Administration de [6]-gingérol intrathécal pour le traitement de la douleur neuropathique chez le rat mâle Sprague-Dawley
[6]-Gingerol is a structural analog of capsaicin, an agonist of the transient receptor potential channel vanilloid 1, which is known to have therapeutic properties for the treatment of pain. Based on this premise, this research project had two main objectives. The first objective was to establish a better characterization of [6]-gingerol metabolism in rat. A selective and sensitive method for the quantification of [6]-gingerol and its metabolites by HPLC-ESI/MS/MS was first developed. An in vitro metabolic stability study using rat liver microsomes was then performed. The results show slow degradation with a T1/2 of 163 min and a relatively low intrinsic clearance of 0.0043 mL/min. Further analyses were performed to characterize in vitro and in vivo metabolites. Three main phase I metabolites and four phase II metabolites were identified by HPLC-MS/MS and HPLC-MSD TOF. The results suggest that glucuronidation of hydroxylated [6]-gingerol is the primary metabolite excreted in urine. The second objective of this study was to determine the central effect of [6]-gingerol on neuropathic pain when injected intrathecally at the level of the lumbar spinal cord. [6]-Gingerol distribution was evaluated following a 40 mg/kg intraperitoneal injection, and the brain-to-plasma and spinal cord-to-plasma ratios (0.73 and 1.7, respectively) suggest that [6]-gingerol has a good distribution in the central nervous system of rats. Induction of pain was performed using the sciatic nerve ligation model on rats. Following the surgery, a 10-µg intrathecal injection of [6]-gingerol was performed to evaluate its central effect. The results suggest a significant decrease of secondary mechanical allodynia assessed with the Von Frey filaments after 30 min, 2 h and 4 h (p < 0.05, p < 0.01 and p < 0.001) and thermal hyperalgesia assessed with the Hargreave’s test after 30 min, 2 h and 4 h (p < 0.05, p < 0.01 and p < 0.01).  In conclusion, [6]-gingerol has a good distribution in the central nervous system of rats, suggesting a possible interaction with the TRPV1 receptors. [6]-Gingerol could therefore alleviate neuropathic pain by acting centrally at the level of the spinal cord and be an interesting alternative to the traditional molecules currently used in pain management.
Rats Metabolism Mass spectrometry Neuropathic pain Pharmacokinetics