In the this study we have investigated the threshold plasma concentration of
lidocaine for reversal of
mechanical 'allodynia' in a
neuropathic pain model in the rat, defined the concentration-dependent limits of that reversal and compared the acute reversal during intravenous
drug infusion with the persistent relief of
allodynia assayed 48 h later. Actions of i.v.
lidocaine on ipsilateral and contralateral legs were also assessed. Forty rats were sorted into five groups (n = 7-10) and underwent spinal root (L5-6)
ligation to produce
allodynia, as quantified by a lower force of von Frey hairs at the plantar hindpaw required to elicit paw withdrawal (PWT, paw withdrawal threshold). During surgery, intravenous
catheters were placed for programmed
lidocaine infusion and in some animals arterial
catheters were also inserted for assaying
lidocaine blood levels. PWTs were measured in ipsilateral and contralateral paws before and after
ligation and during infusions which, beginning at 5 days after surgery, were conducted every other day to incrementing levels (1.1-9.7 microg/ml plasma).
Ligation produced
allodynia in ipsilateral paws (PWT = 1.22 +/- 0.42 g (+/-SEM)) and in contralateral paws (PWT = 4.99 +/- 0.61 g), both markedly lower than pre-operative control values for either paw (11.31 +/- 0.41 g). The ipsilateral
allodynia was partially, but significantly and permanently reversed (to PWT = 6-8 g) after a
lidocaine infusion to 2.1 microg/ml in two separate groups (n = 7, 8). Lower concentrations resulted in elevation of PWT during infusion but no sustained relief. The elevation of PWT during infusion at this threshold level among individual animals was positively correlated with the relief measured 48 h later, but higher
lidocaine concentrations infused in subsequent dosings could exact no further sustained relief. The residual PWT level, after reversal by threshold
lidocaine and greater, was constant for each individual rat tested over the next 14 days but varied substantially among individuals; some were restored to pre-operative PWTs and some were totally unresponsive to
drug. Retrospective analysis revealed a significant and unanticipated correlation between the incidence of low pre-operative PWTs (< 10 g) and a lack of sustained reversal of post-operative
allodynia by
lidocaine. Contralateral
allodynia, despite its acute reversal during infusion to 2.1 microg/ml and higher, was not persistently relieved after infusion of
lidocaine to any concentration. Repeated infusions to subthreshold levels (<2 microg/ml) did not provide persisting relief of
allodynia on either side, and infusions of saline were impotent. These findings show that experimental
allodynia results from multiple factors, only some of which are sensitive to
lidocaine treatment, and that prolonged reversal of
allodynia is limited in extent and likely influenced by pre-existing factors.