Conotoxin - an overview

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Abstract

Conotoxins (conopeptides) are a diverse group of peptides isolated from the venom of marine cone snails. Conus peptides modulate pain by interacting with voltage-gated ion channels and G protein-coupled receptors (GPCRs). Opiate drugs targeting GPCRs have long been used, nonetheless, many undesirable side effects associated with opiates have been observed including addiction. Consequently, alternative avenues to pain management are a largely unmet need. It has been shown that various voltage-gated calcium channels (VGCCs) respond to GPCR modulation. Thus, regulation of VGCCs by GPCRs has become a valuable alternative in the management of pain. In this review, we focus on analgesic conotoxins that exert their effects via GPCR-mediated inhibition of ion channels involved in nociception and pain transmission. Specifically, α-conotoxin Vc1.1 activation of GABAB receptors and inhibition of voltage-gated calcium channels as a novel mechanism for reducing the excitability of dorsal root ganglion neurons is described. Vc1.1 and other α-conotoxins have been shown to be analgesic in different animal models of chronic pain. This review will outline the functional effects of conopeptide modulation of GPCRs and how their signalling is translated to downstream components of the pain pathways. Where available we present the proposed signalling mechanisms that couples metabotropic receptor activation to their downstream effectors to produce analgesia.

This article is part of the Special Issue entitled ‘Venom-derived Peptides as Pharmacological Tools.’

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Conotoxins. Fish-hunting cone snails inhabit the tidal pools of the South Pacific and hunt fish using venom-filled harpoons which they shoot into prey from their “proboscis” (an elongated appendage). The venom contains hundreds of specific peptide toxins, many of which are selective for ion channels or receptors. These include a variety of μ-conotoxins that selectively inhibit voltage-gated sodium channel subtypes, ω-conotoxins that inhibit voltage-gated calcium channel subtypes, and α-contoxins that inhibit specific subtypes of nicotinic receptors. In addition to their use as experimental tools (Terlau and Olivera, 2004), one of the μ-conotoxins has been FDA-approved for use in treating chronic pain (Prialt; Safavi-Hemami et al., 2019; see Box 7.2).

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Toxins can be wonderful pharmacological tools because of their exquisite selectivity, and can also be useful as the starting points for drug development [10]. In the case of conotoxins, synthetic ω-conotoxin MVIIA (known as ziconotide) is awaiting registration as a treatment for intractable pain [11], and ω-conotoxin CVID has been approved to enter clinical trials for treatment of severe pain [12]. These conotoxins act on N-type Ca2 channels. Contulakin-G, a neurotensin receptor agonist, is also being investigated as a potential analgesic, and the NMDA-receptor-blocking conantokins are of interest as potential neuroprotective agents [13,14]. Conantokins have also been shown to have efficacy in animal models of epilepsy [15].

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3.5.1 Conotoxins

Snails of the genus Conus produce a large number of small peptides that they use for defense. The mature peptides share a basic structure of 12–20 amino acids in length and having specifically spaced cysteine residues and disulfide bridges (Lebbe et al., 2014). Variations in the basic structure allow them to be placed in families (i.e., alpha, omega, and mu) and superfamilies such as B3, D, L M, S, T, and J (Abraham & Lewis, 2018).

Numerous conotoxins in the A superfamily, α-conotoxins, are antagonists of nAChRs. Some conotoxins in other superfamilies also can target nAChRs (Abraham & Lewis, 2018). Some conotoxins target muscle nAChRs, but we will focus on those that target neuronal nAChRs. The location of α-conotoxin binding to nAChRs was determined initially by co-crystalizing multiple α-conotoxins with the acetylcholine binding protein (AChBP). These studies demonstrated that the conotoxin was bound in the orthosteric site and that specific interactions between the α-conotoxin and the nAChR subunits provided a basis for the selectivity of different α-conotoxins for different nAChR subtypes (Lebbe et al., 2014). Detailed pharmacophores have been built to understand the binding of α-conotoxins to nAChRs. Site-specific mutagenesis has been used to create even more specific α-conotoxins for use against nAChRs. Some conotoxins may act as noncompetitive inhibitors that may bind outside of the orthosteric site (Abraham & Lewis, 2018).

Conotoxins are being tested for use as analgesics with Vc1.1, RgIA, and RgIA4 used to target α9α10 nAChRs in pain and inflammation (Grau et al., 2019). So far, translating the use of conotoxins in animal models of pain to human use has not had much success. Since these are peptides, they are generally administered in vivo by injection intraperitoneally or intracerebrally. Some conotoxins have been modified by the use of selenocysteines in place of cysteines to make the peptides more stable (Azam & McIntosh, 2009). However, α-conotoxins are important research tools that have been used to determine the function and location of numerous nAChR subtypes (Table 3.1). A number of nAChR subtypes are involved in controlling striatal dopamine release such as α6β2, α6β2β3, or α6α4β2*, and the α-conotoxins MII and PIA have been used to dissect the roles of these subtypes (Azam & McIntosh, 2009). α3β4 nAChRs are involved in hippocampal norepinephrine (NE) release, and AuIB has aided these studies. Hippocampal NE release is modulated by α6α4β2β3 and α6α4β2β4β3 nAChRs and MII, BuIA and PIA have been used in this work (Azam & McIntosh, 2009). While the list is not exhaustive, Table 3.1 shows some of the α-conotoxins used in nAChR research and the subtypes targeted by each. More conotoxins are being discovered and mutations are being made in existing ones to make them more selective. α-conotoxins have been important tools for studying nAChR function and may have many future therapeutic applications.

Table 3.1. Conotoxins targeting nAChRs.

Conotoxin	Subtype
PnIA	α3β2 > α7
PnIB	α7 > α3β2
ImII	α7
ArIB	α7 = α6β2* > α3β2
IMI	α3β2 > α7 > α9
MII	α3β2 = α6β2* > α6β4
PIA	α6β2* > α6β4 = α3β2
OmIA	α3β2 > α7 > α6β2*
GIC	α3β2 = α6β2* > α7
GID	α7 = α3β2 > α4β2
AnIA	α3β2,α7
AuIB	α3β4
RgIA4	α9α10> > α7
ArIA	α7 = α3β2
BuIA	α6β2β3
GID	α7 = α3β2 > α4β2
Vc1.1	α9α10
[V11L;V16D]ArIB	α7
VnIB	α6β4*

Adapted from Azam, L., & McIntosh, J. M. (2009). Alpha-conotoxins as pharmacological probes of nicotinic acetylcholine receptors. Acta Pharmacologica Sinica, 30 (6), 771–783. https://doi.org/10.1038/aps.2009.47.

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2 ω-conotoxins

The family of ω-conotoxins is derived from the venoms of a variety of different marine molluscs that use their venom to hunt fish. They are typically between twenty and thirty amino acids in size and display a rigid backbone structure that is spatially constrained by the formation of disulfide bonds formed between six conserved cysteine residues (Olivera et al., 1986, 1991; Lewis et al., 2012). Blocking affinity and channel subtype selectivity vary with amino acid sequence in the various loops between the cysteine bonds. In general, ω-conotoxins act by physically occluding the pore of the channel, thus preventing calcium influx. In many cases, binding is very tight, leading to slow dissociation rates and hence poorly reversible block (for example, Mintz et al., 1992; Boland et al., 1994; Ellinor et al., 1994).

One of the defining characteristics of Cav2.2 (N-type) calcium channels is their inhibition by ω-conotoxin GVIA, a 27 amino acid peptide isolated from the fish hunting mollusc Conus geographus (Olivera et al., 1994; McCleskey et al., 1987). GVIA block is exquisitely selective for Cav2.2 channels and virtually irreversible (Boland et al., 1994; McDonough et al., 2002), however, strong membrane hyperpolarization has been shown to accelerate the dissociation of this peptide from the channel (Stocker et al., 1997; Feng et al., 2003). Structure-function analysis based on chimeric calcium channel constructs has revealed that GVIA interacts with the outer vestibule of the pore comprised of the extracellular domain III S5S6 (p-loop) region (Ellinor et al., 1994). Moreover, mutations in this region (especially a Glycine residue at position 1326) have been shown to affect not only the blocking rate constant, but also to have the capability to render the block reversible (Feng et al., 2001). These data fit with a structural homology model of Cav2.2 based on the structure of bacterial sodium channels (Lewis et al., 2012). This picture is likely to be refined in light of the recent structural data of the Cav1.1 channel in complex with a Cavα2δ subunit that is docked near the top of the channel pore (Wu et al., 2016). Such structural information may offer some mechanistic insights into why the Cavα2δ subunit affects blocking and unblocking rate constants for certain types of ω-conotoxins (Mould et al., 2004). The venom of Conus geographus also contains other related ω-conotoxins, such as GVIB, GVIC, GVIIA, and GVIIA, however they are not as well characterized at the electrophysiological level as GVIA (Olivera et al., 1994).

A number of calcium channel blocking peptides have been isolated from the venom of Conus magus, another fish hunting snail. This includes ω-conotoxins MVIIA, MVIIB, MVIIC, and MVIID (Hillyard, 1992; Olivera et al., 1994), which for the most part preferentially target Cav2.2 channels (Olivera et al., 1985; Monje et al., 1993; Fox, 1995). However, MVIIC also blocks Cav2.1 calcium channels and its blocking effects are reversible (Woppmann et al., 1994; Grantham et al., 1994), underscoring the point that small changes in amino acid composition between MVIIA and MVIIC are sufficient to alter channel subtype selectivity. The mode of action of these peptides is similar to that of GIVA, and they compete for a common interaction site on the channel (Olivera et al., 1994), although subtle differences in the way these toxins interact with the channel have been suggested (Woppmann et al., 1994).

MVIIA has received particular attention, as this peptide can be synthesized such that it retains its native conformation (Xiao and Bennett, 1995). This has allowed the exploration of this peptide as a therapeutic agent for pain, based on the underlying principle that the Cav2.2 channel plays a major role in the transmission of pain signals in the spinal dorsal horn (Bourinet et al., 2014). Intrathecal delivery of MVIIA (a.k.a. ziconotide or Prialt) mediates analgesic effects in both animals and humans. However, although Prialt is approved for treating intractable cancer pain in humans it has a narrow therapeutic window and the potential for causing severe CNS side effects (Antanassoff et al., 2000; Penn and Paice, 2000; Miljanich, 2004; Staats et al., 2004; Thompson et al., 2006; Wallace et al., 2006; Ver et al., 2008). The toxicity of MVIIA has recently been attributed to a methionine residue at position 12 of the toxin molecule, which is known to dock to a hydrophobic binding pocket comprised of residues I300, F302, L305 of the Cav2.2 subunit (Wang et al., 2016).

A number of additional ω-conotoxins have been identified in the venoms of Conus fulman and Conus catus and shown to mediate potent inhibition of Cav2.2 channels and to exhibit analgesic effects. This includes ω-conotoxins FVIA (a reversible N-type channel blocker; Lee et al., 2010), as well as CVIB (Motin et al., 2007), CVID (Lewis et al., 2000; Scott et al., 2002; Adams et al., 2003), CVIE and CVIF (Berecki et al., 2010). Interestingly, CVID and CVIE (but not CVIF) mediate analgesia in mice even after systemic administration (Sadeghi et al., 2013). Of further note, CVID has been advanced to human clinical trials where a larger therapeutic window was observed compared with Prialt (Schroeder et al., 2006), however, this peptide did to our knowledge not advance beyond phase II. Nonetheless, the larger therapeutic window has been attributed to the fact that CVID shows greater selectivity for Cav2.2 channels over Cav2.1.

The ω-conotoxins SIA, SVIA and SVIB have been isolated from Conus striatus venom. Although they are pore blockers, it has been suggested that their sites of action are distinct from those of GVIA (Ramilo et al., 1992). Moreover, similar to MVIIC, SVIB reversibly blocks Cav2.2 and Cav2.1 channels (Woppmann et al., 1994; Nielsen et al., 1996).

The venoms of Conus Victoriae and Conus regis, respectively, contain α-conotoxins Vc1.1 and Rg1A. These peptides were classified as α-conotoxins in line with their action on nicotinic acetylcholine receptors (Clark et al., 2006; Nevin et al., 2007). Subsequently, potent inhibition by these toxins of Cav2.2 calcium channels was reported. However, both Vc1.1 and Rg1A do not act directly on the channel, but instead by activating GABAB receptors (Callaghan et al., 2008; Callaghan and Adams, 2010; Cuny et al., 2012; Huynh et al., 2015). This is thought to occur by interference with the receptor dimer ectodomain interface (Adams and Berecki, 2013), which then triggers inhibition of Cav2.2 channels via a G protein pathway. By doing so, the Vc1.1 peptide produces analgesia in rodent models of neuropathic and gastrointestinal pain, and reduces the excitability of human dorsal root ganglion neurons (Klimis et al., 2011; Castro et al., 2016). Vc1.1 is being explored as a possible pain therapeutic for humans, and this has been facilitated through the generation of a cyclized version of the peptide that remarkably allows oral delivery of Vc1.1 (Carstens et al., 2011).

While the majority of ω-conotoxins appear to target Cav2.2 and Cav2.1 calcium channels, there are some examples of L-type calcium channel blocking ω-conotoxins. For example, ω-conotoxin TxVII from Conus textile blocks L-type calcium channels from a freshwater pond snail, Lymnaea stagnalis (Fainzilber et al., 1996). Glacontryphan-M, an unusual peptide isolated from the venom of Conus marmoreus contains γ-carboxyglutamyl (Gla) residues in positions 2 and 4 that bestow calcium binding ability onto this toxin. It has been shown to block L-type currents in mouse pancreatic beta cells (Hansson et al., 2004). Block, however, was found to be incomplete with ∼35% inhibition at saturating concentrations. Substitution of the Gla residues with glutamate abolished block, as did removal of extracellular calcium.

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6.8 Spinal Nerve Block With Conotoxin

Although this treatment is already FDA approved for pain, I nevertheless discuss this treatment among the explorative experimental treatments, as it has not become a mainstay in clinical pain management. Nevertheless, for the neuroscientist, conotoxin is exciting, as its development showcases an example of elegant neuroscience-inspired bench-to-bedside translational biology. It had been known for well over 300 years that hunting see snails of the genus Conus, which paralyze their pray by injecting venom (Figure 17), can also be harmful and even deadly to humans. The poisonous venom had fascinated the biologist Baldomero Olivera at the University of Utah for decades. In the early 1980s, he recruited several undergraduates to help him characterize the various peptides contained in the snail venom of Conus geographus. This led to the identification of a number of highly specific peptides with potential clinical use. Of these, a 27 amino acid peptide named ω-conotoxin proved to be a highly specific blocker of presynaptic N-type Ca2  + channels, the very channel required for neurotransmitter release from presynaptic terminal. A synthetic version of this peptide, ziconotide, was subsequently shown to block chronic pain when injected directly into the spinal cord. Following several clinical trails, it was approved to treat chronic pain by the FDA in 2004. Unfortunately, as effective as the drug may be, it is difficult to administer, as it requires implantation of a spinal cord catheter connected to a minipump that delivers drug from a subcutaneous reservoir, providing ample opportunities for complications.

Figure 17. A sea snail of the genus Conus hunting prey. It is caught as it injects its venom into the trunk of a fish, causing it paralysis.

© Alex Kerstitch/Visuals Unlimited, Inc., 2018.

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VI Other Toxins and Channels

VIA α-Conotoxins and the Nicotinic Acetylcholine Receptor-Associated Channel

Although not targeted directly to ion channels, the α-conotoxins will be briefly discussed in the interest of covering all of the conotoxin classes. The α-conotoxins are the smallest of the conotoxin peptides known, comprising 13–15 amino acid residues, of which four are half-cystines involved in disulfide bonds. All of the known α-conotoxins are cationic, with formal charges of +1.5 to +3.5 at neutral pH. Conservative changes are tolerated at most positions without significant loss of activity, so that relatively little information on structure–function relationships can be derived from synthetic analogs. It is clear that the presence of two disulfides in such a short peptide imposes relatively severe constraints upon its three-dimensional structure. The proposed structure for α-conotoxin, based upon NMR measurements, includes β-turns at residues 5–8 and 9–12.

α-Conotoxins are directed at the nicotinic acetylcholine receptor channel and mechanistically act like the snake toxins exemplified by α-bungarotoxin. In fact, the most widely accepted model for α-conotoxin structure places several of its side-chain functional groups into α-conotoxin is consistent with its observed ability to compete with other nAChR antagonists like d-tubocurarine and α-BgTX. On this basis, α-conotoxin is, strictly speaking, not truly directed against the ion channel and will not be discussed further.

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The α-conotoxins are not only selective towards specific subclasses of receptor, but also towards ACh binding pockets between specific subunit pairs, which makes them ideal tools with which to probe the central and peripheral nervous systems for receptor distribution. Additionally, with a growing number of α-conotoxin structures becoming available, they have the potential to be used as templates from which to derive pharmaceutical agents. Several recent reviews report on conotoxins, and specifically on α-conotoxins [4••,13••–16••,17•,18,19], reflecting the current and developing interest in these potent polypeptides. This review considers the selectivity of different α-conotoxins, in conjunction with structural information where determined, with a focus on interactions with mammalian nAChRs. It covers the most recent developments concerning the more established neuromuscular family of α-conotoxins, then turns to the neuronal α-conotoxins. Emphasis is placed on new family members that have been recently identified. Restrictions in the length of this review mean that the few members of the larger α-A-conotoxins cannot be covered (see [4••,20] for reviews).

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α-Conotoxins

In reviewing the breadth of research on animal toxins for the treatment of neuropathic pain, the family of conotoxins from which ziconotide is derived comes into sight. Conotoxins, as inhibitors of a variety of ion channels, present as strong candidates in pain relief and as potential alternatives to ziconotide because of its adverse side effects and invasive route of administration.8

Sodium channels have been found to play a significant role in the mechanism of pain. After nerve injury, it was found that sodium channels began to accumulate at the site of injury and along the length of the axon.10 This situation resulted in hyperexcitability and spontaneous action potential discharges. Another group11 also found that nociceptors spontaneously fired after nerve injury. A popular but controversial route of analgesia revolves around α9 nAchRs (α9nAChRs) and their relationship with α-conotoxins. Although evidence for the involvement of α9nAChRs, and the α9α10 nAChR in particular, in pain treatment has been found,12,13 the types of pain to which these receptors may be related as well as their exact mechanism of action have been contested.14,15 Further research indicates that the putative α9nAChR pain-alleviation mechanism may not require the α9nAChR, but rather incorporate a γ-aminobutyric acid (GABA)-dependent N-type voltage-gated Ca2+ channel pathway15-20; recent evidence both supports and precludes the GABA-dependent calcium channel inhibition mechanism of pain relief through α-conotoxins.21,22 The true mechanism remains unclear. Three α-conotoxins of interest are the peptides α-conotoxin Vc1.1, α-conotoxin RgIA, and α-conotoxin GeXIVA.

α-Conotoxin Vc1.1

This toxin, discovered from the messenger RNA sequence of the Queen Victoria cone sea snail Conus victoriae,23 has been analyzed for its nAChR selectivity and binding to α9α10.24 Intramuscular injection of α-conotoxin Vc1.1 dose-dependently attenuated mechanical hyperalgesia in chronic constriction injury (CCI) and partial nerve ligation (PNL) models of neuropathic pain.25,26 The former model calls for exposure and multiple ligations of the sciatic nerve, usually resulting in forms of hyperalgesia and allodynia. Acute treatment of CCI rats with an intramuscular bolus of α-conotoxin Vc1.1 led to significant attenuation of hyperalgesia, defined by increased weight threshold before paw withdrawal. Compared with saline, rats treated with the toxin were able to tolerate up to approximately double the weight before withdrawing from pain. This effect lasted between 1 and 3 hours after injection. Short-term effects lasted 24 hours after injection and rats that received the maximal dose were restored to preoperative weight levels before withdrawing. Long-term effects yielded significant attenuation of mechanical hyperalgesia even at the lowest dose, with 50% of attenuation lasting 1 week after injections.25 Moreover, treatment with substance P showed a significantly greater vascular inflammatory response 8 weeks after injury in rats treated with Vc1.1 compared with saline control, suggesting an enhanced recovery of injured neurons. Using normal rats as the control for inflammation at 100% after treatment with substance P, rats treated with Vc1.1 showed up to 83% functional recovery, whereas those treated with saline showed 47%.25 Intramuscular administrations of Vc1.1 have also reduced allodynia in PNL and other neuropathic pain models.19,27 Intrathecal administration of Vc1.1 dose-dependently reduced mechanical allodynia without adverse motor effects as shown by rotarod test. Rats treated with the conotoxin had increased paw withdrawal thresholds for up to 6 hours, whereas those treated with saline had no changes in threshold.15 However, other investigators have suggested that the mechanism of conopeptides are dependent on pathways other than Vc1.1.22 However, other investigators have suggested that the mechanism of conopeptides is dependent on pathways other than Vc1.1.22 These investigators found that conopeptides had variable effects on Vc1.1. in different sensory neurons and that there was only minimal inhibition via this pathway. Further research needs to be undertaken to determine the true pathway of analgesia for conopeptides so that improved therapies may be developed.

α-Conotoxin RgIA

Found in the crown cone sea snail Conus regius,28 α-conotoxin RgIA also blocks the α9α10 nAChR and has been examined for its binding mechanism and stability as a potential drug.28-30 Intramuscular administrations of RgIA in CCI neuropathic rat models attenuated hyperalgesia and allodynia in a dose-dependent manner through chronic and acute treatment, without noted adverse effects. In 1 study, CCI rats treated chronically for 14 days with RgIA had progressive decrease in paw withdrawal threshold: 61.7 ± 0.6 g and 65.0 ± 0.9 g in the 2 nmol-treated and 10 nmol-treated group compared with 39.2 ± 1.3 g in the saline-treated group.26,31 Of note is the ability of RgIA to decrease degeneration of both dorsal root ganglion and sciatic nerve morphology in the CCI model as well as reduce the glial cell-mediated inflammatory response after intramuscular injection.31 A recent study using a chemotherapeutic drug-induced (oxaliplatin) model of neuropathic pain showed dose-dependent reductions in mechanical hyperalgesia and mechanical and cold allodynia, alongside prevention of dorsal root ganglion degeneration after intramuscular injection of RgIA conducted at a set dosage. This study found resolution of pain threshold over the control group value after 21 days of treatment with high-dose RgIA. No tolerance to the effect of the toxin was noted.32 In the spinal cord, although no significant effects were seen in microglial expression, cotreatment of RgIA and oxaliplatin reduced astrocyte number, measured by glial fibrillary acidic protein (GFAP) expression, compared with oxaliplatin alone.32 RgIA alone increased astrocyte number compared with oxaliplatin alone.32

αO-Conotoxin GeXIVA

In addition to the former 2 toxins, another conotoxin, αO-conotoxin GeXIVA, isolated from the general cone sea snail Conus generalis, was recently identified and studied for its properties.33 Similar to Vc1.1 and RgIA, GeXIVA inhibits the α9α10 nAChR and presented significant analgesic effects in neuropathic pain.33,34 There are 3 isoforms of GeXIVA: [1,2] (bead form), [1,3] (globular form), and [1] (ribbon form), with the [1,2] isomer most potently inhibiting α9α10 nAChR.33 In a CCI rat model, GeXIVa [1,2] produced dose-dependent attenuation of mechanical hyperalgesia comparable to morphine after intramuscular injection, with no significant deficits in motor control as shown by a rotarod test.33 An additional study of the [1] isomer also showed significant dose-dependent reduction in mechanical hyperalgesia through intramuscular administration, alongside the slightly better effect of the [1,2] isomer and similar nonsignificance in the rotarod test.34 The significant effects of [1] applied only to single, acute, short-term injection patterns; the pain-relieving effect lost significance by 1 week after treatment periods.34 No motor performance effects were found, nor were any behavior disturbances noted.34

Overall, despite the contradicting evidence and uncertainty surrounding the relevancy of α9α10 nAChR and GABA-dependent VGCC pathways of pain relief, these α-conotoxins have clear potential in the treatment of neuropathic pain. Future research will likely elucidate the exact mechanism of pain alleviation and the scope of the effects of the toxins, as well as showing other novel toxins with therapeutic implications.

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Cone snail toxins (conotoxins)

Cone snails are marine gastropods that produce a wide variety of venom peptides referred to as conotoxins. Conantokins are specific conotoxins that are inhibitors of the N-methyl-d-aspartate receptor (NMDAR) and have been found to induce sleep in mice (Bjorn-Yoshimoto et al., 2020). Conus araneosus, a species found in the coastal regions of southeast India and Sri Lanka, as well as C. tulipa, C. geographus, and C. parius, create conantokins that have been confirmed to induce sleep in nice (Franklin and Rajesh, 2015).

There have been a number of studies exploring conotoxins for the management of pain and seizures, as well as neuroprotection against ischemic brain injury (Bjorn-Yoshimoto et al., 2020). However, there are no published studies to date on the effect of conotoxins in sleep and wake in human. Use as a sleep therapeutic would likely be limited by the current need for intrathecal injection given poor permeability of peptides across the blood-brain barrier (Lewis et al., 2012).

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