Pain
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Chronic pain and hyperalgesia, as well as pain resulting from episodes of vaso-occlusion, are characteristic features of sickle cell disease (SCD) and are difficult to treat. Since there is growing evidence that increasing local levels of endocannabinoids can decrease hyperalgesia, we examined the effects of URB597, a fatty acid amide hydrolase (FAAH) inhibitor, which blocks the hydrolysis of the endogenous cannabinoid anandamide, on hyperalgesia and sensitization of cutaneous nociceptors in a humanized mouse model of SCD. Using homozygous HbSS-BERK sickle mice, we determined the effects of URB597 on mechanical hyperalgesia and on sensitization of C-fiber nociceptors in vivo. ⋯ The proportion of Aδ- and C-fiber nociceptors that exhibited spontaneous activity and responses of C-fibers to mechanical and thermal stimuli were greater in HbSS-BERK sickle mice as compared to control HbAA-BERK mice. Spontaneous activity and evoked responses of nociceptors were decreased by URB597 via CB1 receptors. It is suggested that enhanced endocannabinoid activity in the periphery may be beneficial in alleviating chronic pain associated with SCD.
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Despite being a ubiquitous animal pain model, the natural TRPA1-agonist allyl isothiocyanate (AITC, also known as "mustard oil") has only been sparsely investigated as a potential human surrogate model of pain, sensitization, and neurogenic inflammation. Its dose-response as an algogenic, sensitizing irritant remains to be elucidated in human skin. Three concentrations of AITC (10%, 50%, and 90%) and vehicle (paraffin) were applied for 5 minutes to 3 × 3 cm areas on the volar forearms in 14 healthy volunteers, and evoked pain intensity (visual analog scale 0-100 mm) and pain quality were assessed. ⋯ Acute and prolonged inflammation was evoked by all concentrations, and assessments by full-field laser perfusion imaging demonstrated a significant dose-dependent increase with a ceiling effect from 50% to 90%. Topical AITC application produces pain and somatosensory sensitization in a dose-dependent manner with optimal concentrations recommended to be >10% and ≤50%. The model is translatable to humans and could be useful in pharmacological proof-of-concept studies of TRPA1-antagonists, analgesics, and anti-inflammatory compounds or for exploratory clinical purposes, eg, loss- or gain-of-function in peripheral neuropathies.
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Despite the frequency of pain among children, little is known about its effects on learning and school outcomes. The objective of this study was to quantify the association of pain and academic achievement while taking into account the presence of co-occurring emotional symptoms. A population-based stratified random sample of 1239 students aged 8 to 9 years from primary schools in Melbourne, Australia, was recruited for the Childhood to Adolescence Transition Study. ⋯ Children with chronic pain were a year behind their peers in both reading and numeracy. Among primary school students, pain was associated with lower reading scores even after adjusting for the presence of emotional symptoms. Although population-based longitudinal studies will be required to ascertain consistency and possible causality, grounds exist for considering pain and emotional symptoms in the assessment of children with reading difficulties.
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Peripheral tissue inflammation or injury causes glutamate release from nociceptive axons, keratinocytes, and Schwann cells, resulting in thermal hypersensitivity. However, the detailed molecular mechanisms underlying glutamate-induced thermal hypersensitivity are unknown. The aim of this study was to clarify the involvement of peripheral transient receptor potential (TRP) TRP vanilloid 1 (TRPV1), TRP ankyrin 1 (TRPA1), and protein kinase C epsilon (PKCε) in glutamate-induced pain hypersensitivity. ⋯ PKCε phosphorylation in TG was significantly enhanced following glutamate injection into the facial skin. Moreover, neuronal activity of TG neurons was significantly increased following facial glutamate treatment. The present findings suggest that sensitization of TRPA1 and/or TRPV1 through mGluR5 signaling via PKCε is involved in facial thermal and mechanical hypersensitivity.
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Chronic or episodic severe itch is recurrent in atopic dermatitis (AD). Nonhistaminergic itch pathways are suggested to dominate in AD itch, contributing to an "itch-scratch-itch cycle" that prolongs and worsens itch, pain, and skin lesions. We hypothesized that nonhistaminergic neuronal sensitization contributes to itch in AD. ⋯ Lastly, patients exhibited intralesional and extralesional hyperknesis before chemical itch provocations and augmented hyperknesis after itch provocations. Increased itch in response to cowhage (but not histamine) suggests nonhistaminergic pathway-specific itch sensitization in AD, whereas increased susceptibility to mechanically evoked itch and pain, particularly intralesionally suggests sensitization of mechanosensitive circuitry not normally associated with itch. Drugs targeting the nonhistaminergic (PAR2/TRPA1) itch pathway and itch sensitization are promising for treating AD itch.