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

Cannabinoids suppress nociceptive processing of acute stimuli, but little is known about their effects on processes that lead to hyperexcitability of nociceptive neurons following prolonged noxious stimulation. Windup, the increasingly strong response of spinal nociceptive neurons to repetitive noxious electrical stimuli, results from a fast-rising cumulative depolarization and increase in intracellular calcium concentration. These processes produce 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 agonist WIN 55, 212-2, but not the inactive enantiomer, WIN 55,212-3, dose-dependently decreased the wind-up of spinal wide dynamic range and nociceptive-specific neurons independent of acute responses to activation of low- and high-threshold primary afferents. This is the first direct evidence that cannabinoids inhibit the activity-dependent facilitation of spinal nociceptive responses.