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Chronic pain is one of the most critical health issues worldwide. Despite considerable efforts to find therapeutic alternatives, opioid drugs remain the gold standard for pain management. The administration of μ-opioid receptor (MOR) agonists is associated with detrimental and limiting adverse effects. Overall, these adverse effects strongly overshadow the effectiveness of opioid therapy. In this context, the development of neurotensin (NT) ligands has shown to be a promising approach for the management of chronic and acute pain. NT exerts its opioid-independent analgesic effects through the binding of two G protein-coupled receptors (GPCRs), NTS1 and NTS2. In the last decades, modified NT analogues have been proven to provide potent analgesia in vivo. However, selective NTS1 and non-selective NTS1/NTS2 ligands cause antinociception associated with hypothermia and hypotension, whereas selective NTS2 ligands induce analgesia without altering the body temperature and blood pressure. In light of this, various structure-activity relationship (SAR) studies provided for findings addressing the binding affinity of ligands towards NTS2. Herein, we comprehensively review peptide-based NTS2-selective ligands as a robust alternative for future pain management. Particular emphasis is placed on SAR studies governing the desired selectivity and associated in vivo results.

Osteoarthritis (OA) is the most common age-related chronic and disabling joint disease, frequently causing pain and disability in the adult population. Given that there are no proven disease-modifying drugs for OA, it is urgent to gain a deeper understanding of OA pathogenesis. This study intended to uncover the circFOXK2 regulation in OA.

The purpose of this research was to assess the role of heparanase (HPSE)/syndecan1 (SDC1)/nerve growth factor (NGF) on cancer pain from melanoma.

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.

Cluster headache is considered a male-dominated disorder, but we have previously suggested that females may display a more severe phenotype. Studies on sex differences in cluster headache have been conflicting, therefore this study, with the largest validated cluster headache material at present, gives more insights into sex-specific characteristics of the disease. The objective with this study was to describe sex differences in patient demographics, clinical phenotype, chronobiology, triggers, treatment, and lifestyle in a Swedish cluster headache population.

Cannabis and cannabinoids continue to gain popularity as adjuncts or alternatives to opioids in pain management, with evolving evidence of effectiveness. The relationship between cannabis and opioid use has previously been investigated in smaller cohorts or ecological samples, but not yet in a nationally representative sample.

Pain management for patients with dementia is challenging because many experience pain while being unable to communicate their pain. The aim of this study was to describe pain, pain management, and to perform a thorough clinical examination of chronic pain conditions among patients with dementia. Residents (n = 498) from 12 nursing homes were assessed for dementia (Clinical Dementia Rating scale [CDR]) and for pain with the Mobilization-Observation-Behavior-Intensity-Dementia-2 (MOBID-2) assessment form. Of all examined nursing home patients with dementia, 68% had moderate or severe chronic pain. The final study population (n = 262) with a CDR score of ≥1 and a MOBID-2 score of ≥3 were examined by pain expert physicians for chronic pain and categorized according to the International Classification of Disease (ICD-10/-11) classification systems. More than half (54.6%) had chronic pain conditions without underlying disease classified as chronic primary pain by ICD-11. Chronic widespread pain was the most prevalent (14.5%) followed by nonspecific pain from the back (13.4%), whereas the most prevalent chronic secondary pain conditions were chronic pain caused by osteoarthritis (15.4%) and stroke (8.0%). One-fourth received opioids, which was significantly associated with severe pain (P < 0.001) compared with moderate pain, although no significant association was found between opioid use and the type of pain condition. Although knowledge of the severity and specific types of pain conditions is recommended to direct the choice of treatment, these areas are not sufficiently explored in the nursing home populations with dementia and may hinder a better treatment of pain in this population.

In the absence of a gold-standard diagnostic test for different subtypes of dry eye disease (DED), we aimed to identify latent subtypes of DED within a well-characterized cohort.

Emotional Awareness and Expression Therapy (EAET) targets trauma and emotional conflict to reduce or eliminate chronic pain, but video telehealth administration is untested. This uncontrolled pilot assessed acceptability, feasibility, and preliminary efficacy of group-based video telehealth EAET (vEAET) for older veterans with chronic musculoskeletal pain.