Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain

Abstract

Male Sprague-Dawley rats were used to evaluate the antinociceptive properties of the selective N-type voltage-sensitive calcium channel (VSCC) blocker, SNX-111, when the compound is administered spinally by either bolus injection or continuous, constant-rate infusion into the subarachnoid space. SNX-111 produced significant, dose-dependent antinociceptive effects by suppressing both the acute (phase 1: ED50, 14 ng/hr) and tonic (phase 2: ED50, 0.82 ng/hr) phases of the formalin test when it was infused for 72 hr immediately before testing. Phase 2 nociceptive 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 intrathecal bolus injection. In rats with an experimentally induced painful peripheral neuropathy, intrathecal bolus injections of 30 to 300 ng SNX-111 blocked mechanical allodynia in a dose-dependent manner. Subacute administration of SNX-111 (1, 10 and 100 ng/hr) by continuous intrathecal infusion produced a reversible blockade of mechanical allodynia without apparent development of tolerance. These results show that: 1) selective N-type VSCC blockers are potent and efficacious antinociceptive agents when they are administered by the spinal route; 2) selective N-type VSCC blockers are effective in rat models of acute, persistent and neuropathic pain; and 3) N-type VSCCs play a significant role in the spinal processing of noxious somatosensory input.