The distribution of [125I]omega-conotoxin GVIA binding sites, the putative voltage-sensitive calcium channels, was studied by an autoradiographic method in the rat brain. The toxin binding sites were distributed throughout the brain in a highly heterogeneous manner. The highest density of the binding sites was observed in the cerebral cortex, hippocampus, amygdaloid complex, substantia nigra, caudate putamen, superior colliculus, nucleus of the solitary tract, and the dorsal horn of the cervical spine. The glomerular layer of the olfactory bulb, molecular layer of the cerebellar cortex, and posterior lobe of the hypophysis showed intermediate density but the density was higher than in the surrounding areas. The globus pallidus, thalamic areas, inferior olive, and pontine nuclei showed low density, while no binding sites were observed in the white matter tract regions such as the internal and external capsule, corpus callosum, fimbria of the hippocampus, fornix, stria medullaris of the thalamus, and fasciculus retroflexus. This distribution of omega-conotoxin binding sites indicates that the toxin binding sites are localized in those areas of the brain enriched in synaptic connections. This distribution pattern resembles that reported for voltage-sensitive sodium channels but it differs from that of the binding sites of dihydropyridines and verapamil. These results suggest that omega-conotoxin recognizes different molecules from organic calcium channel antagonist binding sites and that omega-conotoxin-sensitive voltage-sensitive calcium channels are concentrated in the synaptic zones and play a key role in the excitation-secretion coupling of neurotransmitters.
"All VGCC isoforms are expressed in the dorsal horn of the spinal cord, as demonstrated in immunocytochemical and electrophysiological studies [40,41,42,43,44]. Using subtype-specific antibodies and peptides in immunohistochemical and audioradiographic studies, respectively, expression of N-type channels was shown to be localized to presynaptic nerve terminals of neurons terminating in laminae I and II [45,46]. Voltage-dependence of activation and rate of inactivation of the N-type VGCCs are intermediate, as compared to other VGCC subtypes. "
[Show abstract][Hide abstract] ABSTRACT: Neuropathic pain afflicts a large percentage of the global population. This form of chronic, intractable pain arises when the peripheral or central nervous systems are damaged, either directly by lesion or indirectly through disease. The comorbidity of neuropathic pain with other diseases, including diabetes, cancer, and AIDS, contributes to a complex pathogenesis and symptom profile. Because most patients present with neuropathic pain refractory to current first-line therapeutics, pharmaceuticals with greater efficacy in pain management are highly desired. In this review we discuss the growing application of ω-conotoxins, small peptides isolated from Conus species, in the management of neuropathic pain. These toxins are synthesized by predatory cone snails as a component of paralytic venoms. The potency and selectivity with which ω-conotoxins inhibit their molecular targets, voltage-gated Ca2+ channels, is advantageous in the treatment of neuropathic pain states, in which Ca2+ channel activity is characteristically aberrant. Although ω-conotoxins demonstrate analgesic efficacy in animal models of neuropathic pain and in human clinical trials, there remains a critical need to improve the convenience of peptide drug delivery methods, and reduce the number and severity of adverse effects associated with ω-conotoxin-based therapies.
"Intrathecal delivery of N-type, but not L-or P-type, VGCC antagonists suppresses allodynia in neuropathic rat models (Chaplan et al., 1994; Calcutt and Chaplan, 1997). Autoradiographic studies showed the highest density of N-VGCC in the spinal dorsal horn (lamina I and II) where primary afferents terminate (Kerr et al., 1988; Takemura et al., 1989). N-VGCCs are also found in dorsal root ganglion (DRG) neurons where they are differentially modulated after sciatic nerve damage (Abdulla and Smith, 1997). "
[Show abstract][Hide abstract] ABSTRACT: The present study was undertaken to investigate the role of spinal voltage-dependent calcium channel alpha(2)delta-1 subunit in the expression of a neuropathic pain-like state induced by partial sciatic nerve ligation in mice. In cultured spinal neurons, gabapentin (GBP), which displays the inhibitory effect of alpha(2)delta-1 subunit, suppressed the extracellular Ca(2+) influx induced by KCl, whereas it failed to inhibit the intracellular Ca(2+) release induced by inositol-1,4,5-triphosphate. Seven days after sciatic nerve ligation, the protein level of alpha(2)delta-1 subunit in the ipsilateral spinal cord was clearly increased compared to that observed in sham-operated mice. In addition, the mRNA level of alpha(2)delta-1 subunit was significantly increased in the dorsal root ganglion, but not in the spinal cord, of nerve-ligated mice. Under these conditions, a marked decrease in the latency of paw-withdrawal against a thermal stimulation and tactile stimulation, induced by sciatic nerve ligation was abolished by repeated intrathecal (i.t.) treatment with GBP. Additionally, the persistent reduction in the nociceptive threshold by i.t. treatment with GBP at the early stage of the neuropathic pain-like state was maintained for 7 days even after GBP withdrawal. It is of interest to note that a single i.t. post-injection of GBP showed a marked and transient inhibitory effect on the developed neuropathic pain-like state, whereas repeated i.t. post-treatment with GBP produced a persistent inhibitory effect during the treatment. In conclusion, we propose here that the neuropathic pain-like state with sciatic nerve ligation is associated with the increased level of the alpha(2)delta-1 subunit of Ca(2+) channels at the sensory nerve terminal in the spinal dorsal horn of mice. Furthermore, the present data provide evidence that the neuropathic pain may be effectively controlled by repeated treatment with GBP at the early stage.
Life Sciences 06/2007; 80(22):2015-24. DOI:10.1016/j.lfs.2007.02.045 · 2.70 Impact Factor
"Intrathecal delivery of N-type (conopeptides ), but not L-or P-type, VGCC antagonists suppresses allodynia in neuropathic rat models (Chaplan et al., 1994b; Calcutt and Chaplan, 1997). Autoradiographic studies showed the highest density of conopeptide-binding sites in the spinal dorsal horn (lamina I and II) where primary afferents terminate (Kerr et al., 1988; Takemura et al., 1989). N-VGCCs are also found in dorsal root ganglion (DRG) neurons where they are differentially modulated after sciatic nerve damage (Abdulla and Smith, 1997). "
[Show abstract][Hide abstract] ABSTRACT: Peripheral nerve injury can lead to a persistent neuropathic pain state in which innocuous tactile stimulation elicits pain behavior (tactile allodynia). Spinal administration of the anticonvulsant gabapentin suppresses allodynia by an unknown mechanism. In vitro studies indicate that gabapentin binds to the alpha(2)delta-1 (hereafter referred to as alpha(2)delta) subunit of voltage-gated calcium channels. We hypothesized that nerve injury may result in altered alpha(2)delta subunit expression in spinal cord and dorsal root ganglia (DRGs) and that this change may play a role in neuropathic pain processing. Using a rat neuropathic pain model in which gabapentin-sensitive tactile allodynia develops after tight ligation of the left fifth and sixth lumbar spinal nerves, we found a >17-fold, time-dependent increase in alpha(2)delta subunit expression in DRGs ipsilateral to the nerve injury. Marked alpha(2)delta subunit upregulation was also evident in rats with unilateral sciatic nerve crush, but not dorsal rhizotomy, indicating a peripheral origin of the expression regulation. The increased alpha(2)delta subunit expression preceded the allodynia onset and diminished in rats recovering from tactile allodynia. RNase protection experiments indicated that the DRG alpha(2)delta regulation was at the mRNA level. In contrast, calcium channel alpha(1B) and beta(3) subunit expression was not co-upregulated with the alpha(2)delta subunit after nerve injury. These data suggest that DRG alpha(2)delta regulation may play an unique role in neuroplasticity after peripheral nerve injury that may contribute to allodynia development.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2001; 21(6):1868-75. · 6.34 Impact Factor
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