SELECTIVE N-TYPE NEURONAL VOLTAGE-SENSITIVE CALCIUM-CHANNEL BLOCKER, SNX-111, PRODUCES SPINAL ANTINOCICEPTION IN RAT MODELS OF ACUTE, PERSISTENT AND NEUROPATHIC PAIN

Male Sprague-Dawley rats were used to evaluate the antinociceptive pro perties of the selective N-type voltage-sensitive calcium channel (VSC C) blocker, SNX-111, when the compound is administered spinally by eit her bolus injection or continuous, constant-rate infusion into the sub arachnoid space. SNX-111 produced significant, dose-dependent antinoci ceptive effects by suppressing both the acute (phase 1: ED(50), 14 ng/ hr) and tonic (phase 2: ED(50), 0.82 ng/hr) phases of the formalin tes t when it was infused for 72 hr immediately before testing. Phase 2 no ciceptive responses were suppressed by bolus injections of 100 ng SNX- 111. SNX-111 was approximately 1000-fold more potent than morphine in blocking phase 2 responses when the compounds were administered by int rathecal bolus injection. In rats with an experimentally induced painf ul peripheral neuropathy, intrathecal bolus injections of 30 to 300 ng SNX-111 blocked mechanical allodynia in a dose-dependent manner. Suba cute administration of SNX-111 (1, 10 and 100 ng/hr) by continuous int rathecal infusion produced a reversible blockade of mechanical allodyn ia without apparent development of tolerance. These results show that: 1) selective N-type VSCC blockers are potent and efficacious antinoci ceptive agents when they are administered by the spinal route; 2) sele ctive N-type VSCC blockers are effective in rat models of acute, persi stent and neuropathic pain; and 3) N-type VSCCs play a significant rol e in the spinal processing of noxious somatosensory input.