Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinociception in models of acute and tonic pain sensitivity
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The effects of neurotoxic destruction of descending catecholaminergic projections on cannabinoid antinociception were examined in models of acute and tonic pain sensitivity. Intrathecal 6- hydroxydopamine depleted spinal norepinephrine (by ~85%) without altering levels of dopamine or serotonin. In the tail- flick test, the antinociceptive effect of WIN55,212-2 observed in lesioned rats was attenuated relative to sham-operated rats. WIN55,212-2 suppressed tonic pain behavior in the formalin test in sham-operated rats during phase 2 (15-60 min). In lesioned rats, WIN55,212-2 suppressed pain behavior during phase 1 (0-9.9 min) and phase 2A (10-39.9 min) but not during phase 2B (40-60 min). WIN55,212-2 suppressed formalin-evoked Fos protein expression in the lumbar dorsal horn of sham-operated rats but not in lesioned rats. These data suggest that cannabinoids produce antinociception, in part, by modulating descending noradrenergic systems and support a differential involvement of noradrenergic projections to the spinal cord in cannabinoid modulation of acute versus tonic pain sensitivity.