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Itching is a sensory phenomenon characterized by an unpleasant sensation that makes you want to scratch the skin, and chronic itching diminishes the quality of life. In recent studies, multiple transient receptor potential (TRP) channels present in keratinocytes or nerve endings have been shown to engage in the propagation of itch signals in chronic dermatological or pruritic conditions, such as atopic dermatitis (AD) and psoriasis (PS). TRPV3, a member of the TRP family, is highly expressed in the epidermal keratinocytes. Normal TRPV3 signaling is essential for maintaining epidermal barrier homeostasis. In recent decades, many studies have suggested that TRPV3 contributes to detecting pruritus signals. Gain-of-function mutations in TRPV3 in mice and humans are characterized by severe itching, hyperkeratosis, and elevated total IgE levels. These studies suggest that TRPV3 is an important channel for skin itching. Preclinical studies have provided evidence to support the development of TRPV3 antagonists for treating inflammatory skin conditions, itchiness, and pain. This review explores the role of TRPV3 in chronic pruritus, collating clinical and experimental evidence. We also discuss underlying cellular and molecular mechanisms and explore the potential of TRPV3 antagonists as therapeutic agents.
Learn More >This study aimed to explore the incidence of adverse events (AEs) reported by patients when initiating medicinal cannabis treatment for chronic pain, and the association of cannabis constituents, dose and concomitant medicines with AE incidence.
Learn More >Viscosupplementation (VS) with hyaluronic acid is widely used in the management of knee osteoarthritis. There is no clear recommendation on the decision-making to achieve VS.
Learn More >In the current management of neuropathic pain, in addition to antidepressants and anticonvulsants, the use of opioids is wide, despite their related and well-known issues. N-palmitoylethanolamine (PEA), a natural fatty-acid ethanolamide whose anti-inflammatory, neuroprotective, immune-modulating and anti-hyperalgesic activities are known, represents a promising candidate to modulate and/or potentiate the action of opioids. This study was designed to evaluate if the preemptive and morphine concomitant administration of ultramicronized PEA, according to fixed or increasing doses of both compounds, delays the onset of morphine tolerance and improves its analgesic efficacy in the chronic constriction injury (CCI) model of neuropathic pain in rats. Behavioral experiments showed that the preemptive and co-administration of ultramicronized PEA significantly decreased the effective dose of morphine and delayed the onset of morphine tolerance. The activation of spinal microglia and astrocytes, commonly occurring both on opioid treatment and neuropathic pain, was investigated through GFAP and Iba-1 immunofluorescence. Both biomarkers were found to be increased in CCI untreated or morphine treated animals in a PEA-sensitive manner. The increased density of endoneural mast cells within the sciatic nerve of morphine- treated and untreated CCI rats was significantly reduced by ultramicronized PEA. The decrease of mast cell degranulation, evaluated in terms of reduced plasma levels of histamine and N-methylhistamine metabolite, was mainly observed at intermediate-high doses of ultramicronized PEA, with or without morphine. Overall, these results show that the administration of ultramicronized PEA in CCI rats according to the study design fully fulfilled the hypotheses of this study.
Learn More >Patients suffering from trigeminal neuralgia (TN) are often accompanied by anxiety and depression. Microglia-mediated neuroinflammation is involved in the development of neuropathic pain and anxiodepression pathogenesis. Whether and how microglia are involved in TN-induced anxiodepression remains unclear.
Learn More >Accumulating evidence shows that N6-methyladenosine (m6A) modulators contribute to the process of chronic pain. However, the exact mechanisms of m6A writers involved in visceral hypersensitivity of IBS remain unclear. This article aimed to reveal a new mechanism for the progression of IBS.
Learn More >In humans, persistent pain often leads to decreased appetite. However, the neural circuits underlying this behaviour remain unclear. Here, we show that a circuit arising from glutamatergic neurons in the anterior cingulate cortex (Glu) projects to glutamatergic neurons in the lateral hypothalamic area (Glu) to blunt food intake in a mouse model of persistent pain. In turn, these Glu neurons project to pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus (POMC), a well-known neuronal population involved in decreasing food intake. In vivo calcium imaging and multi-tetrode electrophysiological recordings reveal that the Glu → Glu → Arc circuit is activated in mouse models of persistent pain and is accompanied by decreased feeding behaviour in both males and females. Inhibition of this circuit using chemogenetics can alleviate the feeding suppression symptoms. Our study indicates that the Glu → Glu → Arc circuit is involved in driving the suppression of feeding under persistent pain through POMC neuronal activity. This previously unrecognized pathway could be explored as a potential target for pain-associated diseases.
Learn More >Spinal cord stimulators (SCSs) are increasingly used for the treatment of chronic pain. There is a need for studies with long-term follow-up.
Learn More >Proline-rich transmembrane protein 2 (PRRT2) is a neuron-specific protein implicated in the control of neurotransmitter release and neural network stability. Accordingly, PRRT2 loss-of-function mutations associate with pleiotropic paroxysmal neurological disorders, including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. PRRT2 is a negative modulator of the membrane exposure and biophysical properties of Na channels Na1.2/Na1.6 predominantly expressed in brain glutamatergic neurons. Na channels form complexes with β-subunits that facilitate the membrane targeting and the activation of the α-subunits. The opposite effects of PRRT2 and β-subunits on Na channels raises the question of whether PRRT2 and β-subunits interact or compete for common binding sites on the α-subunit, generating Na channel complexes with distinct functional properties. Using a heterologous expression system, we have observed that β-subunits and PRRT2 do not interact with each other and act as independent non-competitive modulators of Na1.2 channel trafficking and biophysical properties. PRRT2 antagonizes the β4-induced increase in expression and functional activation of the transient and persistent Na1.2 currents, without affecting resurgent current. The data indicate that β4-subunit and PRRT2 form a push-pull system that finely tunes the membrane expression and function of Na channels and the intrinsic neuronal excitability.
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