The transition from naïve to primed nociceptive state: A novel wind-up protocol in mice

Wind-up (WU) is a progressive, frequency-dependent facilitation of spinal cord neurons in response to repetitive nociceptive stimulation of constant intensity. We identified a new WU-associated phenomenon in naïve mice (not exposed to noxious stimulation immediately prior to WU stimulation), which were subjected to a novel experimental protocol composed of three consecutive trains of WU stimulation. The 1st train produced a typical linear 'wind-up' curve as expected following a repeating series of stimuli; in addition, this 1st train sensitized ('primed') the nociceptive system so that the responses to two subsequent trains (inter-train interval of 10 min) were significantly amplified compared with the response to the 1st train. We named this augmented response potentiation-of-windup, or "PoW". The PoW phenomenon appears to be centrally mediated, as the augmented response was suppressed by administration of an NMDA receptor antagonist (MK-801) and by cutting the spinal cord. Furthermore, the PoW protocol is accompanied by enhanced pain behavior. The 'priming' effect of the 1st train could be mimicked by exposure to natural noxious stimuli prior to the PoW protocol. Presumably, the PoW phenomenon has not been previously reported due to a procedural reason: typically, WU protocols have been executed in 'primed' rather than naïve animals, i.e., animals exposed to nociceptive stimulation prior to the actual WU recording. Our findings indicate that the PoW paradigm can distinguish between 'naïve' and 'primed' states, suggesting its use as a tool for the assessment of central sensitization.