Accepted

Low-level laser therapy (LLLT) is a therapeutic option that stimulates cellular function through intracellular photobiological and photochemical reactions, promoting better tissue repair and an anti-inflammatory, antibacterial, and analgesic effect. Previous studies in human and veterinary medicine have shown the clinical efficacy of LLLT in many fields. In this study, the literature was reviewed using the critically appraised topic (CAT) method to determine the canine skin diseases for which LLLT is an advisable treatment. A meticulous literature search revealed 19 significant clinical trials, which were critically analyzed. The evaluation of the best accessible evidence in July 2022 suggests that fluorescence biomodulation (FBM), a type of LLLT, can, in combination with systemic antibiotic therapy, be a promising and effective adjunctive treatment for canine interdigital pyoderma and canine deep pyoderma. Furthermore, the evidence suggests that the use of LLLT is not recommended as a therapy for pedal pruritus secondary to canine atopic dermatitis. For other canine skin diseases included in the CAT, although LLLT appears to be a promising treatment, there is not yet good scientific evidence to recommend its use.

Approximately 2.7 million individuals in the United States had an opioid use disorder (OUD) in 2020. Chronic pain may exacerbate opioid withdrawal severity, yet most research on opioid withdrawal has not collected data on chronic pain status. Moreover, there is limited evidence that women tend to experience greater opioid withdrawal severity than men, but large, confirmatory studies on this topic have not been published. The goal of this study was to examine the roles of chronic pain and gender on opioid withdrawal severity using a large, multi-site database.

Pain is a persistent symptom of Rheumatoid Arthritis, and the K/BxN serum transfer model recapitulates both association and dissociation between pain and joint inflammation in RA. Furthermore, this model features monocyte/macrophage infiltration in joints and lumbar dorsal root ganglia (DRG), where these immune cells are close to nociceptive neurons. We focussed on CXCR-monocyte/macrophage trafficking and show that at peak paw swelling associated with nociception, CXCR deletion altered neither swelling nor macrophage infiltration/phenotype in paws. However, acute nociception and DRG non-classical monocyte numbers were reduced in CXCR (KO) compared to CXCR (WT). Nociception that persisted despite swelling had resolved was attenuated in KO and correlated with DRG macrophages displaying M2-like phenotype. Still in the DRG, neurons up-regulated neuropeptide CGRP and olcegepant treatment reduced acute swelling, nociception, and leukocyte infiltration in paws and DRG. We delineate in-vitro a signalling pathway showing that CGRP liberates the CXCR ligand fractalkine (FKN) from endothelium, and in bone marrow-derived macrophages, FKN promotes activation of intracellular kinases, polarisation towards M1-like phenotype and release of pro-nociceptive IL-6. These data implicate non-classical CXCR-expressing monocyte and macrophage recruitment into the DRG in initiation and maintenance of arthritis pain.

The naturally occurring coumarin osthole has antipruritic properties, and recent reports suggest that this effect is due an inhibition or desensitization of the cation channels TRPV1 and TRPV3. Osthole was also suggested to activate TRPA1, an effect that should rather be pruritic than antipruritic. Here we characterized the effects of osthole on TRPA1 by means of ratiometric calcium imaging and patch clamp electrophysiology. In HEK 293 expressing human (h) TRPA1, osthole induced a concentration-dependent increase in intracellular calcium that was inhibited by the TRPA1-inhibitor A967079. In mouse dorsal root ganglion (DRG) cells, osthole induced a strong calcium-influx that was partly mediated by TRPA1. Osthole evoked fully reversible membrane currents in whole-cell as well as cell-free inside-out recordings on hTRPA1. Osthole failed to activate the mutant hTRPA1-S873V/T874L, a previously described binding site for the non-electrophilic TRPA1-agonists menthol and carvacrol. The combined application of osthole and carvacrol diminished channel activation, suggesting a competitive binding. Finally, osthole failed to activate TRPM8 and TRPV4 but induced a modest activation of hTRPV1 expressed in HEK 293 cells. We conclude that osthole is a potent non-electrophilic agonist of TRPA1. The relevance of this property for the antipruritic effects needs to be further explored.

Unrelieved pain occurs in 55% of cancer patients. Identification of molecular mechanisms for pain may provide insights into therapeutic targets. Purpose was to evaluate for perturbations in neuroinflammatory pathways between oncology patients with and without severe pain. Worst pain severity was rated using a 0 to 10 numeric rating scale six times over two cycles of chemotherapy. Latent profile analysis was used to identify subgroups of patients with distinct pain profiles. Pathway impact analyses were performed in two independent samples using gene expression data obtained from RNA sequencing (n=192) and microarray (n=197) technologies. Fisher's combined probability test was used to identify significantly perturbed pathways between None versus the Severe pain classes. In the RNA sequencing and microarray samples, 62.5% and 56.3% of patients were in the Severe pain class, respectively. Nine perturbed pathways were related to neuroinflammatory mechanisms (i.e., retrograde endocannabinoid signaling, gamma-aminobutyric acid synapse, glutamatergic synapse, Janus kinase-signal transducer and activator of transcription signaling, phagosome, complement and coagulation cascades, cytokine-cytokine receptor interaction, chemokine signaling, calcium signaling). First study to identify perturbations in neuroinflammatory pathways associated with severe pain in oncology outpatients. Findings suggest that complex neuroimmune interactions are involved in the maintenance of chronic pain conditions.

Development of chronic pain has been attributed to dysfunctional GABA signaling in the spinal cord. Direct pharmacological interventions on GABA signaling are usually not very efficient and often accompanied by side effects due to the widespread distribution of GABA receptors in CNS. Transplantation of GABAergic neuronal cells may restore the inhibitory potential in the spinal cord. Grafted cells may also release additional analgesic peptides by means of genetic engineering to further enhance the benefits of this approach. Conopeptides are ideal candidates for recombinant expression using cell-based strategies. The omega-conopeptide MVIIA is in clinical use for severe pain marketed as FDA approved Prialt in the form of intrathecal injections. The goal of this study was to develop transplantable recombinant GABAergic cells releasing conopeptide MVIIA and to evaluate the analgesic effect of the grafts in a model of peripheral nerve injury-induced pain. We have engineered and characterized the GABAergic progenitors expressing MVIIA. Recombinant and nonrecombinant cells were intraspinally injected into animals after the nerve injury. Animals were tested weekly up to 12 weeks for the presence of hypersensitivity, followed by histochemical and biochemical analysis of the tissue. We observed beneficial effects of the grafted cells in reducing hypersensitivity in all grafted animals, especially potent in the recombinant group. The level of pain-related cytokines was reduced in the grafted animals and correlation between these pain markers and actual behavior was indicated. This study demonstrated the feasibility of recombinant cell transplantation in the management of chronic pain.

This study aims to translate and validate the chronic pain score (CP score) in a cohort of colon cancer patients.