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 39 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

View full text Add to dashboard Cite

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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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“…Cinnamon has been used for centuries as a spice and in traditional medicine (Ranasinghe et al, 2013). Large doses of cinnamon powder (1 -10 g) have been reported for treating diabetes (Pham et al, 2007;Crawford, 2009;Kirkham et al, 2009;Akilen et al, 2010), and the components of cinnamon are under investigation for a wide variety of other maladies including inflammation (Hagenlocher et al, 2016;Schink et al, 2018;Cao et al, 2019;Cheng et al, 2020), multiple sclerosis (Pahan, 2015;Kundu et al, 2016), and pain (Burgess and Williams, 2010;Yokoyama et al, 2011;Weyer-Menkhoff and Lotsch, 2018;Weyer-Menkhoff and Lotsch, 2019). Considering its use in food (Friedman et al, 2000;Rietjens et al, 2020) and as a complementary treatment, there is potential for components in cinnamon to act as precipitants for herb-drug interactions (HDI).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Herb-Drug Interactions Involving Cinnamon and CYP2A6: Focus on Time-Dependent Inhibition by Cinnamaldehyde and 2-Methoxycinnamaldehyde

et al. 2020

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Information is scarce regarding pharmacokinetic-based herb-drug interactions (HDI) with cinnamaldehyde (CA) and 2-methoxycinnamaldehyde (MCA), components of cinnamon. Given the presence of cinnamon in food and herbal treatments for various diseases, HDIs involving the CYP2A6 substrates nicotine and letrozole with MCA (K S = 1.58 µM; Hill slope = 1.16) and CA were investigated. The time-dependent inhibition (TDI) by MCA and CA of CYP2A6-mediated nicotine metabolism is a complex process involving multiple mechanisms. Molecular dynamic simulations showed CYP2A6's active site accommodates two dynamic ligands. The preferred binding orientations for MCA and CA were consistent with the observed metabolism: epoxidation, Odemethylation, and aromatic hydroxylation of MCA, and cinnamic acid formation from CA. The percent remaining activity plots for TDI by MCA and CA were curved, and were analyzed with a numerical method using models of varying complexity. The best fit models support multiple inactivator binding, inhibitor depletion, and partial inactivation. Deconvoluted mass spectra indicated MCA and CA modified CYP2A6 apoprotein with mass additions of 156.79 (142.54-171.04) and 132.67 (123.37-141.98), respectively, and was unaffected by glutathione. Heme degradation was observed in the presence of MCA (48.5 +/-13.4% loss; detected by LC-MS/MS). In the absence of clinical data, HDI predictions were made for nicotine and letrozole using inhibition parameters from the best-fit TDI models and parameters scaled from rats. Predicted AUC-fold changes were 4.29 (CA-nicotine), 4.92 (CA-letrozole), 4.35 (MCA-nicotine), and 5.00 (MCA-letrozole). These findings suggest that extensive exposure to cinnamon (corresponding to ≈ 275 mg CA) would lead to noteworthy interactions.

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

Cited by 39 publications

References 67 publications

Peripheral Sensitization

Peripheral Sensitization

Novel Analgesics with Peripheral Targets

Mechanisms of Herb-Drug Interactions Involving Cinnamon and CYP2A6: Focus on Time-Dependent Inhibition by Cinnamaldehyde and 2-Methoxycinnamaldehyde

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