Spinal Cannabinoid Tolerance Coincided With Increased Pain Sensitivity in Mice
Repeated spinal WIN 55,212-2 administration in mice produced both antinociceptive tolerance and increased sensitivity to mechanical and thermal stimuli. Interventions targeting dynorphin-related or NMDA-related processes reduced these findings under the tested conditions.
The route was directly spinal
Mice received repeated intrathecal injections of the synthetic CB1 agonist, its inactive counterpart or vehicle. The active compound increased stimulus sensitivity over time and raised lumbar spinal dynorphin content by day five. The inactive compound and vehicle did not produce those changes.
Baseline sensitivity complicated the tolerance result
A smaller antinociceptive response can reflect more than reduced receptor responsiveness. Here, increased underlying sensitivity to stimuli potentially contributed to the apparent loss of pain-response potency. The experiment was designed to explore that possibility rather than treating tolerance as a single receptor-level event.
Interventions separated acute and repeated-exposure effects
Dynorphin antiserum and the NMDA antagonist MK-801 reversed increased sensitivity and blocked expression of antinociceptive tolerance in relevant comparisons. They did not alter acute WIN antinociception. Control serum had no effect, providing a comparison for the antiserum intervention.
The study links repeated spinal cannabinoid exposure to a pain-promoting process in a mouse model. It does not show that ordinary cannabis use causes the same syndrome in patients or establish a treatment regimen. Route, stimulus-response behavior and the distinction between baseline sensitivity and drug potency are essential to its interpretation.
Related: interpreting cannabis tolerance claims.
Research cited
Gardell LR; Burgess SE; Dogrul A; Ossipov MH; Malan TP; Lai J; Porreca F. Pronociceptive effects of spinal dynorphin promote cannabinoid-induced pain and antinociceptive tolerance. Pain (2002). doi:10.1016/s0304-3959(01)00475-4. Findings discussed from the study abstract.
