Accepted

TRPM8 is a non-selective cation channel expressed in primary sensory neurons and other tissues, including the prostate and urothelium. Its participation in different physiological and pathological processes such as thermoregulation, pain, itch, inflammation and cancer has been widely described, making it a promising target for therapeutic approaches. The detection and quantification of TRPM8 seems crucial for advancing the knowledge of the mechanisms underlying its role in these pathophysiological conditions. Antibody-based techniques are commonly used for protein detection and quantification, although their performance with many ion channels, including TRPM8, is suboptimal. Thus, the search for reliable antibodies is of utmost importance. In this study, we characterized the performance of six TRPM8 commercial antibodies in three immunodetection techniques: Western blot, immunocytochemistry and immunohistochemistry. Different outcomes were obtained for the tested antibodies; two of them proved to be successful in detecting TRPM8 in the three approaches while, in the conditions tested, the other four were acceptable only for specific techniques. Considering our results, we offer some insight into the usefulness of these antibodies for the detection of TRPM8 depending on the methodology of choice.

Nuclear factor kappa B (NF-κB) signaling is an important modulator in osteoarthritis (OA), and IκB kinase ε (IKKε) regulates the NF-κB pathway. This study was undertaken to identify the functional involvement of IKKε and the effectiveness of IKKε inhibition in OA pathogenesis.

Neuropathic pain is a chronic and debilitating condition characterised by episodes of hyperalgesia and allodynia. It occurs following nerve damage from disease, inflammation or injury and currently impacts up to 17% of the UK population. Existing therapies lack efficacy and have deleterious side effects that can be severely limiting. Galanin receptor 2 (GalR2) is a G-protein coupled receptor (GPCR) implicated in the control and processing of painful stimuli. Within the nervous system it is expressed in key tissues involved in these actions such as dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. Stimulation of GalR2 is widely reported to have a role in the attenuation of inflammatory and neuropathic pain. Several studies have indicated GalR2 as a possible drug target, highlighting the potential of specific GalR2 agonists to both provide efficacy and to address the side-effect profiles of current pain therapies in clinical use. A strong biological target for drug discovery will be well validated with regards to its role in the relevant disease pathology. Ideally there will be good translational models, sensitive probes, selective and appropriate molecular tools, translational biomarkers, a clearly defined patient population and strong opportunities for commercialisation. Before GalR2 can be considered as a drug target suitable for investment, key questions need to be asked regarding its expression profile, receptor signalling and ligand interactions. This article aims to critically review the available literature and determine the current strength of hypothesis of GalR2 as a target for the treatment of neuropathic pain.

(1) Background: The objective was to compare the exploration of chronic pelvic pain syndrome (CPPS) patients in different locations and establish the role of physical examination in CPPS patients. (2) Methods: We reviewed clinical data from 107 female patients with CPPS unresponsive to conventional therapies at Puerta de Hierro University Hospital Madrid, Spain, from May 2018 to June 2022. Patients were classified into three groups: (a) pelvic pain; (b) anorectal pain; or (c) vulvar/perineal pain. (3) Results: Although the demographics of patients with CPPS were different, their physical examinations were strikingly similar. Our study observed a comorbidity rate of 36% and 79% of central sensitization of pain. Seventy-one percent of patients had vulvar allodynia/hyperalgesia. Pain on examination was identified in any pelvic floor muscle, in any pelvic girdle structure, and neuropathic pain in 98%, 96%, and 89%, respectively. Patients with vulvar and perineal pain were more different from the other groups; these patients were younger and had fewer comorbidities and less central sensitization, less anorectal pain, more pain during intercourse, and greater nulliparity ( = 0.022; = 0.040; = 0.048; = 0.000; = 0.006; = 0.005). (4) Conclusions: The findings of this study are related to the understanding of the pathophysiology of CPPS. The physical examination confirms the central sensitization of female patients with CPPS, helps us to determine the therapeutic management of the patient, and can be considered as a prognostic factor of the disease.

Neuronal function relies on the maintenance of appropriate levels of various ion channels at the cell membrane, which is accomplished by balancing secretory, degradative, and recycling pathways. Neuronal function further depends on membrane specialization through polarized distribution of specific proteins to distinct neuronal compartments such as axons. Voltage-gated sodium channel Na1.7, a threshold channel for firing action potentials in nociceptors, plays a major role in human pain, and its abundance in the plasma membrane is tightly regulated. We have recently characterized the anterograde axonal trafficking of Na1.7 channels in Rab6A-positive vesicles, but the fate of internalized channels is not known. Membrane proteins which have undergone endocytosis can be directed into multiple pathways including those for degradation, recycling to the membrane, and transcytosis. Here we demonstrate Na1.7 endocytosis and dynein-dependent retrograde trafficking in Rab7-containing late endosomes together with other axonal membrane proteins using real-time imaging of live neurons. We show that some internalized Na1.7 channels are delivered to lysosomes within the cell body, and that there is no evidence for Na1.7 transcytosis. In addition, we show that Na1.7 is recycled specifically to the axonal membrane as opposed to the soma membrane, suggesting a novel mechanism for the development of neuronal polarity. Together, these results shed light on the mechanisms by which neurons maintain excitable membranes and may inform efforts to target ion channel trafficking for the treatment of disorders of excitability.

Sulfatide is a sulfated glycosphingolipid that is present abundantly in myelin sheaths of the brain and spinal cord. It is synthesized by a cerebroside sulfotransferase encoded by Gal3st1, which catalyzes the transfer of sulfate from 3'-phosphoadenylylsulfate to galactosylceramide. We previously reported that Gal3st1 gene expression in the spinal cord is upregulated 1 day after intraplantar injection of complete Freund's adjuvant (CFA), indicating that sulfatide is involved in inflammatory pain. In the present study, we found that intrathecal injection of sulfatide led to mechanical allodynia. Sulfatide caused levels of glial fibrillary acidic protein (GFAP) and nitric oxide in the spinal cord to increase. Mechanical allodynia induced by intrathecal injection of sulfatide was blocked by nitric oxide synthase inhibitors and by suppression of astrocyte activation by L-α-aminoadipate. These results suggest that sulfatide-induced mechanical allodynia involved glial activation and nitric oxide production. Blocking selectin, a sulfatide-binding protein, with bimosiamose attenuated sulfatide-induced allodynia and ameliorated CFA-induced mechanical allodynia during inflammatory pain. Finally, elevated levels of sulfatide concentration in the spinal cord was observed during CFA-induced inflammatory pain. The elevated sulfatide levels enhanced selectin activation in the spinal cord, resulting in mechanical allodynia. Our data suggest that sulfatide-selectin interaction plays a key role in inflammatory pain.

Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex-midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.

This review synthesizes recent findings related to the biopsychosocial processes that underlie racial disparities in chronic pain, while highlighting opportunities for interventions to reduce disparities in pain treatment among BIPOC.

Pain science education is commonly integrated into treatments for childhood-onset chronic pain. A core component of pain science education is learning about, and often reconceptualizing, the biology of chronic pain. Yet, few interventions have been developed specifically for young adults and little is known about how young adults conceptualize the biology of pain. This study used a qualitative methodology to examine how young adults with childhood-onset chronic pain understand the biology of pain, and the language they use in this meaning-making process, which may inform future interventions tailored to this age group.

Endometriosis is a pathophysiological condition characterized by glands and stroma outside the uterus in regions such as the bladder, ureter, fallopian tubes, peritoneum, ovaries, and even in extra pelvic sites. One of the main clinical problems of endometriosis is chronic pelvic pain (CPP), which considerably affects the patients' quality of life. Patients with endometriosis may, cyclically or non-cyclically (80% of cases) experience CPP. High levels of anxiety and depression have been described in patients with endometriosis related to CPP; however, this has not been evaluated in endometriosis women with different types of CPP. Therefore, the research question of this study was whether there is a difference in the emotional dysregulation due to the type of pain experienced by women with endometriosis?