Cannabinoid WIN 55,212-2 inhibits the activity-dependent facilitation of spinal nociceptive responses

Cannabinoids suppress nociceptive processing of acute stimuli, but little i s known about their effects on processes that lead to hyperexcitability of nociceptive neurons following prolonged noxious stimulation. Windup, the in creasingly strong response of spinal nociceptive neurons to repetitive noxi ous electrical stimuli, results from a fast-rising cumulative depolarizatio n and increase in intracellular calcium concentration. These processes prod uce central sensitization, the increased excitability of spinal nociceptive neurons that contributes to the hyperalgesia and allodynia associated with chronic pain. Intravenous injection of the potent, synthetic cannabinoid a gonist WIN 55, 212-2, but not the inactive enantiomer, WIN 55,212-3, dose-d ependently decreased the wind-up of spinal wide dynamic range and nocicepti ve-specific neurons independent of acute responses to activation of low- an d high-threshold primary afferents. This is the first direct evidence that cannabinoids inhibit the activity-dependent facilitation of spinal nocicept ive responses.