Peripheral versus central potencies of N-type voltage-sensitive calcium channel blockers

Abstract

The ability of a series of synthetic analogues of omega-conopeptides MVIIA (SNX-111) and TVIA (SNX-185) to prevent electrically-evoked norepinephrine release from rat tail artery and hippocampal slice preparations was determined in an effort to identify voltage-sensitive calcium channel (VSCC) blockers that selectively target N-type VSCCs in central nervous system tissue. Electrical field stimulation (3 Hz, 1 ms in duration. 80 V for 1 min) caused a high and consistent tritium outflow from rat tail artery and hippocampal slice preparations preloaded with [3H]-norepinephrine. All conopeptides, chosen for their selective affinities for high-affinity SNX-111 binding sites (i.e., N-type VSCCs) over high-affinity omega-conopeptides MVIIC (SNX-230) binding sites (i.e., P/Q-type VSCCs), produced a concentration-dependent inhibition of calcium dependent electrically-evoked tritium outflow from both tail arteries and hippocampal slices: IC50s ranged from 1.2 nM to 1.2 microM. Blocking potencies (IC50s) in the tail artery assay were significantly correlated with those measured in the hippocampal slice preparation (r = 0.91, P = 0.00000012). There was a significant correlation between IC50s for blockade of hippocampal norepinephrine release and the inhibition of high-affinity [125I]-SNX-I11 binding in rat brain synaptosomes (r = 0.76, P = 0.00028). Blockade of hippocampal norepinephrine release was not significantly correlated with the inhibition of high-affinity SNX-230 binding (r = 0.46, P = 0.056). Maximum inhibition of tritium outflow in the tail artery assay was 22+/-1.4% of control, approximating the value (20.9+/-16.0% of control) obtained in the absence of extracellular Ca2+. In contrast, the maximum inhibition of tritium release from hippocampal slices was 36.8+/-2.5% of control (P < 0.05, compared to that of the tail artery assay). These results suggest that (1) N-type VSCCs alone mediate low frequency electrical stimulation-evoked neurotransmitter release from peripheral sympathetic efferents (tail artery) while both N-type and non-N type(s) mediate neurotransmitter release from CNS neurons (hippocampus); and (2) analogues of omega-conopeptides MVIIA and TVIA do not differentiate between N-type VSCCs mediating norepinephrine release from central and peripheral neural tissues.

Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel–CRMP-2 signaling complex

“…Unlike release from other synapses, which can involve multiple calcium channel subtypes, norephinephrine release from sympathetic neurons is mostly dependent upon the N-type channel. 13,14 Indeed, Ziconotide inhibits sympathetic norephinephrine release, 15 which is likely the mechanism underlying decreases in sympathetic tone observed during treatment. 10,16 In contrast, i.p.…”

Drug Targets in the Voltage-Gated Calcium Channel Family: Why Some Are and Some Are Not

“…106 These divergent results indicate the difficulties in working with different nerve injury models. Finally, gabapentin, an agent introduced originally as a GABA-like anticonvulsant, but subsequently demonstrated to be effective both preclinically and clinically in neuropathic pain and believed to interact directly at the a 2 d subunit, 16,107 has been shown to be effective only in those models of neuropathic pain that are accompanied by an up-regulation of the a 2 d 1 subunit. 104 Limitations exist for the definition of Ca V 2.2 as a target for pain therapy.…”

Conus Venom Peptide Pharmacology

“…Based on the behav- Woppmann et al, 1994; Wang et al, 1998 Fainzilber et al, 1996 P, fish; M, molluscs; V, worms; *, C-terminal amidation; N.D., not determined.…”