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Overactivation of N-methyl-D-aspartate receptor (NMDAR) in the spinal cord dorsal horn (SDH) in the setting of injury represents a key mechanism of neuropathic pain. However, directly blocking NMDAR or its downstream signaling, interaction between postsynaptic density-95 (PSD-95) and neuronal nitric oxide synthase (nNOS), causes analgesic tolerance, mainly due to GABAergic disinhibition. The aim of this study is to explore the possibility of preventing analgesic tolerance through co-targeting NMDAR downstream signaling and γ-aminobutyric acid type A receptors (GABARs). Mechanical/thermal hyperalgesia were quantified to assess analgesic effects. Miniature postsynaptic currents were tested by patch-clamp recording to evaluate synaptic transmission in the SDH. GABA-evoked currents were tested on HEK293 cells expressing different subtypes of recombinant GABARs to assess the selectivity of (+)-borneol and ZL006-05. The expression of α2 and α3 subunits of GABARs and BDNF, and nNOS-PSD-95 complex levels were analyzed by western blotting and coimmunoprecipitation respectively. Open field test, rotarod test and Morris water maze task were conducted to evaluate the side-effect of ZL006-05. (+)-Borneol selectively potentiated α2- and α3-containing GABARs and prevented the disinhibition of laminae I excitatory neurons in the SDH and analgesic tolerance caused by chronic use of ZL006, a nNOS-PSD-95 blocker. A dual-target compound ZL006-05 produced by linking ZL006 and (+)-borneol through an ester bond blocked nNOS-PSD-95 interaction and potentiated α2-containing GABAR selectively. Chronic use of ZL006-05 did not produce analgesic tolerance and unwanted side effects. By targeting nNOS-PSD-95 interaction and α2-containing GABAR simultaneously, chronic use of ZL006-05 can avoid analgesic tolerance and unwanted side effects. Therefore, we offer a novel candidate drug without analgesic tolerance for treating neuropathic pain.
Learn More >Recent studies have shown that ZBTB20, a zinc-finger protein containing transcription factor, is highly expressed in small-diameter primary sensory neurons in mice, and modulates pain through regulating TRP channels. However, whether ZBTB20 regulates itch sensation has not been demonstrated. In this study, small-diameter primary sensory neuron-specific ZBTB20 knockout (PN-ZB20KO) mice were used to investigate the role of ZBTB20 in the regulation of itch sensation. First, both histamine-dependent and non-histamine-dependent itch behaviors induced by injection of histamine and chloroquine (CQ) into the cheek were significantly diminished in PN-ZB20KO mice. Second, double immunohistochemistry showed that ZBTB20 was mainly expressed in CGRP-labeled small peptidergic neurons and was expressed at low levels in IB4-labeled small non-peptidergic and NF200-labeled large neurons in the trigeminal ganglia (TG). ZBTB20 was also expressed in most TRPV1 and TRPA1 neurons and to a lesser extent in TRPM8 neurons in the TG. Furthermore, cheek injection of histamine and CQ enhanced the mRNA expression of TRPV1 and TRPA1 but not TRPM8 in the TG. Moreover, TRPV1 and TRPA1 knockout (KO) mice exhibited attenuation of itch behavior induced by histamine and CQ, respectively. Finally, silencing endogenous ZBTB20 with recombinant lentivirus expressing a short hairpin RNA against ZBTB20 (LV-shZBTB20) in TG neurons attenuated histamine- and non-histamine-induced itch and downregulated TRP channels in the TG. Our study suggests that ZBTB20 plays an important role in mediating itch in small primary sensory neurons.
Learn More >Alcohol is an effective and widely utilized analgesic. However, the chronic use of alcohol can actually facilitate nociceptive sensitivity over time, a condition known as hyperalgesia. Excessive and uncontrollable alcohol drinking is also a hallmark feature of alcohol use disorder (AUD). Both AUD and chronic pain are typically accompanied by negative affective states that may underlie reinforcement mechanisms contributing to AUD maintenance or progression. Frequent utilization of alcohol to relieve pain in individuals suffering from AUD or other chronic pain conditions may thus represent a powerful negative reinforcement construct. This chapter will describe ties between alcohol-mediated pain relief and potential exacerbation of AUD. We describe neurobiological systems engaged in alcohol analgesia as well as systems recruited in the development and maintenance of AUD and hyperalgesia. Although few effective therapies exist for either chronic pain or AUD, the common interaction of these conditions will likely lead the way for promising new discoveries of more effective and even simultaneous treatment of AUD and co-morbid hyperalgesia. An abundance of neurobiological findings from multiple laboratories has implicated a potentiation of central amygdala (CeA) signaling in both pain and AUD, and these data also suggest that attenuation of stress-related systems (including corticotropin-releasing factor, vasopressin, and glucocorticoid receptor activity) would be particularly effective and comprehensive therapeutic strategies targeting the critical intersection of somatic and motivational mechanisms driving AUD, including alcohol-induced hyperalgesia.
Learn More >Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2 (PAK2) and improves skin lesions in Nc/Nga mice as an AD model. In the present study, we investigate the effect of PQA-18 on sensory nerves in lesional skin. PQA-18 alleviates cutaneous nerve fiber density in the skin of Nc/Nga mice. PQA-18 also inhibits IL-31-induced sensory nerve fiber outgrowth in dorsal root ganglion cultures. Signaling analysis reveals that PQA-18 suppresses phosphorylation of PAK2, Janus kinase 2, and signal transducer and activator of transcription 3 (STAT3), activated by IL-31 receptor (IL-31R), resulting in inhibition of neurite outgrowth in Neuro2A cells. Gene silencing analysis for PAK2 confirms the requirement for STAT3 phosphorylation and neurite outgrowth elicited by IL-31R activation. LC/MS/MS analysis reveals that PQA-18 prevents the formation of PAK2 activation complexes induced by IL-31R activation. These results suggest that PQA-18 inhibits the IL-31 pathway through suppressing PAK2 activity, which suppresses sensory nerve outgrowth. PQA-18 may be a valuable lead for the development of a novel drug for pruritus of AD.
Learn More >Patients with irritable bowel syndrome (IBS) in referral practice commonly report mental disorders and functional impairment. Our aim was to determine the prevalence of mental, physical and sleep-related comorbidities in a nationally representative sample of IBS patients and their impact on functional impairment.
Learn More >To synthesize results of somatosensory processing tests in people with upper- and lower-limb tendinopathy, compared to controls.
Learn More >Dyspareunia, also known as vaginal hyperalgesia, is a prevalent and debilitating symptom of gynaecological disorders such as endometriosis and vulvodynia. Despite this, the sensory pathways transmitting nociceptive information from female reproductive organs remain poorly characterised. As such, the development of specific treatments for pain associated with dyspareunia is currently lacking. Here, we examined, for the first time, (1) the mechanosensory properties of pelvic afferent nerves innervating the mouse vagina; (2) the expression profile of voltage-gated sodium (NaV) channels within these afferents; and (3) how pharmacological modulation of these channels alters vaginal nociceptive signalling ex vivo, in vitro, and in vivo. We developed a novel afferent recording preparation and characterised responses of pelvic afferents innervating the mouse vagina to different mechanical stimuli. Single-cell reverse transcription-polymerase chain reaction determined mRNA expression of NaV channels within vagina-innervating dorsal root ganglia neurons. Vagina-innervating dorsal root ganglia neuroexcitability was measured using whole-cell patch-clamp electrophysiology. Nociception evoked by vaginal distension was assessed by dorsal horn neuron activation within the spinal cord and quantification of visceromotor responses. We found that pelvic afferents innervating the vagina are tuned to detect various mechanical stimuli, with NaV channels abundantly expressed within these neurons. Pharmacological modulation of NaV channels (with veratridine or tetrodotoxin) correspondingly alters the excitability and mechanosensitivity of vagina-innervating afferents, as well as dorsal horn neuron activation and visceromotor responses evoked by vaginal distension. This study identifies potential molecular targets that can be used to modulate vaginal nociceptive signalling and aid in the development of approaches to manage endometriosis and vulvodynia-related dyspareunia.
Learn More >Endometriosis (EM) is characterized by the growth of endometrium-like tissue outside the uterus, leading to chronic inflammation and pelvic pain. Lesion proliferation, vascularization, and associated inflammation are the hallmark features of EM lesions. The legalization of recreational cannabinoids has garnered interest in the patient community and is contributing to a greater incidence of self medication; however, it remains unknown if cannabinoids possess marked disease-modifying properties. In this study, we assess the effects of synthetic cannabinoid, WIN 55212-2 (WIN 55), in EM-representative and syngeneic mouse models. WIN 55 reduced proliferation and angiogenesis MAPK/Akt-mediated apoptosis. These findings were corroborated in a mouse model of EM, where we found reduced TRPV1 expression in the dorsal root ganglia of the EM mouse model exposed to WIN 55, suggesting reduced signaling of pain stimuli. Ultimately, these pieces of evidence support the use of cannabinoid receptor agonists as a potential therapeutic intervention for EM associated pain and inflammation.
Learn More >Diabetic neuropathy is the most entrenched complication of diabetes. Usually, it affects the distal foot and toes, which then gradually approaches the lower part of the legs. Diabetic foot ulcer (DFU) could be one of the worst complications of diabetes mellitus. Long-term diabetes leads to hyperglycemia, which is the utmost contributor to neuropathic pain. Hyperglycemia causing an upregulation of voltage-gated sodium channels in the dorsal root ganglion (DRG) was often observed in models of neuropathic pain. DRG opening frequency increases intracellular sodium ion levels, which further causes increased calcium channel opening and stimulates other pathways leading to diabetic peripheral neuropathy (DPN). Currently, pain due to diabetic neuropathy is managed antidepressants, opioids, gamma-aminobutyric acid (GABA) analogs, and topical agents such as capsaicin. Despite the availability of various treatment strategies, the percentage of patients achieving adequate pain relief remains low. Many factors contribute to this condition, such as lack of specificity and adverse effects such as light-headedness, languidness, and multiple daily doses. Therefore, nanotechnology outperforms in every aspect, providing several benefits compared to traditional therapy such as site-specific and targeted drug delivery. Nanotechnology is the branch of science that deals with the development of nanoscale materials and products, even smaller than 100 nm. Carriers can improve their efficacy with reduced side effects by incorporating drugs into the novel delivery systems. Thus, the utilization of nanotechnological approaches such as nanoparticles, polymeric nanoparticles, inorganic nanoparticles, lipid nanoparticles, gene therapy (siRNA and miRNA), and extracellular vesicles can extensively contribute to relieving neuropathic pain.
Learn More >Transient receptor potential vanilloid 4 (TRPV4) is a non-selective mechanosensitive ion channel expressed by various macrophage populations. Recent reports have characterized the role of TRPV4 in shaping the activity and phenotype of macrophages to influence the innate immune response to pathogen exposure and inflammation. TRPV4 has been studied extensively in the context of inflammation and inflammatory pain. Although TRPV4 activity has been generally described as pro-inflammatory, emerging evidence suggests a more complex role where this channel may also contribute to anti-inflammatory activities. However, detailed understanding of how TRPV4 may influence the initiation, maintenance, and resolution of inflammatory disease remains limited. This review highlights recent insights into the cellular processes through which TRPV4 contributes to pathological conditions and immune processes, with a focus on macrophage biology. The potential use of high-throughput and omics methods as an unbiased approach for studying the functional outcomes of TRPV4 activation is also discussed.
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