Analgesic effect in rodents of native and recombinant Phα1β toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom

Abstract

Calcium influx through neuronal voltage-sensitive calcium channels (VSCC S) mediates nociceptive information in the spinal dorsal horn. In fact, spinally administered VSCC S blockers, such as omega-conotoxin MVIIA, have analgesic effect apart of their low therapeutic index and many side effects. Here we study the analgesic potential of Ph alpha 1beta, a calcium channel blocker, in rodent models of acute and persistent pain. Spinally administered Ph alpha 1beta showed higher efficacy and long-lasting analgesia in a thermal model of pain, when compared with omega-conotoxin MVIIA. Moreover, Ph alpha 1beta was more effective and potent than omega-conotoxin MVIIA not only to prevent, but especially to reverse, previously installed persistent chemical and neuropathic pain. Furthermore, the analgesic action of both toxins are related with the inhibition of Ca2+-evoked release of pro-nociceptive neurotransmitter, glutamate, from rat spinal cord synaptosomes and decrease of glutamate overflow in cerebrospinal fluid. When side effects were assessed, we found that Ph alpha 1beta had a therapeutic index wider than omega- conotoxin MVIIA. Finally, recombinant Ph alpha 1beta expressed in Escherichia coli showed marked analgesic activity similar to the native toxin. Taken together, the present study demonstrates that native and recombinant Ph alpha 1beta have analgesic effects in rodent models of pain, suggesting that this toxin may have potential to be used as a drug in the control of persistent pathological pain.

Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy

“…N-and P/Q-type channels blockers are suggested to lead to a clinical improvement of cognitive decline in Alzheimer's patients (Amenta et al, 2009) and to an absence of seizures in epilepsy (Zamponi et al, 2010). Additionally, peptide neurotoxins found in animal venoms have received great interest and have been related to neuropathic pain control (Souza et al, 2008;Rigo et al, 2013a) and the management of cancer-associated pain (Rigo et al, 2013b) in animal models during P/Q-and N-type modulation. Pinheiro et al (2006Pinheiro et al ( , 2009 showed a neuroprotective role for a P/Q-type blocker in an in vitro model of hippocampal ischemia induced by oxygen and glucose deprivation; the neurotoxins prevented neuronal death by inhibition of glutamate release.…”

Inhibition of Transmitter Release and Attenuation of Anti-retroviral-associated and Tibial Nerve Injury-related Painful Peripheral Neuropathy by Novel Synthetic Ca2+ Channel Peptides

“…As such, regulation of CaV2.2 expression and function is posited to have a major impact on the presentation of multiple pain states. Indeed, inhibition of CaV2.2 by synthetic conopeptides provides analgesic relief in a variety of platforms (3)(4)(5)(6). However, given the importance of CaV2.2 integrity in peripheral and central synapses, directly targeting channel function is complicated by a myriad of adverse side effects (7)(8)(9).…”

ω-conotoxin MVIIA intralesional injection in spinal cord injury in rats

“…This is the first study that evaluates the neuroprotective effects of ω-conotoxin MVIIA in vivo in rats subjected to SCI. In this experiment, MVIIA concentrations were chosen from 5 to 20μM of MVIIA due to the variability of doses reported in the literature, mostly antinociceptive studies where concentrations of 3 to 200μM showed efficacy in blocking the N-type VDCC (SOUZA et al, 2008;HAMA & SAGEN, 2009;SOUZA et al, 2011;, with side effects as a limiting factor. In agreement with HAMA &SAGEN (2009), the lowest dose (5μM) had no complications.…”

“…Mean (± standard deviation) concentration of glutamate in the cerebrospinal fluid compared to placebo (100) were 124.14%±22.46 (SHAM), 100.1%±58.21 (5μM MVIIA), 95.92%±89.75 (10μM MVIIA) and 52.02%±35.25 (20μM MVIIA) ( Figure 1B). Despite the observation of MVIIA in reducing glutamate at early times (SOUZA et al, 2008;GONÇAVES et al, 2011), some authors pointed out that this fact is not the only implicated in toxin neuroprotection (VALENTINO et al, 1993), since high doses are required for regulation of glutamate release in less than 50% when compared to effective inhibitors levels (BOWERSOX et al, unpublished data, 1999cited by WANG & BOWERSOX, 2000.…”

“…Toxins from cone snails such as ω-conotoxin MVIIA or Ziconotide, initially purified as SNX-111, is a potent reversible blocker of N type calcium channels (OLIVERA et al, 1985), capable to inhibit, in synaptosomes, neurotransmitters release such as norepinephrine (BOWERSOX et al, 1995) and glutamate (GONÇAVES et al, 2011), essential in the development of secondary spinal injury. This drug was approved by the Food and Drug Administration in the United States, for analgesic therapeutic use to treat severe chronic and neuropathic cancer pain (SOUZA et al, 2008;BINGHAM et al, 2010).…”