Human pharmacological approaches to TRP-ion-channel-based analgesic drug development

Weyer-Menkhoff, Iris; Lötsch, Jörn

doi:10.1016/j.drudis.2018.06.020

Cited by 38 publications

(32 citation statements)

References 67 publications

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“…As is known to all, the most popular analgesia drug, opioid, is hampered by desirable side-effects such as tolerance, respiratory depression, and addiction [13,14]. The transient receptor potential vanilloid 1 (TRPV1) antagonists have side-effects such as loss of the noxious heat sensation, increased burn risk, and hyperthermia [15]. Obviously, these challenges drive us to find drugs targeting selectively on modulation of peripheral mechanisms and not crossing the blood-brain-barrier, through which the side-effects may be avoided.…”

Section: Challenges In Developing Effective Drugsmentioning

confidence: 99%

Peripheral Sensitization

Wei¹,

Tao²,

Yang³

et al. 2020

Peripheral Nerve Disorders and Treatment

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Peripheral sensitization indicates increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation, which usually occurs after peripheral tissue injury and inflammation. As an integral part of pain, peripheral sensitization and its mechanisms have received much attention, and numerous types of neurotransmitters and chemicals related to peripheral sensitization were investigated. We developed an animal model of peripheral sensitization, and it provides evidence that some neurotransmitters, such as glutamate and substance P, release from adjacent peripheral nerves contributing to the peripheral sensitization of pathological pain. In this chapter, we reviewed the advances in peripheral sensitization, and it will provide a basis for new targets to attenuate pain of peripheral origin.Several animal models of various pain states have been established to investigate the mechanisms of peripheral sensitization, for example, inflammation pain models, neuropathic pain evoked by disease or damage to peripheral nerves, and post-operative pain models. Animal models of inflammatory pain have used a number of different irritants that are injected into skin, paw, muscle, joint, and visceral organ. Carrageenan, complete Freund's adjuvant (CFA), and capsaicin are commonly used inflammatory irritants to induce hyperalgesia. Common nerve injury models include: (1) ligating or transecting the spinal nerves, such as spinal nerve ligation model (SNL); (2) ligating or lesioning the sciatic nerve, such as chronic constriction injury (CCI); and (3) ligating distal branches (peroneal and tibial) of the sciatic nerve (spared nerve injury) [16].To better understand the mechanisms of transmission between peripheral sensory nerve endings, we have successfully established an electrophysiological animal model in which antidromic electrical stimulation of a sensory nerve excites the adjacent primary afferents from the different spinal segments [17]. In this model, two adjacent cutaneous branches of spinal dorsal rami in the thoracic segments, T9 and T10, were dissociated and transected proximally from the spinal cord in anesthetized rats. Then antidromic electrical stimulation with 0.5 ms pulse duration, 20 Hz frequency, and 1 mA intensity was applied to T9 spinal nerve branch, and the nerve activities of T10 nerve branch were recorded [18]. All recorded afferent neurons from the T10 cutaneous branch were classified as Aβ, Aδ, and C fibers according to the conduction velocity and the receptive properties [19]. The discharges of the isolated Aβ, Aδ, and C fibers of the T10 cutaneous branch were significantly enhanced by antidromic electrical stimulation of the adjacent T9 spinal nerve branch [18]. It is in line with our previous studies that antidromic stimulation of T9 spinal nerve branch can activate and sensitize Aβ, Aδ, and C fibers obtained from the adjacent T10 dorsal cutaneous branch [20][21][22][23]. The activation and sensitization of these fibers not only occur between the peripheral sensory nerve...

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Section: Challenges In Developing Effective Drugsmentioning

confidence: 99%

Peripheral Sensitization

Wei¹,

Tao²,

Yang³

et al. 2020

Peripheral Nerve Disorders and Treatment

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“…The respective chapter is somewhat overrepresented as an example, but also as it reflects the core expertise of the authors. The scope of this review is broader; TRP channel-directed development of analgesics has been addressed in more focal reviews [ 149 – 151 ].…”

Section: Effects Predominantly or Exclusively On Sensory Neuronsmentioning

confidence: 99%

Novel Analgesics with Peripheral Targets

Ciotu

Fischer

2020

Neurotherapeutics

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A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.

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“…The importance of thermal pain is emphasized by the observation that human experimental pain models that use thermal nociceptive stimuli provide a comparatively good prediction of clinical analgesic drug effects [ 6 , 7 ]. For drugs targeting thermosensitive ion channels, heat or cold-triggered nociception is relevant in both the experimental and clinical setting [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Machine-Learned Association of Next-Generation Sequencing-Derived Variants in Thermosensitive Ion Channels Genes with Human Thermal Pain Sensitivity Phenotypes

Lötsch

Kringel

Geißlinger

et al. 2020

IJMS

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Genetic association studies have shown their usefulness in assessing the role of ion channels in human thermal pain perception. We used machine learning to construct a complex phenotype from pain thresholds to thermal stimuli and associate it with the genetic information derived from the next-generation sequencing (NGS) of 15 ion channel genes which are involved in thermal perception, including ASIC1, ASIC2, ASIC3, ASIC4, TRPA1, TRPC1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4. Phenotypic information was complete in 82 subjects and NGS genotypes were available in 67 subjects. A network of artificial neurons, implemented as emergent self-organizing maps, discovered two clusters characterized by high or low pain thresholds for heat and cold pain. A total of 1071 variants were discovered in the 15 ion channel genes. After feature selection, 80 genetic variants were retained for an association analysis based on machine learning. The measured performance of machine learning-mediated phenotype assignment based on this genetic information resulted in an area under the receiver operating characteristic curve of 77.2%, justifying a phenotype classification based on the genetic information. A further item categorization finally resulted in 38 genetic variants that contributed most to the phenotype assignment. Most of them (10) belonged to the TRPV3 gene, followed by TRPM3 (6). Therefore, the analysis successfully identified the particular importance of TRPV3 and TRPM3 for an average pain phenotype defined by the sensitivity to moderate thermal stimuli.

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Human pharmacological approaches to TRP-ion-channel-based analgesic drug development

Cited by 38 publications

References 67 publications

Peripheral Sensitization

Peripheral Sensitization

Novel Analgesics with Peripheral Targets

Machine-Learned Association of Next-Generation Sequencing-Derived Variants in Thermosensitive Ion Channels Genes with Human Thermal Pain Sensitivity Phenotypes

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