The Role of Toxins in the Pursuit for Novel Analgesics

Abstract

Chronic pain is a major medical issue which reduces the quality of life of millions and inflicts a significant burden on health authorities worldwide. Currently, management of chronic pain includes first-line pharmacological therapies that are inadequately effective, as in just a portion of patients pain relief is obtained. Furthermore, most analgesics in use produce severe or intolerable adverse effects that impose dose restrictions and reduce compliance. As the majority of analgesic agents act on the central nervous system (CNS), it is possible that blocking pain at its source by targeting nociceptors would prove more efficient with minimal CNS-related side effects. The development of such analgesics requires the identification of appropriate molecular targets and thorough understanding of their structural and functional features. To this end, plant and animal toxins can be employed as they affect ion channels with high potency and selectivity. Moreover, elucidation of the toxin-bound ion channel structure could generate pharmacophores for rational drug design while favorable safety and analgesic profiles could highlight toxins as leads or even as valuable therapeutic compounds themselves. Here, we discuss the use of plant and animal toxins in the characterization of peripherally expressed ion channels which are implicated in pain.

From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery

“…Hi1a, a PcTx1-related toxin isolated from the Australian funnel-web spider Hadronyche infensa, partially inhibits ASIC1a and does not affect ASIC1b (Maatuf et al, 2019). This toxin strongly attenuates brain damage after stroke and could be used to protect the brain from ischemic injury (Chassagnon et al, 2017), being considered as a lead for development of neuroprotective agents (Ren et al, 2018).…”

Marine Toxins and Nociception: Potential Therapeutic Use in the Treatment of Visceral Pain Associated with Gastrointestinal Disorders

“…Neurotoxins, including marine toxins, represent biologically active molecules able to interact with high selectivity and potency with a wide range of ion channels and receptors involved in pain generation [8]. Neurotoxins can be used to investigate the properties of the functionally essential domains of pain-related ion channels and receptors, improving the knowledge of their pathophysiological properties [11,54].…”

“…However, these drugs exert several effects on the body other than nociception, and may worsen symptoms associated with the disease. One of the possible approaches to overcome adverse actions of these conventional therapies is to peripherally block pain generation by affecting the function of target receptors and ion channels located on peripheral terminals and along axons of primary afferent neurons [8]. These mainly comprise ion channels, such as transient receptor potential (TRP), voltage-gated sodium channels (VGSC), voltage-gated calcium channels (VGCC), and acid-sensing ion channels (ASICs).…”

Psychotropic Drugs for the Management of Chronic Pain and Itch

“…Moreover, plant and animal toxins have been widely tested as potent pain therapeutics. In the paper [50], information was gathered about the toxins inhibiting sodium channels and having an antinociceptive effect. The authors of [51] collected the data on cysteine knot peptides from spider venoms that modulate Nav and performed analysis of the structure–activity relationships of the compounds.…”