Actions of intrathecal ω-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat

Scott, David A.; Wright, Christine E.; Angus, James A.

doi:10.1016/s0014-2999(02)02247-1

Cited by 170 publications

(150 citation statements)

References 23 publications

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“…It has been shown that pharmacological blockade or gene knock-out of N-type calcium channels does not affect acute pain processing in tail-flick assays (Saegusa et al, 2001;Scott et al, 2002). To confirm the specificity of our siRNA constructs, we conducted tail-flick assays on animals injected with siRNA[a], siRNA [b], or siRNA[a ϩ b].…”

Section: Resultsmentioning

confidence: 99%

“…In the dorsal horn of the spinal cord, these channels control the release of glutamate and neuropeptides such as substance P (Smith et al, 2002), thereby supporting pain transmission via afferent A␤, A␦, and C fibers to neurons projecting to the thalamus (Krarup, 2003). Consequently, inhibition of N-type channels via activation of opioid receptors or by N-type channel antagonists mediates analgesia in animals and humans (Hu et al, 1999;Scott et al, 2002;Seko et al, 2002;Staats et al, 2004). Moreover, Ca V 2.2 channel knock-out mice have decreased pain responses in models of neuropathic and inflammatory pain (Hatakeyama et al, 2001;Kim et al, 2001;Saegusa et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Differential Role of N-Type Calcium Channel Splice Isoforms in Pain

Altier¹,

Dale²,

Kisilevsky³

et al. 2007

Journal of Neuroscience

148

144

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N-type calcium channels are essential mediators of spinal nociceptive transmission. The core subunit of the N-type channel is encoded by a single gene, and multiple N-type channel isoforms can be generated by alternate splicing. In particular, cell-specific inclusion of an alternatively spliced exon 37a generates a novel form of the N-type channel that is highly enriched in nociceptive neurons and, as we show here, downregulated in a neuropathic pain model. Splice isoform-specific small interfering RNA silencing in vivo reveals that channels containing exon 37a are specifically required for mediating basal thermal nociception and for developing thermal and mechanical hyperalgesia during inflammatory and neuropathic pain. In contrast, both N-type channel isoforms (e37a-and e37b-containing) contribute to tactile neuropathic allodynia. Hence, exon 37a acts as a molecular switch that tailors the channels toward specific roles in pain.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Role of N-Type Calcium Channel Splice Isoforms in Pain

Altier¹,

Dale²,

Kisilevsky³

et al. 2007

Journal of Neuroscience

148

144

View full text Add to dashboard Cite

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“…Ziconotide (Prialt), discovered in the venom of fishkilling marine snails [155], was demonstrated to be a potent antihyperpathic agent in rodents and humans after intrathecal delivery as a bolus or an infusion [156][157][158][159]. Ziconotide was observed to be a highly selective ligand blocking the N-type voltage-sensitive calcium channel (VSCC) [160].…”

Section: Spinal Antagonistsmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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“…51) In contrast, ziconotide or w-conotoxin MVIIA, when injected intrathecally at higher doses that elicit marked antinociceptive effects, produces side-effects, including serpentine-like tail movement, whole body shaking, or allodynia. 4,5,33,52,53) For example, Chen et al showed that w-conotoxin MVIIA, when intrathecally injected at 0.1, 0.5, and 1.0 mg/kg, dose-dependently suppressed formalin-induced nociception in rats. 53) Intrathecal w-conotoxin MVIIA at 1.0 mg/kg, however, caused whole body shaking and tail movement.…”

Section: 237-41)mentioning

confidence: 99%

Suppression of Formalin-Induced Nociception by Cilnidipine, a Voltage-Dependent Calcium Channel Blocker

Koganei

Shoji

Iwata

2009

Biological & Pharmaceutical Bulletin

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Cilnidipine is a 1,4-dihydropyridine-derived voltage-dependent calcium channel (VDCC) blocker and suppresses N-type VDCC currents in addition to L-type VDCC currents. An earlier investigation has suggested that intrathecally injected cilnidipine produces antinociception by blocking N-type VDCCs in mice. The present study using the rat formalin model examined antinociceptive effects of intrathecally and orally administered cilnidipine to elucidate a putative site of antinociception of cilnidipine, assess the efficacy of oral cilnidipine for pain relief, and clarify the mechanism(s) responsible for the antinociceptive effect of oral cilnidipine. Cilnidipine (whether intrathecal or oral) suppressed nociception in phases 1 and 2 of the formalin model. In addition, the potency of oral cilnidipine to suppress formalin-induced nociception in phase 2 was greater than that of oral gabapentin, a clinically available drug for treatment of neuropathic pain. Cilnidipine elicited antinociceptive effects without neurological side-effects including serpentine-like tail movement, whole body shaking, and allodynia. Such side-effects can be induced by higher doses of intrathecal ziconotide, a clinically available N-type VDCC blocker. In contrast, orally administered nifedipine, an L-type VDCC blocker, had no effect on either phase of formalin-induced nociception. These results suggest that cilnidipine acts on the spinal cord to produce antinociception and is efficacious for pain relief after oral administration with better safety profile than that of ziconotide. Furthermore, the failure of orally administered nifedipine to affect formalin-induced nociception raises the possibility that oral cilnidipine produces antinociception through, at least in part, spinal N-type VDCC blockade.

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Actions of intrathecal ω-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat

Cited by 170 publications

References 23 publications

Differential Role of N-Type Calcium Channel Splice Isoforms in Pain

Differential Role of N-Type Calcium Channel Splice Isoforms in Pain

Current and Future Issues in the development of spinal agents for the management of pain

Suppression of Formalin-Induced Nociception by Cilnidipine, a Voltage-Dependent Calcium Channel Blocker

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