
  • Hyperalgesia / drug therapy
  • Hyperalgesia / physiopathology
  • Male
  • Microdialysis / methods
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Neurons / drug effects
  • Neurons / physiology
  • Pain Measurement / methods
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Raphe Nuclei / drug effects*
  • Raphe Nuclei / metabolism
  • Raphe Nuclei / pathology
  • Rats
  • Rats, Wistar
  • Reaction Time / drug effects
  • Rimonabant
  • Sciatic Neuropathy / drug therapy
  • Sciatic Neuropathy / metabolism*
  • Sciatic Neuropathy / pathology*
  • Sciatic Neuropathy / prevention & control
  • Serotonin / metabolism*
  • Touch


  • Arachidonic Acids
  • Benzoxazines
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Serotonin
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Rimonabant
  • N-(4-hydroxyphenyl)arachidonylamide