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α-Conotoxins are small disulfide-rich peptides found in the venom of marine cone snails and are potent antagonists of nicotinic acetylcholine receptors (nAChRs). They are valuable pharmacological tools and have potential therapeutic applications for the treatment of chronic pain or neurological diseases and disorders. In the present study, we synthesized and functionally characterized a novel α-conotoxin Bt1.8, which was cloned from Conus betulinus. Bt1.8 selectively inhibited ACh-evoked currents in Xenopus oocytes expressing rat(r) α6/α3β2β3 and rα3β2 nAChRs with an IC of 2.1 nM and 9.4 nM, respectively, and similar potency for human (h) α6/α3β2β3 and hα3β2 nAChRs Additionally, Bt1.8 had higher binding affinity with a slower dissociation rate for the rα6/α3β2β3 subtype compared to rα3β2. The amino acid sequence of Bt1.8 is significantly different from other reported α-conotoxins targeting the two nAChR subtypes. Further Alanine scanning analyses demonstrated that residues Ile9, Leu10, Asn11, Asn12 and Asn14 are critical for its inhibitory activity at the α6/α3β2β3 and α3β2 subtypes. Moreover, the NMR structure of Bt1.8 indicated the presence of a relatively larger hydrophobic zone than other α4/7-conotoxins which may explain its potent inhibition of α6/α3β2β3 nAChRs.
Learn More >Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.
Learn More >The medium spiny neurons (MSNs) in the nucleus accumbens (NAc) integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output. Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation (SNL). SNL increased the frequency, but not the amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs), and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the MSNs. SNL also decreased the paired-pulse ratio (PPR) of evoked IPSCs but increased the PPR of evoked EPSCs. Moreover, acute bath application of C-C motif chemokine ligand 2 (CCL2) increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs, and especially strengthened the amplitude of N-methyl-D-aspartate receptor (NMDAR)-mediated miniature EPSCs. Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio. Finally, Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression (LTD) in the NAc after SNL. These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.
Learn More >Patients with chronic pain who are tapering prescription opioids report a need for greater support for coping with symptoms of pain and withdrawal. Mobile health (mHealth) technologies (SMS text messaging- or app-based) have the potential to provide patients with educational, emotional, and motivational support for opioid tapering beyond what is offered by their health care provider. However, it is not known whether patients with chronic pain who are tapering opioids would be willing or able to engage with technology-based support.
Learn More >Opioids are perhaps the most effective analgesics in medicine. However, between 1999 to 2018, over 400,000 people in the United States died from opioid overdose. Excessive opioids make breathing lethally slow and shallow, a side-effect called opioid induced respiratory depression. This doubled-edged sword has sparked the desire to develop novel therapeutics that provide opioid-like analgesia without depressing breathing. One such approach has been the design of so-called 'biased agonists' that signal through some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This rationale stems from a study suggesting that MOR-induced ß2-arrestin dependent signaling is responsible for opioid respiratory depression, whereas adenylyl cyclase inhibition produces analgesia. To verify this important result that motivated the 'biased agonist' approach, we re-examined breathing in ß2-arrestin deficient mice and instead find no connection between ß2-arrestin and opioid respiratory depression. This result suggests that any attenuated effect of 'biased agonists' on breathing is through an as-yet defined mechanism.
Learn More >Chronic post-surgical pain (CPSP) is a highly prevalent complication following thoracic surgery. This is a prospective cohort study that aims to describe the pain trajectories of patients undergoing thoracic surgery beginning preoperatively and up to 1 year after surgery METHODS: Two hundred and seventy nine patients undergoing elective thoracic surgery were enrolled. Participants filled out a preoperative questionnaire containing questions about their sociodemographic information, comorbidities as well as several psychological and pain-related statuses. They were then followed-up during their immediate postoperative period and at the three, six and 12 month time-points to track their postoperative pain, complications and pain-related outcomes. Growth mixture modeling was used to construct pain trajectories.
Learn More >: Much is known about the impact of pain in terms of medical costs and missed work. Less is known about its associations when individuals are present for work. This study examines "presenteeism" by analyzing the psychosocial costs of pain in the workplace, using the 2015 European Working Conditions Survey (EWCS). : We conducted cross-sectional analysis of 2384 individuals with chronic pain and 2263 individuals without pain (matched by age and sex) using data from the 2015 EWCS. We compared groups in terms of the following psychosocial factors: supervisor support, job responsibility, team cohesion, discrimination, threats/abuse, job competency, job reward, sexual harassment, stress, and job security. The groups were also compared in terms of days lost due to illness. : People with pain were 64% less likely to view their job as rewarding (odds ratio [OR] = 0.61; 95% confidence interval [CI], 0.57-0.65), 47% more likely to be subjected to threats/abuse in the workplace (OR = 0.68; 95% CI, 0.63-0.73), 30% more likely to report poor supervisor support (OR = 0.77; 95% CI, 0.73-0.82), and 28% more likely to perceive discrimination in the workplace (OR = 0.78; 95% CI, 0.71-0.85). People with pain missed approximately nine more days of work per year than respondents without pain. : Chronic pain was associated with lower vocational fulfillment and feelings of being ostracized in the workplace. These findings suggest that the presence of pain in the workplace goes well beyond lost productivity due to absenteeism.
Learn More >Hereditary sensory neuropathies (HSN) are a group of rare neurological disorders with heterogeneous clinical and genetic characteristics. Although at least 17 different genes have already been associated with HSN, the epidemiology of the disorder in Brazil is still unknown. Performing whole genome sequencing (WGS) in 23 unrelated Brazilian families diagnosed with HSN, we detected pathogenic variants in ATL3, SPTLC2, and SCN9A in 12 patients belonging to five unrelated families. Clinical features associated with heterozygous mutations in ATL3 (c.575A > G; p.(Tyr192Cys)) and SPTLC2 (c.529A > G; p.(Asn177Asp)) were sensory deficits, neuropathic pain, and recurrent ulcerations. Presenting as congenital insensitivity to pain, three unrelated probands carried biallelic loss-of-function mutations in SCN9A. The so far undescribed stop mutation c.2106G > A (p.(Trp702Ter)) and the likewise novel splicing variant c.3319-1G > A were found in compound-heterozygosity with, respectively, the known pathogenic variants c.2908G > T (p.Trp970Ter) and c.2690G > A (p.Glu897Ter). In total, we identified pathogenic mutations in 21.7% of our families, which suggests that most of the cases could be explained by yet to be discovered genes or unusual alleles. Our study represents the first mutational screen in a Brazilian HSN cohort, enabling additional insights for genotype-phenotype correlations, reducing misdiagnoses, and providing early treatment considerations.
Learn More >Chronic postsurgical pain (CPSP) and disability after cardiothoracic surgery are highly prevalent and difficult to treat. Researchers have explored a variety of presurgical risk factors for CPSP and disability after cardiothoracic surgery, including one study that examined distress from bodily sensations. The current prospective, longitudinal study sought to extend previous research by investigating presurgical distress about bodily sensations as a risk factor for CPSP and disability after cardiothoracic surgery while controlling for several other potential psychosocial predictors. Participants included 543 adults undergoing nonemergency cardiac or thoracic surgery who were followed over 6 months postsurgically. Before surgery, participants completed demographic, clinical, and psychological questionnaires. Six months after surgery, participants reported the intensity of CPSP on a 0 to 10 numeric rating scale and pain disability, measured by the Pain Disability Index. Multinomial logistic regression analyses were conducted to evaluate the degree to which presurgical measures predicted pain outcomes 6 months after surgery. The results showed that CPSP intensity was significantly predicted by age and presurgical scores on the Symptom Checklist-90-Revised Somatization subscale (Nagelkerke R2 = 0.27, P < 0.001), whereas chronic pain disability was only predicted by presurgical Symptom Checklist-90-Revised Somatization scores (Nagelkerke R2 = 0.29, P < 0.001). These findings demonstrate that presurgical distress over bodily sensations predicts greater chronic pain intensity and disability 6 months after cardiothoracic surgery and suggest that presurgical treatment to diminish such distress may prevent or minimize CPSP intensity and disability.
Learn More >Chronic pain is a common symptom experienced during cancer progression. Additionally, some patients experience bone pain caused by cancer metastasis, which further complicates the prognosis. Cancer pain is often treated using opioid-based pharmacotherapy, but these drugs possess several adverse effects. Accordingly, new mechanisms for cancer pain management are being explored, including transient receptor potential channels (TRPs). TRP ion channels are expressed in several tissues and play a key role in pain detection, especially TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1). In the present review, we describe the role of TRPV1 and TRPA1 involved in cancer pain mechanisms. Several studies have revealed that the administration of TRPV1 or TRPA1 agonists/antagonists and TRPV1 or TRPA1 knockdown reduced sensitivity to nociception in cancer pain models. TRPV1 was also found to be involved in various models of cancer-induced bone pain (CIBP), with TRPV1 expression reportedly enhanced in some models. These studies have demonstrated the TRPV1 or TRPA1 association with cancer pain in models induced by tumour cell inoculation into the bone cavity, hind paw, mammary fat pad, and sciatic nerve in mice or rats. To date, only resiniferatoxin, a TRPV1 agonist, has been evaluated in clinical trials for cancer pain and showed preliminary positive results. Thus, TRP channels are potential targets for managing cancer-related pain syndromes.
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