Neuropathic pain (NP) remains maltreated for a wide number of patients by the currently available treatments and little research has been done in finding new drugs for treating NP. Ziconotide (Prialt TM) had been developed as the new drug, which belongs to the class of ω-conotoxin MVIIA. It inhibits N-type calcium channels. Ziconotide is under the last phase of the clinical trial, a new non-narcotic drug for the management of NP. Synthetically it has shown the similarities with ω-conotoxin MVIIA, a constituent of poison found in fish hunting snails (Conus magus). Ziconotide acts by selectively blocking neural N-type voltage-sensitized Ca 2+ channels (NVSCCs). Certain herbal drugs also have been studied but no clinical result is there and the study is only limited to preclinical data. This review emphasizes the N-type calcium channel inhibitors, and their mechanisms for blocking calcium channels with their remedial prospects for treating chronic NP.
N-type calcium channel blockers, neuropathic pain, conotoxin, ω-conotoxin, ziconotide, peptide inhibitor
Neuropathic pain (NP) is the pain triggered by primary laceration or somatosensory disfunction as defined by International Association for the Study of Pain [1]. Throughout the world, approximate 9% population is affected by this pain [2]. This pain is mostly divided into two categories: one is peripheral which is the most common, while the other is central. The peripheral pain is the result of nerve injury, neuralgia, or radiculopathy. The reason for the central pain may be the brain injury, spinal injury, brain stroke, or multiple sclerosis [3]. NP is recognized by several symptoms such as spontaneous shooting, burning pain, and allodynia. It affects the life quality of a patient [4, 5], leading to depression, certain other mental and physical health issues [6, 7]. The explanation of NP is not much clear but rather quite confusing resulting in lack of fixed treatment strategy. So, certain invasive therapies are used for mitigation of pain due to a lack of treatment. Treatment is totally a literature-based outcome. Certain antidepressant and antiepileptic drugs are used to cure the symptoms although these methods are associated with certain side effects such as addiction. Beyond these, surgical methods are also used. So, there is much space for the development of new medication in this field, which should be specific with less side effects. The International Association for the Study of Pain (IASP) defines NP as pain initiated or caused by a primary lesion or due to dysfunction within the nervous system [8]. This condition arises as the outcome of sequence of several pathological mechanisms which are frequently described on the basis of anatomic localization [9]. Neuropathic syndromes are typically characterized with several intricate neuronal episodes that incorporate all types of allodynia, hyperalgesia, paraesthesia, and dysesthesias [10]. These signs are typically followed by depression, anxiety, and sleep disturbances [11]. Large numbers of neuropathic patients do not attain satisfactory relief from popular treatment methods [12–14]. The failure of present treatment methods highlights the crucial requirement for brand new categories of drugs and improved use of available treatments. Medicines presently in use for treating NP are mentioned in Table 1 [15–17]. Certain herbal drugs also have been preclinically studied for the treatment of NP such as Aconiti tuber, Curcuma longa, Ocimum sanctum, but with no clinical application yet.
SNRI: serotonin-norepinephrine reuptake inhibitors; TCAs: tricyclic antidepressants; VGCCs: voltage-gated calcium channels
Because of the crucial side effect offered by current treatments, novel approach towards management of nerve pain is desperately required [18]. Ziconotide (Prialt TM), which was studied as N-type calcium channel blocker, was developed on account of the new drug in the class of ω-conotoxins. Synthetically it was similar to conotoxin MVIIA, an N-type calcium channel inhibitor permitted for NP [19]. The calcium channel is made up of three different subunits (Figure 1). For channel activity α-1 subunit is important. Gabapentin/pregabalin binds at a site in the extracellular region of α 2 subunit [20]. N-type voltage-dependent calcium channel (VDCC) controls the discharge of neurotransmitters towards synaptic cleft [21, 22]. These neurochemicals carry nociceptive signals across the afferent nerve, and the pain signals get suppressed due to antagonism at the channel. Structure of voltage-gated Ca 2+ channel is shown in these articles [23–25].
Peripheral nerve lesion causes aberrant regeneration which unusually sensitizes the neurons that cause abnormal excitability [26]. This process is recognized as superficial stimulation, which results in NP. Peripheral nervous system injury causes the release of certain mediators of inflammation like histamine, cytokines, potassium, and neuropeptides [27]. These mediators cause the change in the quantity and location of sodium ion channels in the damaged nerve fibres [27, 28]. This results in the depression of depolarization threshold and ectopic discharge resulting in the higher nociceptor response to any type of external stimuli known as peripheral sensitization [28, 29]. Ectopic discharge results from the demyelinated nerve fibres due to shrivelled blood supply [30, 31]. Due to injury, the chemical mediated electrical connections are developed between adjoining neurons called ephaptic conductions resulting in pain in a normal calm nociceptor [27, 31, 32]. Hyperalgesia and burning sensation mediated through uninterrupted excretion in C-fibres [33]. Dysesthesias and paraesthesias are the results of sporadic spontaneous discharges in A-δ or A-β fibres, all due to peripheral sensitization [34, 35]. The pathophysiology of peripheral NP is stated below in Figure 2.
The tachykinins and neurotransmitters released as a result of peripheral injury causes the hype in the excitability of central nociceptor receptors present in the spinal cord [36]. Overexcitation of these receptors causes the hyperexcitation of N-methyl-D-aspartate (NMDA) receptor, rising intracellular calcium levels [37] through N-type calcium channels [38], considered imperative for the maintenance of central sensitization [38, 39]. The hyperactivity results in the biochemical abnormalities in the dorsal horn neurons of the spinal cord, which lowers the threshold for activation and thus response to stimuli is enhanced with enlarged receptive field [36]. Another mechanism responsible for central NP is suppression of central inhibitory control, resulting in overexpression of excitatory mechanism [39, 40]. All these mechanisms collectively lead to allodynia, which is a clinical state in NP in which the condition is induced by stimulus not usually evoking any pain [36, 41]. The drugs which are used to treat central NP act by affecting the levels of calcium, 5-hydroxytryptamine (5HT) and noradrenaline etc. Ziconotide, gabapentin and anticonvulsants drugs act by antagonizing N-type calcium channel, and oxcarbazepine, lamotrigine and lidocaine act by modulating the sodium channels [42–44]. Tricyclic antidepressants act both peripherally and centrally. Peripherally by modulating sodium channels and centrally by modulating neurotransmitter levels (e.g., 5HT, NE). Opioids act by closure of calcium channels, and thus further reducing the release of key neurotransmitters involved in the pain transmission [36].
The major ascending nociceptive pathway constituted by the spinothalamic tract (STT) forms the neurons of the spinal cord [45]. Due to the rise in the spontaneous activity in the periphery, the background activity of STT neurons increases, the receptive fields became enlarged and the response to afferent impulse increases [46]. The stated event is called central sensitization [47]. The pathophysiology of central NP is stated below in Figure 3.
The detail peripheral and central pathophysiology depends on changes that occur at cellular and molecular levels [48]. Functional changes occur due to change in sodium and calcium channel subunit expression related to NP. During a nerve injury, the sodium and calcium channel subunits reshuffle, which results in the sudden firing of neurotransmitters [49].
Pain, a complicated medical condition that has considerable unsatisfied clinical requirements. The opioid treatment remains standard despite of their side effects like tolerance and respiratory depression bounded to their continuous use. The foundation for pain comprises different pathways from dorsal root ganglion to brainstem [50–52]. The downward pathways vigorously regulate the upward pain pathways [53]. G protein-coupled opioid receptor is the main target of opioid analgesics, and the neuronal excitability decreases when these receptors are activated [54–57].
These channels are strongly blocked by numerous peptides obtained from the toxin of fish-trapping cone snails from Conus species, along with GVIA, MVIIA and CVID [58–60]. At elevated concentrations the peptides even can block 0 channel subtypes [61, 62]. Along with MVIIA, a specific conotoxin Ca v 2.2 blocker is approved for managing neuronal pain. Medicinal prospective of ω-conotoxins specific for Ca v 2.2 for pain management has been recognized as the Ca v 2.2 channel, which plays a vital role in the transmission of pain [63–65].
The GVIA conotoxin obtained from Conus geographus permanently blocks Ca v 2.2 channels in the nanomolar range [61, 66]. GVIA has more potency in vivo, compared to other structurally similar peptides [67, 68]. GVIA is three to four folds more effective than other peptides, and almost 40 times more effective compared to morphine, when given to rats intrathecally. Because of the permanent blockage of the Ca v 2.2 channel, it is possibly difficult to decide the safe dose in an experimental setting [69].
MVIIA obtained from Conus magus, inhibits the Ca v 2.2 channels. The synthetic form (ziconotide) has been developed, which is injected intrathecally for treatment of NP clinically [70–72]. The USA and Europe permitted MVIIA for managing NP [73, 74]. This peptide shows appreciable relief from pain. Like morphine, there is no adverse effect of tolerance and addiction in the case of MVIIA [75, 76].
CVID is obtained from Conus catus, the major selective antagonist of Ca v 2.2 channels among all peptides [77, 78]. It is presently under clinical trials by the name of AM336 [79]. In the previous studies, it has been proved that CVID is a highly selective antagonist for Ca v 2.2 rather than Ca v 2.1. Different Conus species [80] with their actions and the biological sources are shown in Table 2.
Ziconotide has a neuroprotective activity and is derived from the venom of cone snail. However, it is the synthetic peptide that has similarities with ω-conopeptide (MVIIA) obtained from Conus magus. The pharmacodynamics and pharmacokinetics affect living cells, and their dosage
