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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and social interaction and the presence of restricted, repetitive behaviors. Additionally, difficulties in sensory processing commonly occur in ASD. Sensory abnormalities include heightened or reduced sensitivity to pain, but the mechanism underlying sensory phenotypes in ASD remain unknown. Emerging evidence suggests that microglia play an important role in forming and refining neuronal circuitry, and thus contribute to neuronal plasticity and nociceptive signaling. In the present study, we investigated the age-dependent tactile sensitivity in an animal model of ASD induced by prenatal exposure to valproic acid (VPA) and subsequently assessed the involvement of microglia in the spinal cord in pain processing. Pregnant ICR (CD1) mice were intraperitoneally injected with either saline or VPA (500 mg/kg) on embryonic day 12.5. Male offspring of VPA-treated mothers showed mechanical allodynia at both 4 and 8 weeks of age. In the spinal cord dorsal horn in prenatally VPA-treated mice, the numbers and staining intensities of ionized calcium-binding adapter molecule 1-positive cells were increased and the cell bodies became enlarged, indicating microglial activation. Treatment with PLX3397, a colony-stimulating factor 1 receptor inhibitor, for 10 days resulted in a decreased number of spinal microglia and attenuated mechanical allodynia in adult mice prenatally exposed to VPA. Additionally, intrathecal injection of Mac-1-saporin, a saporin-conjugated anti-CD11b antibody to deplete microglia, abolished mechanical allodynia. These findings suggest that prenatal VPA treatment causes allodynia and that spinal microglia contribute to the increased nociceptive responses.
Learn More >Voltage-gated sodium channels (Na) in nociceptive neurons initiate action potentials required for transmission of aberrant painful stimuli observed in osteoarthritis (OA). Targeting Na subtypes with drugs to produce analgesic effects for OA pain management is a developing therapeutic area. Previously, we determined the receptor site for the tamoxifen analog N-desmethyltamoxifen (ND-Tam) within a prokaryotic Na. Here, we report the pharmacology of ND-Tam against eukaryotic Nas natively expressed in nociceptive neurons. ND-Tam and analogs occupy two conserved intracellular receptor sites in domains II and IV of Na1.7 to block ion entry using a "bind and plug" mechanism. We find that ND-Tam inhibition of the sodium current is state dependent, conferring a potent frequency- and voltage-dependent block of hyperexcitable nociceptive neuron action potentials implicated in OA pain. When evaluated using a mouse OA pain model, ND-Tam has long-lasting efficacy, which supports the potential of repurposing ND-Tam analogs as Na antagonists for OA pain management.
Learn More >The efficacy of ubrogepant 50 mg versus 100 mg daily for migraine remained controversial. We conducted a systematic review and meta-analysis to compare the efficacy and safety of ubrogepant 50 mg versus 100 mg daily on treatment in migraine patients. We have searched PubMed, EMbase, Web of science, EBSCO, Cochrane library databases and SCOPUS through March 21, 2022 for randomized controlled trials (RCTs) assessing the effect of ubrogepant 50 mg versus 100 mg on treatment efficacy in migraine patients. This meta-analysis was performed using the random-effect model. Three RCTs were included in the meta-analysis. Overall, compared with ubrogepant 100 mg in migraine patients, ubrogepant 50 mg obtained comparable pain freedom at 2 hours (OR =0.86; 95% CI =0.64 to 1.15; P = 0.310), sustained pain freedom 2-24 hours (OR =0.76; 95% CI =0.54 to 1.07; P = 0.110), photophobia absence at 2 h (OR =0.80; 95% CI =0.63 to 1.02; P = 0.070), phonophobia absence at 2 h (OR =1.07; 95% CI =0.82 to 1.40; P = 0.620) and nausea absence at 2 h (OR =1.02; 95% CI =0.79 to 1.32; P = 0.880). In terms of safety, adverse events was found to be increased in ubrogepant 100 mg as compared to ubrogepant 50 mg (OR =0.81; 95% CI =0.67 to 0.99; P = 0.040), and there was no statistical difference of serious adverse events between two groups (OR =0.87; 95% CI =0.40 to 1.91; P = 0.720). Ubrogepant 50 mg and 100 mg may be equally effective to alleviate migraine, but ubrogepant 100 mg led to increase incidence of adverse events.
Learn More >To assess the relationship between pre-operative psychological state, postoperative pain and function one year after total shoulder, hip or knee arthroplasty.
Learn More >As an emerging dietary essential fatty acid, pentadecanoic acid (C15:0) is expected to have bioactive metabolites with broad health benefits. Here, we evaluated pentadecanoylcarnitine, an endogenous C15:0 metabolite, for dose dependent cell-based activities, including measurement of its effects on 148 clinically relevant biomarkers across twelve primary human cell systems mimicking various disease states. Mechanisms of action for pentadecanoylcarnitine were also assessed across 78 cell-based target assays. Pentadecanoylcarnitine had dose-dependent anti-inflammatory activities, including lower IL-1α, ITAC, MCP-1, and IP-10, across five cell systems relevant to treating cardiovascular, immune, neoplastic, pulmonary, and skin diseases. Targeted assays showed pentadecanoylcarnitine as a full-acting cannabinoid 1 and 2 receptor agonist (EC50 3.7 and 3.2 µM, 111% and 106% maximum activity compared to the positive control, respectively). Pentadecanoylcarnitine also had 5-HT1A and 5-HT1B receptor agonist and histamine H1 and H2 receptor antagonist activities. In summary, pentadecanoylcarnitine, a second discovered full-acting endocannabinoid, had broad pleiotropic activities relevant to regulating inflammation, pain, mood, and sleep. This study's findings further the need to evaluate the potential health impacts of C15:0 nutritional deficiencies caused by population-wide avoidance of all dietary saturated fats, including C15:0.
Learn More >We assessed whether total sleep deprivation (TSD) in combination with pain tests yields a reliable method to assess altered pain thresholds, which subsequently may be used to investigate (novel) analgesics in healthy subjects.
Learn More >Youth with sickle cell disease (SCD) and chronic pain, defined in this study as pain on most days for 3 months, experience variability in daily pain and physical and psychosocial functioning. This study aimed to 1) empirically derive chronic pain subgroups based on pain characteristics among youth with chronic SCD pain; and 2) investigate derived subgroups for differences in socio-demographics, clinical characteristics, and psychosocial and functional outcomes.
Learn More >The pathophysiological mechanism underlying migraine-associated peripheral hypersensitivity remains unclear. Acid-sensing ion channels (ASICs) and transient receptor potential ankyrin 1 (TRPA1) are known to be causative pathogenic factors of mechanical and cold allodynia, respectively. Here, we sought to investigate their involvement in cold and mechanical allodynia of the face and hindpaws, respectively, in a mouse model of repetitive nitroglycerin (NTG)-induced migraine. NTG (10 mg/kg) was administered to the mice every other day for 9 days, followed 90 min later by HC-030031 (a TRPA1 blocker) or amiloride (a non-selective ASIC blocker). Mechanical or cold sensitivity of the hindpaw and facial regions was quantified using von-Frey filaments or acetone solution, respectively. Immunohistochemistry revealed that c-Fos expression was significantly increased in the trigeminal nucleus caudalis region but not in the spinal cord. Amiloride treatment only reduced NTG-induced hindpaw mechanical allodynia, whereas HC-030031 treatment only improved facial cold allodynia. Interestingly, the number of c-Fos positive cells decreased to a similar level in each drug treatment group. These findings demonstrate that facial cold allodynia and hindpaw mechanical allodynia are differentially mediated by activation of TRPA1 and ASIC, respectively, in mice with repetitive NTG-induced hypersensitivity.
Learn More >The aim of this study was to differentiate the effects of spinal cord injury (SCI) and central neuropathic pain (CNP) on effective connectivity during motor imagery of legs, where CNP is typically experienced.
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