Analgesic effects of Phα1ß toxin: a review of mechanisms of action involving pain pathways.

Phα1ß is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Phα1ß to treat chronic pain reverted opioid tolerance with a safer profile than ω-conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Phα1ß (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Phα1ß antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.

Analgesic effects of Phα1ß toxin: a review of mechanisms of action involving pain pathways

Phα1ß is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Phα1ß to treat chronic pain reverted opioid tolerance with a safer profile than ω-conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Phα1ß (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Phα1ß antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.

Analgesic effects of Phalfa1 beta toxin: a review of mechanisms of action involving pain pathways

Phα1ß is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Phα1ß to treat chronic pain reverted opioid tolerance with a safer profile than ω-conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Phα1ß (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Phα1ß antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.

Analgesic effects of Ph1 toxin: a review of mechanisms of action involving pain pathways

Abstract Ph1 is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Ph1 to treat chronic pain reverted opioid tolerance with a safer profile than -conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Ph1 (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Ph1 antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.

Envolvimento das células da glia na ação antinociceptiva da toxina phα1ß e da ω-conotoxina mviia na dor inflamatória periférica / Involvement of glial cells in the antinociceptive action of phα1ß toxin and ω-conotoxin mviia in peripheral inflammatory pain

A lesão inflamatória de origem periférica aumenta a sensibilidade sensória a um estímulo mecânico de leve intensidade, provocando dor, um processo conhecido como alodinia. A recente descoberta de que astrócitos e micróglia da medula espinal tornam-se reativos devido à inflamação periférica, sugere que a glia deve estar envolvida na manifestação patológica da dor. Nesta tese, observou-se que a inflamação periférica, induzida pela injeção intraplantar do adjuvante completo de Freund (CFA), causa alodinia mecânica assim como mudanças na glia. Dentre essas mudanças destacamos o aumento de marcadores específicos da glia, aumento da proliferação de astrócitos assim como alterações morfológicas na micróglia, todas elas características do fenótipo reativo da glia. Além disso, este estudo descobriu que a injeção intratecal da toxina de aranha Phα1ß, um peptídeo com ação analgésica que bloqueia canais de cálcio dependente de voltagem (VGCC), reverte todas as alterações da glia da medula espinal causadas pela inflamação periférica. Essas observações, em resumo, sugerem que a toxina Phα1ß, além de sua já reconhecida ação analgésica, também possui efeitos anti-inflamatórios sobre a plasticidade glial.

A peripheral inflammatory injury increases the mechanical sensitivity in response to light-touch, also named as allodynia. The discovery that spinal astrocytes and microglia become reactive to the peripheral inflammation suggests that the glia presumably engage with the pain pathophysiology. Here, we found that the peripheral inflammation induced by intraplantar injection of complete Freund's adjuvant (CFA) produce mechanical allodynia and robust changes in the spinal glial. Among these changes we found an increase of specific glial markers, increment of astrocytes proliferation, elevation of microglia density and morphologic changes, all of them compatible with the glia reactive phenotype. Moreover, we found that intrathecal injection with the analgesic Phα1ß spider toxin, a voltage-gated calcium channel (VGCC) blocker, reverses all the glial pathological features of the peripheral inflammation. We therefore suggest that the Phα1ß toxin, apart from its notable analgesic effects, is also a potent anti-inflammatory compound acting on glial plasticity.