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Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signalling is currently unknown. Using male and female mice, we show with single-cell RT-PCR that sub-populations of dorsal root ganglion (DRG) neurons innervating the mouse bladder express (14%) and either individually or in combination, with high levels of co-expression with (81-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22 and neuropeptide FF) activated sub-populations of bladder-innervating DRG neurons, showing functional evidence of co-expression between MrgprA3, MrgprC11 and TRPV1. In bladder-nerve preparations chloroquine, BAM8-22 and neuropeptide FF all evoked mechanical hypersensitivity in sub-populations (20-41%) of bladder afferents. These effects were absent in recordings from mice. whole-cell patch clamp recordings showed that application of an MrgprA3/C11 agonist cocktail induced neuronal hyper-excitability in 44% of bladder-innervating DRG neurons. Finally, instillation of an MrgprA3/C11 agonist cocktail into the bladder of wild-type mice induced a significant activation of dorsal horn neurons within the lumbosacral spinal cord, as quantified by pERK-immunoreactivity. This MrgprA3/C11 agonist-induced activation was particularly apparent within the superficial dorsal horn and the sacral parasympathetic nuclei of wild-type, but not mice. This study demonstrates, for the first time, functional expression of MrgprA3 and MrgprC11 in bladder afferents. Activation of these receptors triggers hypersensitivity to distension, a critically valuable factor for therapeutic target development.Determining how bladder afferents become sensitized is the first step in finding effective treatments for common urological disorders such as overactive bladder and interstitial cystitis/bladder pain syndrome. Here we show that two of the key receptors, MrgprA3 and MrgprC11, that mediate itch from the skin are also expressed on afferents innervating the bladder. Activation of these receptors results in sensitization of bladder afferents, resulting in sensory signals being sent into the spinal cord that prematurely indicate bladder fullness. Targeting bladder afferents expressing MrgprA3 or MrgprC11 and preventing their sensitisation may provide a novel approach for treating overactive bladder and interstitial cystitis/bladder pain syndrome.
Learn More >Our previous study showed the intrinsic ability of descending noradrenergic neurons projecting from the locus coeruleus to the spinal dorsal horn (SDH) to suppress itch-related behaviors. Noradrenaline and α-adrenaline receptor (α-AR) agonist increase inhibitory synaptic inputs onto SDH interneurons expressing gastrin-releasing peptide receptors, which are essential for itch transmission. However, the contribution of α-ARs expressed in SDH inhibitory interneurons to itch-related behavior remains to be determined. In this study, RNAscope in situ hybridization revealed that Adra1a mRNA is expressed in SDH inhibitory interneurons that are positive for Slc32a1 mRNA (known as vesicular GABA transporter). Mice with conditional knock-out of α-ARs in inhibitory interneurons (Vgat-Cre;Adra1a mice) exhibited an increase in scratching behavior when induced by an intradermal injection of chloroquine, but not compound 48/80, which are known as models of histamine-independent and dependent itch, respectively. Furthermore, knockout of inhibitory neuronal α-ARs in the SDH using the CRISPR-Cas9 system also increased the scratching behavior elicited by chloroquine but not compound 48/80. Our findings demonstrated for the first time that α-ARs in SDH inhibitory interneurons contribute to the regulation of itch signaling with preference for histamine-independent itch.
Learn More >Emotions are involved in the identification of safety cues in the environment, and are also related to social interaction through recognition of emotional facial expressions. Heart rate variability (HRV) can be an indicator of the adaptive response of the autonomic nervous system to stressful conditions, including pain. This study aimed to investigate the emotional processing in a sample of patients with chronic musculoskeletal by measuring the resting-state HRV and the ability to recognize facial emotion expressions.
Learn More >Persistent pain is common in HIV patients and breast cancer (BC) survivors. The aim of this study was to compare two patient groups with neuropathic pain (NP) regarding several psychological variables and Health-related Quality of Life. Although, treatment of pain is always planned individually, the knowledge of the differences and similarities between the patient groups may help us to understand more precisely the targets of the interventions for pain.
Learn More >Little is known about the pain experience of the Mexican American (MA) population. We investigated the associations between language use and generation status with chronic pain prevalence, health insurance coverage, and analgesic medication use. We examined 3373 MA respondents from the National Health and Nutrition Examination Survey. We found higher levels of English use and generation status were associated with higher odds of reporting chronic pain. For respondents reporting chronic pain, higher levels of English use and generation status were associated with higher odds of being covered by health insurance, lower odds of having a period of time last year without health insurance, and higher odds of being prescribed any analgesic medication, especially opioid medications. We found language use and generation status play a role in MAs' experience, access, and treatment of chronic pain. Patient-, provider-, and systems-level interventions may be needed to reduce these disparities.
Learn More >Excessive pain during medical procedures is a pervasive health challenge. This study tested the (additive) analgesic efficacy of combining hypnotic analgesia and virtual reality (VR) pain distraction. A single blind, randomized, and controlled trial was used to study 205 undergraduate volunteers aged 18 to 20. The individual and combined effects of hypnotic analgesia (H) and VR distraction on experimentally induced acute thermal pain were examined using a 2 X 2, between-groups parallel design (4 groups total). Participants in groups that received hypnosis remained hypnotized during the test phase pain stimulus. The main outcome measure was "worst pain" ratings. Hypnosis reduced acute pain even for people who scored low on hypnotizability. As predicted, H+ VR was significantly more effective than VR distraction alone. However, H+ VR was not significantly more effective than hypnotic analgesia alone. Being hypnotized during thermal pain enhanced VR distraction analgesia.
Learn More >The present study aimed to determine whether specific cognitive domains part of the Montreal Cognitive Assessment (MoCA) are significantly lower in community-dwelling older adults with chronic pain compared with older adults without pain and whether these domains would be associated with self-reported pain, disability, and somatosensory function.
Learn More >Inhibition of the pituitary adenylate cyclase 1 receptor (PAC1R) is a novel mechanism that could be used for abortive treatment of acute migraine. Our research began with comparative analysis of known PAC1R ligand scaffolds, PACAP38 and Maxadilan, which resulted in the selection of des(24-42) Maxadilan, , as a starting point. C-terminal modifications of improved the peptide metabolic stability and . SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the PAC1R inhibitory activity of the analogs to the pM IC range. Our modifications further enabled deletion of up to six residues without impacting potency, thus improving peptide ligand binding efficiency. Analogs and exhibited robust efficacy in the rat Maxadilan-induced increase in blood flow (MIIBF) pharmacodynamic model at 0.3 mg/kg subcutaneous dosing. The first cocrystal structure of a PAC1R antagonist peptide () with PAC1R extracellular domain is reported.
Learn More >Treatment of pain associated with osteoarthritis (OA) is unsatisfactory and innovative approaches are needed. The secretome from human adipose-derived mesenchymal stem cells (hASC-Conditioned Medium, CM) has been successfully used to relieve painful symptoms in models of chronic pain. The aim of this study was to explore the efficacy of the hASC-CM to control pain and neuroinflammation in an animal model of OA.
Learn More >Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel activated by various physical stimuli such as cell swelling and shear stress. TRPV4 is expressed in bladder sensory nerves and epithelium, and its activation produces urinary dysfunction in rodents. However, there have been few reports regarding its involvement in bladder pain. Therefore, we investigated whether TRPV4 is involved in bladder pain in mouse cystitis model. Intraperitoneal injection of cyclophosphamide (CYP; 300 mg/kg) produced mechanical hypersensitivity in the lower abdomen associated with a severe inflammatory bladder in mice. The mechanical threshold was reversed significantly in Trpv4-knockout (KO) mice. Repeated injections of CYP (150 mg/kg) daily for 4 days provoked mild bladder inflammation and persistent mechanical hypersensitivity in mice. Trpv4-KO mice prevented a reduction of the mechanical threshold without an alteration in bladder inflammation. A selective TRPV4 antagonist also reversed the mechanical threshold in chronic cystitis mice. Although expression of Trpv4 was unchanged in the bladders of chronic cystitis mice, the level of phosphorylated TRPV4 was increased significantly. These results suggest involvement of TRPV4 in bladder pain of cystitis mice. A TRPV4 antagonist might be useful for patients with irritable bladder pain such as those with interstitial cystitis/painful bladder syndrome.
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