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.