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Pain-related scorpion species. Scorpion species of medical importance are circled in red, those that are harmless to humans are circled in blue. Red drop: scorpions with highly painful stings; pink drop: scorpions whose sting is mildly painful. Tx: presence of pro-algic toxins in the venom; Tx: presence of antinociceptive toxins in the venom; Tx: presence of toxins having an effect only on pain-related channels.
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Abstract Pain is a common symptom induced during envenomation by spiders and scorpions. Toxins isolated from their venom have become essential tools for studying the functioning and physiopathological role of ion channels, as they modulate their activity. In particular, toxins that induce pain relief effects can serve as a molecular basis for the d...
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Context 1
... more than 1.2 million stings a year and more than 3250 deaths, scorpionism is a major public health problem in subtropical areas worldwide [5] despite the fact that less than 25 species are considered dangerous to humans. The "Old Word" (Africa) species of medical interest belong to Andoctonus, Buthus, Hottentota, Leiurus genera while "New World" (America) species are part of Centruroides and Tityus genera, all in the Buthid family ( Figure 1). Severe envenomation in humans primarily occurs in tropical regions and during hot seasons (North and Sub-Saharan Africa, Middle East, Asia, Latin America), with stings inoculating a few microliters of venom. ...
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Alpha-latrotoxin (ɑLTx) is the component responsible for causing the pathophysiology in patients bitten by spiders from the genus Latrodectus, commonly known as black widow spiders. The current antivenom used to treat these envenomations in Mexico is produced using the venom of thousands of spiders, obtained through electrical stimulation. This wor...
Citations
... One of the remarkable aspects of animal peptides is the diversity in their sources and structures. Venomous creatures, such as snakes, spiders [40,41], and cone snails, are wellknown for producing peptides with potent bioactivities, including antinociceptive effects [42]. Additionally, peptides derived from insects or the skin secretions of amphibians have also shown promise in pain modulation. ...
... Spider venom contains a broad range of peptide toxins, exerting several activities in biological systems. To date, a large number of peptides with antinociceptive properties have been isolated from several spider venoms [40,41,52]. Typical spider peptides are rich in disulfide brides, which form the inhibitor cystine knot (ICK) motif. ...
Pain affects one-third of the global population and is a significant public health issue. The use of opioid drugs, which are the strongest painkillers, is associated with several side effects, such as tolerance, addiction, overdose, and even death. An increasing demand for novel, safer analgesic agents is a driving force for exploring natural sources of bioactive peptides with antinociceptive activity. Since the G protein-coupled receptors (GPCRs) play a crucial role in pain modulation, the discovery of new peptide ligands for GPCRs is a significant challenge for novel drug development. The aim of this review is to present peptides of human and animal origin with antinociceptive potential and to show the possibilities of their modification, as well as the design of novel structures. The study presents the current knowledge on structure-activity relationship in the design of peptide-based biomimetic compounds, the modification strategies directed at increasing the antinociceptive activity, and improvement of metabolic stability and pharmacodynamic profile. The procedures employed in prolonged drug delivery of emerging compounds are also discussed. The work summarizes the conditions leading to the development of potential morphine replacements.
... Nine subtypes of sodium channels (Nav1.1ÀNav1.9) encoded by the genes SCN1A-SCN5A and SCN8A-SCN11A are known (Bennett et al., 2019;de Lera Ruiz and Kraus, 2015;Díaz-García and Varela, 2020;Diochot, 2021), and they can to expressed in different cells type of the central nervous system (CNS; Nav1.1, Nav1.2, Nav1.3, Nav1.5, and Nav1.6) and the peripheral nervous system (PNS; Nav1.7, Nav1.8, and Nav1.9) (Candenas et al., 2006;Lai and Jan, 2006;Pappalardo et al., 2016;Vacher et al., 2008;Wang et al., 2017), as well as skeletal (Nav 1.4) and cardiac muscle (Nav1.1, ...
... In neurons, these channels contribute to the electrical properties membrane, determine the frequency and the shape of the action potential waveform, control the strength of synaptic contacts between neurons, and set and maintain resting membrane potentials. The Kv1.1, Kv2, Kv3, Kv4, Kv7, K Ca 1, K Ca 2, K ir 3, K 2P 2, K 2P 3, K 2P 4, and K 2P9 channels are localized differentially in the somatic nervous system, axonal, presynaptic terminal, and dendritic membranes (Alexander et al., 2021;Conte Camerino et al., 2007;Diochot, 2021;Judge et al., 2007). ...
... A vast array of venom toxins has been identified to interact with both voltage-gated and ligand-gated ion channels. Many of the toxins that target voltage-gated ion channels have been extracted from arthropod venoms, such as those found in scorpions and spiders (Gilchrist et al., 2014;Diochot, 2021). In terms of venom toxins affecting ligand-gated ion channels (Nasiripourdori et al., 2011), the most extensively studied toxins are those derived from cone snail venoms (Arias and Blanton, 2000) and snake venoms (Barber et al., 2013). ...
Ion channels play a crucial role in diverse physiological processes, including neurotransmission and muscle contraction. Venomous creatures exploit the vital function of ion channels by producing toxins in their venoms that specifically target these ion channels to facilitate prey capture upon a bite or a sting. Envenoming can therefore lead to ion channel dysregulation, which for humans can result in severe medical complications that often necessitate interventions such as antivenom administration. Conversely, the discovery of highly potent and selective venom toxins with the capability of distinguishing between different isoforms and subtypes of ion channels has led to the development of beneficial therapeutics that are now in the clinic. This review encompasses the historical evolution of electrophysiology methodologies, highlighting their contributions to venom and antivenom research, including venom-based drug discovery and evaluation of antivenom efficacy. By discussing the applications and advancements in patch-clamp techniques, this review underscores the profound impact of electrophysiology in unravelling the intricate interplay between ion channels and venom toxins, ultimately leading to the development of drugs for envenoming and ion channel-related pathologies.
... Spiders inject venom when they bite and it contains a substantial array of components [100]. Many of these activate nociceptors and result in pain (in humans) but there can also be antinociceptive compounds that have the opposite effect. ...
... Many of these activate nociceptors and result in pain (in humans) but there can also be antinociceptive compounds that have the opposite effect. The functional significance of these substances that influence nociceptors is not clear and it is not known if they are used to deter arthropod predators [100]. Most attention is directed toward their use against vertebrate predators, but it is estimated that the venoms were originally used against arthropods [101]. ...
Pain in response to tissue damage functions to change behaviour so that further damage is minimised whereas healing and survival are promoted. This paper focuses on the behavioural criteria that match the function to ask if pain is likely in the main taxa of arthropods. There is evidence consistent with the idea of pain in crustaceans, insects and, to a lesser extent, spiders. There is little evidence of pain in millipedes, centipedes, scorpions, and horseshoe crabs but there have been few investigations of these groups. Alternative approaches in the study of pain are explored and it is suggested that studies on traumatic mating, agonistic interactions, and defensive venoms might provide clues about pain. The evolution of high cognitive ability, sensory systems, and flexible decision-making is discussed as well as how these might influence the evolution of pain-like states.
... Mostly, no pain was found post-envenomation of these spiders, but the wound grows broader and deeper with time, and the site might become gangrenous and very painful. Along with localized effects, envenomation of these spiders also showed systemic effects like hemolysis, kidney damage, and muscle cramps 234,249 . ...
The mere glimpse of venomous animals has always terrified humans because of the devastating effects of their venoms. However , researchers across the globe have isolated therapeutically active ingredients from these venoms and continue to explore them for drug leads. These efforts lead to the discovery of therapeutic molecules that the US-FDA has approved to treat different diseases, such as hypertension (Captopril), chronic pain (Ziconotide), and diabetes (Exenatide). The main active constituents of most venoms are proteins and peptides, which gained more attention because of advancements in biotechnology and drug delivery. The utilization of newer screening approaches improved our understanding of the pharmacological complexity of venom constituents and facilitated the development of novel therapeutics. Currently, with many venom-derived peptides undergoing different phases of clinical trials, more are in pre-clinical drug development phases. This review highlights the various sources of venoms, their pharmacological actions, and the current developments in venom-based therapeutics.
... Mostly, no pain was found post-envenomation of these spiders, but the wound grows broader and deeper with time, and the site might become gangrenous and very painful. Along with localized effects, envenomation of these spiders also showed systemic effects like hemolysis, kidney damage, and muscle cramps 234,249 . ...
The mere glimpse of venomous animals has always terrified humans because of the devastating effects of their venoms. However, researchers across the globe have isolated therapeutically active ingredients from these venoms and continue to explore them for drug leads. These efforts lead to the discovery of therapeutic molecules that the US-FDA has approved to treat different diseases, such as hypertension (Captopril), chronic pain (Ziconotide), and diabetes (Exenatide).
The main active constituents of most venoms are proteins and peptides, which gained more attention because of advancements in biotechnology and drug delivery. The utilization of newer screening approaches improved our understanding of the pharmacological complexity of venom constituents and facilitated the development of novel therapeutics. Currently, with many venom-derived peptides undergoing different phases of clinical trials, more are in pre-clinical drug development phases. This review highlights the various sources of venoms, their pharmacological actions, and the current developments in venom-based therapeutics.
... Toxins are bioactive peptides that act with high affinity and specificity on various molecular targets, among them ion channels [20,21]. These peptides can have a neurotoxic, cardiotoxic, antimicrobial, antifungal, or enzymatic action, can produce paralysis or death, and can aid prey digestion [22]. Considering the number of spider species and data from the mass spectrometric analysis of venoms, spiders may produce an estimated 2-20 million peptides [20,23,24]. ...
Background:
Phonotimpus pennimani (Araneae, Phrurolithidae) is a small-sized (3-5 mm) spider endemic to the Tacaná volcano in Chiapas, Mexico, where it is found in soil litter of cloud forests and coffee plantations. Its venom composition has so far not been investigated, partly because it is not a species of medical significance. However, it does have an important impact on the arthropod populations of its natural habitat.
Methods:
Specimens were collected in Southeastern Mexico (Chiapas) and identified taxonomically by morphological characteristics. A partial sequence from the mitochondrial gene coxI was amplified. Sequencing on the Illumina platform of a transcriptome library constructed from 12 adult specimens revealed 25 toxin or toxin-like genes. Transcripts were validated (RT-qPCR) by assessing the differential expression of the toxin-like PpenTox1 transcript and normalising with housekeeping genes.
Results:
Analysis of the coxI-gene revealed a similarity to other species of the family Phrurolithidae. Transcriptome analysis also revealed similarity with venom components of species from the families Ctenidae, Lycosidae, and Sicariidae. Expression of the toxin-like PpenTox1 gene was different for each developmental stage (juvenile or adult) and also for both sexes (female or male). Additionally, a partial sequence was obtained for the toxin-like PpenTox1 from DNA.
Conclusion:
Data from the amplification of the mitochondrial coxI gene confirmed that P. pennimani belongs to the family Phrurolithidae. New genes and transcripts coding for venom components were identified.
... Although spider envenomation commonly results in localized pain, most spider peptides studied to date block Na V and Ca V channels and therefore act to inhibit neuronal excitability. 34,35,52 This however is almost certainly a reflection of "discovery bias" because most spider venom-screening efforts have focused on finding inhibitors of key analgesic targets, such as Na V 1.7 and Ca V 2.2. 47,69,118 Nevertheless, several spider venom-derived peptides with algogenic activity have provided crucial insights into the structure and function of TRPV1 and Na V channels, and these are discussed in greater detail below. ...
... Peptide toxins can modulate TRPV1 activation by binding to specific domains, including the outer pore domain [6]. Various peptide toxins directly inhibit or activate this channel by binding to sites in the outer pore domain involved in the channel's gating mechanism [90,91]. In particular, some toxins, including DxTx, BmP01, and RhTx, have been shown to activate or inhibit TRPV1 by binding to the outer pore domain of the channels (Figure 1) [6,90,91]. ...
... Various peptide toxins directly inhibit or activate this channel by binding to sites in the outer pore domain involved in the channel's gating mechanism [90,91]. In particular, some toxins, including DxTx, BmP01, and RhTx, have been shown to activate or inhibit TRPV1 by binding to the outer pore domain of the channels (Figure 1) [6,90,91]. This implies that the outer pore region of TRPV1 is a common domain for binding and channel gating by different peptide animal toxins and highlights the importance of the outer pore domain in TRPV1 activation [36]. ...
The transient receptor potential vanilloid 1 (TRPV1) ion channel plays an important role in the peripheral nociceptive pathway. TRPV1 is a polymodal receptor that can be activated by multiple types of ligands and painful stimuli, such as noxious heat and protons, and contributes to various acute and chronic pain conditions. Therefore, TRPV1 is emerging as a novel therapeutic target for the treatment of various pain conditions. Notably, various peptides isolated from venomous animals potently and selectively control the activation and inhibition of TRPV1 by binding to its outer pore region. This review will focus on the mechanisms by which venom-derived peptides interact with this portion of TRPV1 to control receptor functions and how these mechanisms can drive the development of new types of analgesics.
For almost as long as the ion channels in our brains have powered conscious thought, we have been fascinated by venoms and toxins. Initially thought of as magical, now we are understanding their true power and utility in drug discovery. A diverse range of venoms and toxins have been used to decipher the properties of ion channels and as a result hold a key functional place as positive controls in many assays. Such control toxins include tetrodotoxin, protoxin and charybdotoxin that are found in diverse species. The latest advances in computational chemistry and structural biology, such as cryogenic electron microscopy and free energy perturbation, are opening our drug discovery gaze to the atomic interactions of toxins and ion channels. Coupled with advances in ion channel screening and peptide biochemistry, we are on the verge of a new wave of toxin discovery and clinical application. These toxins also tackle challenging drug targets that are in desperate need of new chemical modalities. This chapter details the advances in toxin drug discovery though clinical development and new understanding of licensed drugs that feeds back to improve further therapeutic opportunities.
