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Limited efficacy of α-conopeptides, Vc1.1 and RgIA, to inhibit sensory neuron CaV current.

Wright AB, Norimatsu Y, McIntosh JM, Elmslie KS - eNeuro (2015 Jan-Feb)

Bottom Line: Unlike the previous findings, we found highly variable effects among individual sensory neurons, but on average only minimal inhibition induced by Vc1.1, and no significant effect on the current by RgIA.While many pre-clinical studies support the analgesic effects of α-conopeptides, Vc1.1 and RgIA, the mechanism is controversial.The development of improved α-conopeptide analgesics would be greatly facilitated by a complete understanding of the analgesic mechanism.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Baker Laboratory of Pharmacology, Department of Pharmacology, Kirksville College of Osteopathic Medicine, AT Still University of Health Sciences, Kirksville, MO.

ABSTRACT

: Chronic pain is very difficult to treat. Thus, novel analgesics are a critical area of research. Strong pre-clinical evidence supports the analgesic effects of α-conopeptides, Vc1.1 and RgIA, which block α9α10 nicotinic acetylcholine receptors (nAChRs). However, the analgesic mechanism is controversial. Some evidence supports the block of α9α10 nAChRs as an analgesic mechanism, while other evidence supports the inhibition of N-type CaV (CaV2.2) current via activation of GABAB receptors. Here we reassess the effect of Vc1.1 and RgIA on CaV current in rat sensory neurons. Unlike the previous findings, we found highly variable effects among individual sensory neurons, but on average only minimal inhibition induced by Vc1.1, and no significant effect on the current by RgIA. We also investigated the potential involvement of GABAB receptors in the Vc1.1 induced inhibition, and found no correlation between the size of CaV current inhibition induced by baclofen (GABAB agonist) vs. that induced by Vc1.1. Thus, GABAB receptors are unlikely to mediate the Vc1.1 induced CaV current inhibition. Based on the present findings, CaV current inhibition in dorsal root ganglia is unlikely to be the predominant mechanism by which either Vc1.1 or RgIA induce analgesia.

Significance statement: Better analgesic drugs are desperately needed to help physicians to treat pain. While many pre-clinical studies support the analgesic effects of α-conopeptides, Vc1.1 and RgIA, the mechanism is controversial. The development of improved α-conopeptide analgesics would be greatly facilitated by a complete understanding of the analgesic mechanism. However, we show that we cannot reproduce one of the proposed analgesic mechanisms, which is an irreversible inhibition of CaV current in a majority of sensory neurons.

No MeSH data available.


Related in: MedlinePlus

Rapid recovery from Vc1.1-induced inhibition. A, Example traces from a neuron with a 40% inhibition of CaV current induced by 1 µM Vc1.1 (blue trace). Note the almost full recovery from inhibition in the washout trace (Wash). B, The time course of inhibition by Vc1.1. The asterisks indicate the traces used in A. C, The average time constant (τ) for recovery from block by 1 µM Vc1.1 from the four neurons with inhibition >10%. Recovery τ was determined by fitting the Vc1.1 washout time course using a single exponential equation.
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Figure 2: Rapid recovery from Vc1.1-induced inhibition. A, Example traces from a neuron with a 40% inhibition of CaV current induced by 1 µM Vc1.1 (blue trace). Note the almost full recovery from inhibition in the washout trace (Wash). B, The time course of inhibition by Vc1.1. The asterisks indicate the traces used in A. C, The average time constant (τ) for recovery from block by 1 µM Vc1.1 from the four neurons with inhibition >10%. Recovery τ was determined by fitting the Vc1.1 washout time course using a single exponential equation.

Mentions: While the effect of Vc1.1 and RgIA was on average small or insignificant, there were a few neurons that responded with inhibitions >10%. This includes 4/21 (19%) neurons tested with Vc1.1 and 2/12 (17%) neurons tested with RgIA. This contrasts with the previous report showing that CaV current in ∼75% of sensory neurons was inhibited by 100 nM Vc1.1 (Callaghan et al., 2008). We wanted to further investigate the peptide-induced inhibition to determine if the properties were similar to those reported previously (Callaghan et al., 2008). It was previously reported that CaV current block by Vc1.1 was irreversible, but we found that the block by Vc1.1 was readily reversible with an average recovery τ = 0.5 ± 0.2 min (n = 4; Fig. 2). Thus, this inhibition appears to be distinct from that previously reported (Callaghan et al., 2008).


Limited efficacy of α-conopeptides, Vc1.1 and RgIA, to inhibit sensory neuron CaV current.

Wright AB, Norimatsu Y, McIntosh JM, Elmslie KS - eNeuro (2015 Jan-Feb)

Rapid recovery from Vc1.1-induced inhibition. A, Example traces from a neuron with a 40% inhibition of CaV current induced by 1 µM Vc1.1 (blue trace). Note the almost full recovery from inhibition in the washout trace (Wash). B, The time course of inhibition by Vc1.1. The asterisks indicate the traces used in A. C, The average time constant (τ) for recovery from block by 1 µM Vc1.1 from the four neurons with inhibition >10%. Recovery τ was determined by fitting the Vc1.1 washout time course using a single exponential equation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4465272&req=5

Figure 2: Rapid recovery from Vc1.1-induced inhibition. A, Example traces from a neuron with a 40% inhibition of CaV current induced by 1 µM Vc1.1 (blue trace). Note the almost full recovery from inhibition in the washout trace (Wash). B, The time course of inhibition by Vc1.1. The asterisks indicate the traces used in A. C, The average time constant (τ) for recovery from block by 1 µM Vc1.1 from the four neurons with inhibition >10%. Recovery τ was determined by fitting the Vc1.1 washout time course using a single exponential equation.
Mentions: While the effect of Vc1.1 and RgIA was on average small or insignificant, there were a few neurons that responded with inhibitions >10%. This includes 4/21 (19%) neurons tested with Vc1.1 and 2/12 (17%) neurons tested with RgIA. This contrasts with the previous report showing that CaV current in ∼75% of sensory neurons was inhibited by 100 nM Vc1.1 (Callaghan et al., 2008). We wanted to further investigate the peptide-induced inhibition to determine if the properties were similar to those reported previously (Callaghan et al., 2008). It was previously reported that CaV current block by Vc1.1 was irreversible, but we found that the block by Vc1.1 was readily reversible with an average recovery τ = 0.5 ± 0.2 min (n = 4; Fig. 2). Thus, this inhibition appears to be distinct from that previously reported (Callaghan et al., 2008).

Bottom Line: Unlike the previous findings, we found highly variable effects among individual sensory neurons, but on average only minimal inhibition induced by Vc1.1, and no significant effect on the current by RgIA.While many pre-clinical studies support the analgesic effects of α-conopeptides, Vc1.1 and RgIA, the mechanism is controversial.The development of improved α-conopeptide analgesics would be greatly facilitated by a complete understanding of the analgesic mechanism.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Baker Laboratory of Pharmacology, Department of Pharmacology, Kirksville College of Osteopathic Medicine, AT Still University of Health Sciences, Kirksville, MO.

ABSTRACT

: Chronic pain is very difficult to treat. Thus, novel analgesics are a critical area of research. Strong pre-clinical evidence supports the analgesic effects of α-conopeptides, Vc1.1 and RgIA, which block α9α10 nicotinic acetylcholine receptors (nAChRs). However, the analgesic mechanism is controversial. Some evidence supports the block of α9α10 nAChRs as an analgesic mechanism, while other evidence supports the inhibition of N-type CaV (CaV2.2) current via activation of GABAB receptors. Here we reassess the effect of Vc1.1 and RgIA on CaV current in rat sensory neurons. Unlike the previous findings, we found highly variable effects among individual sensory neurons, but on average only minimal inhibition induced by Vc1.1, and no significant effect on the current by RgIA. We also investigated the potential involvement of GABAB receptors in the Vc1.1 induced inhibition, and found no correlation between the size of CaV current inhibition induced by baclofen (GABAB agonist) vs. that induced by Vc1.1. Thus, GABAB receptors are unlikely to mediate the Vc1.1 induced CaV current inhibition. Based on the present findings, CaV current inhibition in dorsal root ganglia is unlikely to be the predominant mechanism by which either Vc1.1 or RgIA induce analgesia.

Significance statement: Better analgesic drugs are desperately needed to help physicians to treat pain. While many pre-clinical studies support the analgesic effects of α-conopeptides, Vc1.1 and RgIA, the mechanism is controversial. The development of improved α-conopeptide analgesics would be greatly facilitated by a complete understanding of the analgesic mechanism. However, we show that we cannot reproduce one of the proposed analgesic mechanisms, which is an irreversible inhibition of CaV current in a majority of sensory neurons.

No MeSH data available.


Related in: MedlinePlus