Multiple phases of relief from experimental mechanical allodynia by systemic lidocaine: responses to early and late infusions.

Systemic lidocaine can relieve various forms of neuropathic pain that develop after nerve injury. Mechanical allodynia, defined by a significant drop in paw withdrawal threshold force following spinal nerve ligation (L5-L6) in rats, can be reversed by one 30min lidocaine infusion at a constant plasma concentration as low as 1-2 microg/ml, an effect that is still present when the rats are tested days and weeks afterwards. In this study, we resolved the detailed time course of reversal of ipsilateral and contralateral allodynia in rats with spinal nerve ligation by a single systemic infusion of lidocaine, to 4 microg/ml, given either 2 days after ligation (POD2) or 7 days after ligation (POD7). Male Sprague-Dawley rats were examined for 21 days after undergoing sham operation or spinal nerve ligation to produce allodynia, which was quantified by a lower force of von Frey hairs at the plantar hind paw just required to produce paw withdrawal (paw withdrawal threshold, PWT). Six experimental protocols were followed: rats were infused with lidocaine on POD2 (L2) or on POD7 (L7), or with saline on POD2 (S2) or on POD7 (S7), and sham operated rats were infused with lidocaine on POD2 or on POD7. PWTs were measured during the last 5min of a single 30min lidocaine infusion; at 30, 60, 90, 120, 240 and 360min, and 24, 48 and 72h after beginning infusion, and then every 1-3 days up to 21 days. Three distinct sequential phases of ipsilateral relief were apparent in both L2 and L7 groups: (1) an acute elevation of PWT during the infusion, returning to the pre-infusion allodynic level within 30-60min after infusion; (2) a second, transient elevation of PWT within the next 360min; (3) a sustained elevation of PWT developing slowly over 24h after infusion and maintained over the next 21 days. A significant, although weaker contralateral allodynia developed more slowly (>POD8) than the ipsilateral condition, and could be delayed for more than 2 weeks by lidocaine infusion on POD2 but for only 1 week by the same treatment on POD7. None of the sham operated animals had any allodynic signs and no saline infusions elevated PWT in ligated, allodynic rats. These results of separate phases imply that there are mechanistic differences between the acute relief and the sustained relief of allodynia after a single infusion of lidocaine, and may present an experimental paradigm for investigating the advantages of earlier rather than late therapeutic intervention.