Fatty-acid amide hydrolase (FAAH) is an enzyme that metabolizes several endocannabinoids and fatty acid amides. A functional variant of the gene encoding FAAH, which reduces the enzymatic activity, has been associated with decreased human pain sensitivity. In addition, several preclinical studies suggest that increased activity in the endocannabinoid system by inactivating FAAH may be a promising strategy to promote antinociceptive effects.
Spinal long-term potentiation (LTP) may represent a cellular memory of nociceptive information. In the present study spinal LTP was induced by high frequency stimulation (HFS) conditioning applied to the sciatic nerve of anaesthetized rats. Extracellular field potential recordings in the spinal dorsal horn were performed to observe the expression of spinal LTP, and to examine if maintenance of spinal LTP is affected by administration of the FAAH inhibitor URB597 (0.3 or 1.0 mg/kg i.v.). Quantitative real-time RT-PCR was used to explore if HFS conditioning alone, or in combination with URB597 (1.0 mg/kg i.v.), is associated with changes in spinal dorsal horn expression of the genes encoding Zif and iNOS.
The field potential recording experiments confirmed the previous observations that sciatic HFS conditioning can induce a robust LTP. The maintenance of LTP was, however, attenuated by administration of URB597 (1.0 mg/kg i.v.). Moreover, an increase in ipsilateral dorsal horn expression of the genes encoding Zif and iNOS was observed following HFS conditioning. The dorsal horn expression of both genes was less pronounced after HFS conditioning in combination with URB597 (1.0 mg/kg i.v.).
The present data suggest that inhibition of FAAH activity, and thereby possible accumulation of endocannabinoids, attenuates expression of spinal LTP and also diminish the increase of Zif and iNOS gene expression associated with spinal LTP.