Chronic Pain: Clarifying Toxin Analgesic Mechanism
Material below summarizes the article Limited Efficacy of α-Conopeptides, Vc1.1 and RgIA, to Inhibit Sensory Neuron Cav Current, published on January 16, 2015, in eNeuro and authored by Andrew B. Wright, Yohei Norimatsu, J. Michael McIntosh, and Keith S. Elmslie.
Chronic pain reduces the quality of life for millions of people, and the available treatments are limited and ineffective for many patients. Thus, novel analgesics are a critical area of research.
Strong preclinical evidence supports the analgesic effects of the 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) channels via activation of GABAB receptors.
The inhibition of CaV2.2 current is an attractive mechanism since the FDA-approved analgesic drug ziconotide works by inhibiting CaV2.2 channel activity to reduce excitatory neurotransmitter (glutamate) release from nociceptor nerve terminals in the spinal cord dorsal horn (Elmslie, 2004). However, it was recently shown that Vc1.1 fails to affect excitatory post-synaptic currents (eEPSCs) in the dorsal horn of rat spinal cord, which were almost completely blocked by GABAB receptor agonist baclofen (Napier et al., 2012). This finding, along with others (McInstosh e al., 2009), prompted us to reassess the effect of Vc1.1 and RgIA on CaV current in rat sensory neurons.
Unlike previous work that showed 40-50 percent inhibition of CaV current in approximately 80 percent of rat sensory neurons (Callaghan et al., 2008; Callaghan and Adams, 2010), we found Vc1.1 and RgIA-induced inhibition by greater than 10 percent in less than 20 percent of these neurons. Importantly, this inhibition was not correlated with baclofen-induced CaV current inhibition, since the baclofen response was found in 90 percent of sensory neurons. Indeed, some neurons with the largest baclofen-induced inhibitions failed to respond to either Vc1.1 or RgIA. Another difference was that we found a relatively fast recovery from Vc1.1 and RgIA-induced block instead of the irreversible block observed in the previous work (Callaghan et al., 2008). Thus, while we did observe Vc1.1 and RgIA-induced CaV block in a subpopulation of sensory neurons, the properties of that block failed to match that from previous reports.
Since we did find a few α-conopeptide-sensitive neurons, we were interested to determine if this was an identifiable population (e.g., nociceptors). As a first step, we examined neuronal size, but found some small (< 30 µm), medium, and large (> 40 µm) diameter neurons were conopeptide-sensitive, while other neurons within the same size ranges were insensitive. As a result, it seems unlikely that a single subgroup (e.g., nociceptors) defines the α-conopeptide-sensitive population.
Based on the available evidence, the analgesic mechanism likely involves block of α9α10 nAChR.
Many experiments have demonstrated the analgesic properties of α-conopeptides that block α9α10 nAChR, including Vc1.1 and RgIA (Satkunanathan et al., 2005; Vincler et al., 2006; Napier et al., 2012; Di Cesare Mannelli et al., 2014). There are also small molecule antagonists of α9α10 nAChRs that have been shown to be analgesic, which lends further support for the importance of this mechanism (Holtman et al., 2011; Zheng et al., 2011; Wala et al., 2012).
Recent work has demonstrated a possible role of α9 nAChR in pain, since mechanical hyperalgesia was reduced in α9 nAChR knockout mice following chronic nerve constriction and in an inflammatory pain model (Mohammadi and Christie, 2014).
Vc1.1 and RgIA are analgesic when injected intravenously, but are unlikely to cross the blood-brain barrier to reach CaV2.2 channels in the dorsal horn. The analgesic mechanism of the ω-conopeptide, ziconitide, involves the direct block of presynpatic CaV2.2 channels (Elmslie, 2004), which blocks pain transmission from primary to secondary nociceptors in the dorsal horn of the spinal cord (Vanegas and Schaible, 2000; Elmslie, 2004). This FDA-approved drug must be delivered by intrathecal administration for therapeutic effect (Sanford, 2013), since it is ineffective when given peripherally by intravenous injection (Chaplan et al., 1994).
Together, these findings suggest non-CaV channel mechanisms are important for RgIA and Vc1.1-induced analgesia.
One target of these α9α10 nAChR-blocking conopeptides may be non-neuronal cells. Indeed, a major effect of RgIA appears to be on the glial/immunological response to chronic nerve injury to prevent pathological changes within the nervous system that are thought to result in neuropathic pain (Di Cesare Mannelli et al., 2014).
Limited Efficacy of α-Conopeptides, Vc1.1 and RgIA, To Inhibit Sensory Neuron CaV Current. Andrew B. Wright,Yohei Norimatsu, J. Michael McIntosh, Keith S. Elmslie. eNeuro Jan 2015, 2 (1). DOI: 10.1523/ENEURO.0057-14.2015