Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: Involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors

Inflammation is the first response of the immune system to harmful stimuli such as infection or irritation, consists of a cascade of biochemical events that propagates and matures the inflammatory response. Number of anti-inflammatory drugs are available for treatment of acute and chronic inflammation. Many anti-inflammatory drugs cause adverse side effects. The quinoline class of compounds are important for searching the safe and effective anti-inflammatory drugs. These drugs are classified based on the number of substituents present on the quinoline ring or compounds containing a quinoline ring fused to other heterocyclic compounds. Quinolines have the ability to target several causes of inflammation includes transient receptor potential vanilloid 1 receptor. The TRPV1 receptor, first cloned and characterized in 1997, is a non-selective cation channel expressed in primary sensory neurons, and is a key pain sensor and integrator. This review provides the discovery of various quinoline derivatives as transient receptor potential vanilloid 1 (TRPV1) antagonists. Overall, the quinoline moiety will be used as a new template for designing and identifying the novel anti-inflammatory drugs in future. Keywords: Quinoline, Inflammation, Transient receptor Potential Vanilloid 1, Antagonists.

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Antioxidative and Analgesic Effects of Naringin through Selective Inhibition of Transient Receptor Potential Vanilloid Member 1

Antioxidants ◽

10.3390/antiox11010064 ◽

2021 ◽

Vol 11 (1) ◽

pp. 64

Author(s):

Sanung Eom ◽

Bo-Bae Lee ◽

Shinhui Lee ◽

Youngseo Park ◽

Hye Duck Yeom ◽

...

Keyword(s):

Neuropathic Pain ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Selective Inhibition ◽

Transient Receptor Potential Vanilloid ◽

Amino Acid Residues ◽

Suppression Effect ◽

Analgesic Effects ◽

Inward Currents ◽

Transient Receptor

Transient receptor potential vanilloid member 1 (TRPV1) is activated in response to capsaicin, protons, temperature, and free reactive oxygen species (ROS) released from inflammatory molecules after exposure to harmful stimuli. The expression level of TRPV1 is elevated in the dorsal root ganglion, and its activation through capsaicin and ROS mediates neuropathic pain in mice. Its expression is high in peripheral and central nervous systems. Although pain is a response evolved for survival, many studies have been conducted to develop analgesics, but no clear results have been reported. Here, we found that naringin selectively inhibited capsaicin-stimulated inward currents in Xenopus oocytes using a two-electrode voltage clamp. The results of this study showed that naringin has an IC50 value of 33.3 μM on TRPV1. The amino acid residues D471 and N628 of TRPV1 were involved in its binding to naringin. Our study bridged the gap between the pain suppression effect of TRPV1 and the preventive effect of naringin on neuropathic pain and oxidation. Naringin had the same characteristics as a model selective antagonist, which is claimed to be ideal for the development of analgesics targeting TRPV1. Thus, this study suggests the applicability of naringin as a novel analgesic candidate through antioxidative and analgesic effects of naringin.

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Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn

Anesthesiology ◽

10.1097/aln.0000000000001700 ◽

2017 ◽

Vol 127 (2) ◽

pp. 355-371 ◽

Cited By ~ 10

Author(s):

Nobuko Ohashi ◽

Daisuke Uta ◽

Mika Sasaki ◽

Masayuki Ohashi ◽

Yoshinori Kamiya ◽

...

Keyword(s):

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Direct Application ◽

Transient Receptor Potential Vanilloid ◽

Analgesic Effects ◽

Spinal Dorsal ◽

C Fibers ◽

Transient Receptor

Abstract Background The widely used analgesic acetaminophen is metabolized to N-acylphenolamine, which induces analgesia by acting directly on transient receptor potential vanilloid 1 or cannabinoid 1 receptors in the brain. Although these receptors are also abundant in the spinal cord, no previous studies have reported analgesic effects of acetaminophen or N-acylphenolamine mediated by the spinal cord dorsal horn. We hypothesized that clinical doses of acetaminophen induce analgesia via these spinal mechanisms. Methods We assessed our hypothesis in a rat model using behavioral measures. We also used in vivo and in vitro whole cell patch-clamp recordings of dorsal horn neurons to assess excitatory synaptic transmission. Results Intravenous acetaminophen decreased peripheral pinch-induced excitatory responses in the dorsal horn (53.1 ± 20.7% of control; n = 10; P < 0.01), while direct application of acetaminophen to the dorsal horn did not reduce these responses. Direct application of N-acylphenolamine decreased the amplitudes of monosynaptic excitatory postsynaptic currents evoked by C-fiber stimulation (control, 462.5 ± 197.5 pA; N-acylphenolamine, 272.5 ± 134.5 pA; n = 10; P = 0.022) but not those evoked by stimulation of Aδ-fibers. These phenomena were mediated by transient receptor potential vanilloid 1 receptors, but not cannabinoid 1 receptors. The analgesic effects of acetaminophen and N-acylphenolamine were stronger in rats experiencing an inflammatory pain model compared to naïve rats. Conclusions Our results suggest that the acetaminophen metabolite N-acylphenolamine induces analgesia directly via transient receptor potential vanilloid 1 receptors expressed on central terminals of C-fibers in the spinal dorsal horn and leads to conduction block, shunt currents, and desensitization of these fibers.

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Chronic pain models amplify transient receptor potential vanilloid 1 (TRPV1) receptor responses in adult rat spinal dorsal horn

Neuropharmacology ◽

10.1016/j.neuropharm.2019.107753 ◽

2019 ◽

Vol 160 ◽

pp. 107753 ◽

Cited By ~ 2

Author(s):

Daisuke Uta ◽

Megumu Yoshimura ◽

Kohei Koga

Keyword(s):

Chronic Pain ◽

Spinal Dorsal Horn ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Trpv1 Receptor ◽

Adult Rat ◽

Spinal Dorsal ◽

Pain Models ◽

Transient Receptor

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Angelica dahurica extracts attenuate CFA-induced inflammatory pain via TRPV1 in mice

10.21203/rs.3.rs-151543/v1 ◽

2021 ◽

Author(s):

Chan Zhu ◽

Meiyuan Wang ◽

Jun Guo ◽

Shu-Lan Su ◽

Guang Yu ◽

...

Keyword(s):

Inflammatory Pain ◽

Analgesic Effect ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Ultra Performance Liquid Chromatography ◽

Transient Receptor Potential Vanilloid ◽

Angelica Dahurica ◽

Protein Activity ◽

Pain Models ◽

Transient Receptor

Abstract Background: Angelica dahurica, belonging to the family Apiaceae, is a well-known herbal medicine. The roots of Angelica dahurica is commonly used for the treatment of headache, toothache, abscess, furunculosis, and acne. However, little is known about their analgesic molecular mechanism underlying pain relief. Here, we investigated the anti-nociceptive activity of Angelica dahurica extracts（ADE） in complete freund's adjuvant(CFA)-induced inflammatory pain mice models, and its possible mechanism of the action associated with transient receptor potential vanilloid member 1 (TRPV1) was also explored. Material and Methods: In this study, we used behavioral tests to assess the analgesic effect of the ADE on CFA-induced inflammatory pain mice models. TRPV1 protein activity in dorsal root ganglion (DRG) was assessed with calcium imaging assay. TRPV1 expression was detected with western blot and immunohistochemistry. Then we examined the constituents of ADE using combined ultra-performance liquid chromatography-quadrupole time-of-light mass spectrometry (UPLC/Q−TOF−MS).Results: Our results showed that ADE effectively attenuated mechanical and thermal hypersensitivities in CFA-induced inflammatory pain model in mice. ADE also significantly reduced the activity and the protein expression of TRPV1 in DRG from CFA mice. Conclusion: These findings suggest that ADE exhibits an analgesic effect in CFA inflammatory pain models by targeting TRPV1. Therefore, ADE might be an attractive and suitable analgesic agent for the management of chronic inflammatory pain.

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Differential Effects of Peripheral versus Central Coadministration of QX-314 and Capsaicin on Neuropathic Pain in Rats

Anesthesiology ◽

10.1097/aln.0b013e318260de41 ◽

2012 ◽

Vol 117 (2) ◽

pp. 365-380 ◽

Cited By ~ 15

Author(s):

Jun Shen ◽

Lyle E. Fox ◽

Jianguo Cheng

Keyword(s):

Neuropathic Pain ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Intrathecal Administration ◽

Vanilloid Receptor ◽

Transient Receptor Potential Vanilloid ◽

Spontaneous Pain ◽

Analgesic Effects ◽

Vanilloid Receptor 1 ◽

Transient Receptor

Background Neuropathic pain is common and difficult to treat. Recently a technique was developed to selectively inhibit nociceptive inputs by simultaneously applying two drugs: capsaicin, a transient receptor potential vanilloid receptor-1 channel activator, and QX-314, a lidocaine derivative that intracellularly blocks sodium channels. We used this technique to investigate whether transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain. Methods The rat chronic constriction injury model was used to induce neuropathic pain in order to test the analgesic effects of both peripheral (perisciatic) and central (intrathecal) administration of the QX-314/capsaicin combination. The Hargreaves and von Frey tests were used to monitor evoked pain-like behaviors and visual observations were used to rank spontaneous pain-like behaviors. Results Perisciatic injections of the QX-314/capsaicin combination transiently increased the withdrawal thresholds by approximately 3-fold, for mechanical and thermal stimuli in rats (n = 6/group) with nerve injuries suggesting that peripheral transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain. In contrast, intrathecal administration of the QX-314/capsaicin combination did not alleviate pain-like behaviors (n = 5/group). Surprisingly, intrathecal QX-314 alone (n = 9) or in combination with capsaicin (n = 8) evoked spontaneous pain-like behaviors. Conclusions Data from the perisciatic injections suggested that a component of neuropathic pain was mediated by peripheral nociceptive inputs. The role of central nociceptive terminals could not be determined because of the severe side effects of the intrathecal drug combination. We concluded that only peripheral blockade of transient receptor potential vanilloid receptor 1-expressing nociceptive afferents by the QX-314/capsaicin combination was effective at reducing neuropathic allodynia and hyperalgesia.

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