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Nociceptors can fine-tune local or systemic immunity, but the mechanisms of nociceptive modulation in endotoxic death remain largely unknown. Here, we identified C-type lectin Reg3γ as a nociceptor-enriched hormone that protects the host from endotoxic death. During endotoxemia, nociceptor-derived Reg3γ penetrates the brain and suppresses the expression of microglial indoleamine dioxygenase 1, a critical enzyme of the kynurenine pathway, via the Extl3-Bcl10 axis. Endotoxin-administered nociceptor-null mice and nociceptor-specific Reg3γ-deficient mice exhibit a high mortality rate accompanied by decreased brain HK1 phosphorylation and ATP production despite normal peripheral inflammation. Such metabolic arrest is only observed in the brain, and aberrant production of brain quinolinic acid, a neurotoxic metabolite of the kynurenine pathway, causes HK1 suppression. Strikingly, the central administration of Reg3γ protects mice from endotoxic death by enhancing brain ATP production. By identifying nociceptor-derived Reg3γ as a microglia-targeted hormone, this study provides insights into the understanding of tolerance to endotoxic death.
Learn More >The mechanisms underlying facial pain are still incompletely understood, posing major therapeutic challenges. Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase involved in pain signaling. However, the regulatory roles of Cdk5 in facial pain signaling and the possibility of therapeutic intervention at the level of mouse trigeminal ganglion primary neurons remain elusive. In this study, we use optimized intravital imaging to directly compare trigeminal neuronal activities after mechanical, thermal, and chemical stimulation. We then test whether facial inflammatory pain in mice could be alleviated by the Cdk5 inhibitor peptide TFP5. We demonstrate regulation of total Ca intensity by Cdk5 activity using transgenic and knockout mouse models. In mice with vibrissal pad inflammation, application of TFP5 specifically decreases total Ca intensity in response to noxious stimuli. It also alleviates inflammation-induced allodynia by inhibiting activation of trigeminal peripheral sensory neurons. Cdk5 inhibitors may provide promising non-opioid candidates for pain treatment.
Learn More >Studies have shown that poly (ADP-ribose) polymerase 1 (PARP1) was involved in the pathological process of diabetes. Mitophagy is widely acknowledged to be a key regulatory process in maintaining reactive oxygen species homeostasis via lysosome degradation of damaged mitochondria. However, the regulatory role of PARP1 in mitophagy-related mitochondrial oxidative injury and progression of painful diabetic neuropathy (PDN) is unclear. In this study, we studied the in vitro and in vivo mechanisms of PARP1-mediated mitophagy blockade in a leptin gene-mutation (db/db) mouse model of PDN. Db/db mice models of PDN were established by assessing the sciatic nerve conduction velocity (SNCV), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL). The results showed that PARP1 activity and mitochondrial injury of dorsal root ganglion (DRG) neurons were increased, and mitophagy was impaired in PDN mice. PARP1 was found to mediate the impairment of mitophagy in DRG neurons isolated from PDN mice. PARP1 inhibitors (PJ34 or AG14361) attenuated diabetes-induced peripheral nerve hyperalgesia, restored DRG neuron mitophagy function and decreased mitochondrial oxidative injury. Mitophagy impairment induced by lysosome deacidificant (DC661) aggravated diabetes-induced DRG neuron mitochondrial oxidative stress and injury. Taken together, our data revealed that PARP1 induced defective mitophagy of DRG neurons is a key mechanism in diabetes-induced peripheral neuropathic injury. Inhibition of PARP1 and restoration of mitophagy function are potential therapeutic targets for PDN.
Learn More >The management of chronic neuropathic pain remains a challenge, because pain is subjective, and measuring it objectively is usually out of question. However, neuropathic pain is also a signal provided by maladaptive neuronal activity. Thus, the integral management of chronic neuropathic pain should not only rely on the subjective perception of the patient, but also on objective data that measures the evolution of neuronal activity. We will discuss different objective and subjective methods for the characterization of neuropathic pain. Additionally, the gaps and proposals for an integral management of chronic neuropathic pain will also be discussed. The current management that relies mostly on subjective measures has not been sufficient, therefore, this has hindered advances in pain management and clinical trials. If an integral characterization is achieved, clinical management and stratification for clinical trials could be based on both questionnaires and neuronal activity. Appropriate characterization may lead to an increase of effectiveness for new therapies, and a better quality of life for neuropathic pain sufferers.
Learn More >It is well known that exercise produces analgesic effects (exercise-induced hypoalgesia (EIH)) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we describe drastic changes in the mesocorticolimbic system of the brain which permit the induction of EIH effects. The amygdala (Amyg) is a critical node for the regulation of emotions, such as fear and anxiety, which are closely associated with chronic pain. In our recent studies using neuropathic pain (NPP) model mice, we extensively examined the association between the Amyg and EIH effects. We found that voluntary exercise (VE) activated glutamate (Glu) neurons in the medial basal Amyg projecting to the nucleus accumbens (NAc) lateral shell, while it almost completely suppressed NPP-induced activation of GABA neurons in the central nucleus of the Amyg (CeA). Furthermore, VE significantly inhibited activation of pyramidal neurons in the ventral hippocampus-CA1 region, which play important roles in contextual fear conditioning and the retrieval of fear memory. This review describes novel information concerning the brain mechanisms underlying EIH effects as a result of overcoming the fear-avoidance belief of chronic pain.
Learn More >Opioid tolerance (OT) leads to dose escalation and serious side effects, including opioid-induced hyperalgesia (OIH). We sought to better understand the mechanisms underlying this event in the gastrointestinal tract. Chronic administration of morphine by intraperitoneal (i.p.) injection in male C57BL/6 mice evoked tolerance and evidence of OIH in an assay of colonic afferent nerve mechanosensitivity; this was inhibited by the δ-opioid receptor (DOPr) antagonist naltrindole when i.p. injected previous morphine administration. Patch clamp studies of dorsal root ganglia (DRG) neurons following overnight incubation with high concentrations of morphine, the µ-opioid receptors (MOPr) agonist DAMGO or the DOPr agonist DADLE evoked hyperexcitability. The pronociceptive actions of these opioids were blocked by the DOPr antagonist SDM25N but not the MOPr antagonist CTOP. The hyperexcitability induced by DAMGO was reversed after a 1 hr washout but reapplication of low concentrations of DAMGO or DADLE restored the hyperexcitability, an effect mediated by protein kinase C (PKC). DOPr-dependent DRG neuron hyperexcitability was blocked by the endocytosis inhibitor Pitstop 2 and the weakly internalizing DOPr agonist ARM390 did not cause hyperexcitability. BRET studies in HEK cells showed no evidence of switching of G-protein signaling from G to a G pathway in response to either high concentrations or overnight incubation of opioids. Thus, chronic high dose opioid exposure leads to OT and features of OIH in the colon. This action is mediated by DOPr signaling and is dependent on receptor endocytosis and downstream PKC signaling.Opioids are effective in the treatment of abdominal pain but escalating doses can lead to opioid tolerance (OT) and potentially opioid-induced hyperalgesia (OIH). We found that δ-opioid receptor (DOPr) plays a central role in the development of OT and OIH in colonic afferent nociceptors following prolonged exposure to high concentrations of MOPr or DOPr agonists. Furthermore, the role of DOPr was dependent on OPr internalization and activation of a protein kinase C (PKC) signaling pathway. Thus, targeting DOPr or key components of the downstream signaling pathway could mitigate adverse side effects by opioids.
Learn More >Background Fibromyalgia syndrome is characterised by extensive muscular pain and chronic fatigue. Among the pharmacologic and other nutrient supplements that have been studied, Vitamin D has garnered attention owing to the critical role it plays in inflammatory and pain pathways. We conducted a systematic literature review to examine the efficacy of vitamin D supplemen-tation in improving the clinical status of the patients and alleviating the symptoms of fibrom-yalgia. Methods We searched Cochrane CENTRAL, PubMed, Science Direct, Scopus, grey literature (medrXiv and biorXiv) for observational studies, randomized controlled trials, case-control studies, and case reports published in English from January 2011 to May 2021, using the terms vitamin D and fibromyalgia or FMS. References were reviewed manually and articles were only included if they were specific in their diagnosis of fibromyalgia. Results 2651 studies were retrieved, with 12 studies fulfilling the inclusion criteria. 11 out of these 12 studies were of high quality and showed low risk of bias. 11 of these also demonstrated de-finitive improvement in clinical status and various outcome measures following supplementa-tion with Vitamin D. Conclusions Our study emphasises an association between supplementation of vitamin D and improve-ment of the clinical condition fibromyalgia through a systematic review of high-quality stud-ies. The study also identified areas for future scope for research that is needed for standardis-ing the detection and treatment of this chronic condition through cost-effective supplements such as Vitamin D.
Learn More >Fabry disease (FD) is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3). A hallmark symptom of FD patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. Previous studies have shown that Acetyl-L-carnitine (ALC) has neuroprotective, neurotrophic, and analgesic activity in animal models of neuropathic pain. To study the action of ALC on neuropathic pain associated with FD, we treated α-GalA gene null mice (α-GalA(-/0)) with ALC for 30 days. In α-Gal KO mice ALC treatment induced acute and long-lasting analgesia, which persisted 1 month after drug withdrawal. This effect was antagonized by single administration of LY341495, an orthosteric antagonist of mGlu2/3 metabotropic glutamate receptors. We also found an up-regulation of mGlu2 receptors in cultured DRG neurons isolated from 30-day ALC treated α-GalA KO mice. However, the up-regulation of mGlu2 receptors was no longer present in DRG neurons isolated 30 days after the end of treatment. Taken together, these findings suggest that ALC induces analgesia in an animal model of FD by up-regulating mGlu2 receptors, and that analgesia is maintained by additional mechanisms after ALC withdrawal. ALC might represent a valuable pharmacological strategy to reduce pain in FD patients.
Learn More >Around 20% of the American population have chronic pain and estimates in other Western countries report similar numbers. This represents a major challenge for global health care systems. Additional problems for the treatment of chronic and persistent pain are the comparably low efficacy of existing therapies, the failure to translate effects observed in preclinical pain models to human patients and related setbacks in clinical trials from previous attempts to develop novel analgesics. Drug repurposing offers an alternative approach to identify novel analgesics as it can bypass various steps of classical drug development. In recent years, several approved drugs were attributed analgesic properties. Here, we review available data and discuss recent findings suggesting that the approved drugs minocycline, fingolimod, pioglitazone, nilotinib, telmisartan, and others, which were originally developed for the treatment of different pathologies, can have analgesic, antihyperalgesic, or neuroprotective effects in preclinical and clinical models of inflammatory or neuropathic pain. For our analysis, we subdivide the drugs into substances that can target neuroinflammation or substances that can act on peripheral sensory neurons, and highlight the proposed mechanisms. Finally, we discuss the merits and challenges of drug repurposing for the development of novel analgesics.
Learn More >This consensus statement has been developed by the Thai Interest Group for Endometriosis (TIGE) for use by Thai clinicians in the diagnosis and management of endometriosis. TIGE is a group of clinical and academic gynaecologists with a particular interest in endometriosis. Endometriosis is an oestrogen-dependent inflammatory disease which causes chronic symptoms such as dysmenorrhoea, chronic pelvic pain, dyspareunia and subfertility, and it is common in reproductive-age women. There is limited overall data on its prevalence in different clinical settings in Thailand, but it is clear that the disease causes significant problems for patients in terms of their working lives, fertility, and quality of life, as well as placing a great burden on national healthcare resources. Decisions about selecting the appropriate treatment for women with endometriosis depend on many factors including the age of the patient, the extent and severity of disease, concomitant conditions, economic status, patient preference, access to medication, and fertility need. Several hormonal treatments are available but no consensus has been reached about the best option for long-term prevention of recurrence. Bearing in mind differences in environment, genetics, and access to the healthcare system, this treatment guideline has been tailored to the particular circumstances of Thai women.
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