COMPARABLE DOSE-DEPENDENT INHIBITION OF AP-7 SENSITIVE STRYCHNINE-INDUCED ALLODYNIA AND PAW PINCH-INDUCED NOCICEPTION BY MEXILETINE IN THE RAT

The blockade of spinal glycine receptors with intrathecal (i.t.) stryc hnine produces segmentally-localized allodynia in the rat; a reversibl e and highly reproducible effect that is attained without peripheral o r central nerve injury. We investigated the effect of i.v. mexiletine, an orally active congener of lidocaine, on strychnine allodynia and c ompared the dose response relationship of mexiletine in normal (noxiou s paw pinch) versus abnormal (i.t. strychnine) nociceptive conditions. In addition, we determined the dose-response effect of i.t. AP-7 (an NMDA antagonist) on strychnine allodynia. Male, Sprague-Dawley rats, f itted with chronic i.t. catheters, were Lightly anesthetized with uret hane. Stimulus evoked changes in blood pressure and heart rate were re corded from the left carotid artery and cortical electroencephalograph ic (EEG) activity was continuously monitored using subdermal needle el ectrodes. After i.t. strychnine (40 mu g), repetitive brushing of the hair (hair deflection) evoked a progressive increase in mean arterial pressure and heart rate, an abrupt motor withdrawal response, and desy nchronization of the EEG, equivalent to those elicited by the chemical nociceptive agent, mustard oil (without strychnine). Pretreatment wit h mexiletine (5-30 mg/kg i.v. 5 min before i.t. strychnine) dose-depen dently inhibited the responses evoked by noxious hind paw pinch (no st rychnine) and hair deflection (after i.t. strychnine) with equal poten cy (ED50's = 9.1-17 mg/kg). Below 30 mg/kg, this effect was achieved w ithout a change in EEG synchrony (cortical activity reflecting the lev el of anesthesia) and without affecting motor efferent pathways. Stryc hnine allodynia was also significantly blocked by i.t. AP-7. The ED50' s and 95% confidence intervals were 1.1 mu g (0.7-1.8) for mean arteri al pressure, 1.7 mu g (0.5-6.0) for heart rate, and 0.4 mu g (0.07-2.0 ) for withdrawal duration. Cortical EEG synchrony was unchanged after i.t. AP-7 consistent with a spinal site of action. The data indicate t hat. (i) robust allodynia can be selectively induced with i.t. strychn ine in animals whose somatosensory systems are otherwise normal; (ii) sub-anesthetic doses of i.v. mexiletine inhibit the abnormal responses to low-threshold (A-fiber) afferent input in the strychnine model of allodynia (i.e., in the absence of peripheral or central nerve injury) at doses which affect normal nociception; and (iii) in the presence o f i.t. strychnine, low-threshold afferent input activates a spinal NMD A-receptor mediated process normally restricted to noxious afferent in put. Systemic mexiletine may have an important spinal site of action i n abnormal pain stales. (C) 1997 International Association for the Stu dy of Pain. Published by Elsevier Science B.V.