Accepted

Over 90% of Chronic pain (CP) patients receive opioids-based treatments which led to a public health crisis with lasting impacts on social and economic wellbeing based on opioid addiction. Opioids act through activation of μ (MOR), δ (DOR) and κ (KOR) opioid receptors which are broadly and differentially distributed throughout the brain. Chronic opioid consumption leads to brain changes such as alterations on neurotransmission, dendritic branching and spine density, as well as an increase in apoptosis. To overcome opioid-related issues, extensive efforts have been made to search for an alternative treatment. Bioactive molecules secreted by Stem Cells, collectively known as secretome, have shown a positive impact in different pain models. However, there is a lack of studies on the role of secretome in modulating opioid receptors. By using cerebral organoids (CeO), a self-organized, functional and multicellular 3D structure that resemble the brain, we were able to identify MOR, DOR and KOR at different stages of maturation. Treatment with secretome increased MOR expression highlighting a possible role in pain signaling mechanisms. Opioid treatments did not impact the expression of neuronal maturation markers but together with secretome, they increased astrogliogenesis. Opioid treated organoids presented higher dopamine secretion recapitulating an important physiological event after opioid exposure. This work demonstrates that CeO is an important model system for the study of opioid signaling with potential implications to the understanding of basic mechanisms related to pain physiology.

The objective of this paper is to investigate the published evidence regarding effects of cannabinoids (natural and synthetic) on post-operative and/or out-of-office pain management in patients suffering from orofacial pain that presents in the dental setting. Three online databases (Ovid (MEDLINE), PubMed (MEDLINE), Scopus) were searched (July 2021). Additional studies were sought through grey literature searching (Cochrane Library Trials and ClinicalTrials.gov) and hand-searching the reference lists of included articles. All studies that analysed cannabinoid products and pain management of conditions that present in the general or specialist dental setting in the English language were included. Of the five articles included, one reported a significant effect on temporomandibular disorder pain relief using a topical cannabidiol formulation compared to a placebo. Four articles reported no significant effects of cannabinoids for pain management across various orofacial pain conditions. Although one study reported a positive effect, insufficient evidence exists to support a tangible clinical benefit of cannabinoids in managing orofacial pain, further research is recommended to investigate the benefits of cannabinoids' use. © 2022 Australian Dental Association.

Pain medicine is rapidly expanding. The gap in treatment for patients with chronic pain in between traditional conservative therapy and major invasive surgery is closing. Neuromodulation is one therapeutic area that has continued to show promise for treatment of chronic pain. Our aim is to review updates in non-invasive neuromodulation (NIN) techniques as an adjunct for various chronic pain conditions.

Background Psoriasis is a common chronic skin inflammatory disease. Understanding the pathogenesis of psoriasis and identifying novel therapeutic targets are under investigation. Methods Gene expression profiles were obtained from GSE13355, GSE30999 and GSE54456 datasets to identify differentially expressed genes (DEGs) between psoriasis and normal controls. Enrichment analysis was used to identify the biological functions and pathways of common genes from three groups of DEGs. Protein-protein interaction (PPI) network was then constructed to identify key genes according to degree of connectivity. Expression of genes was detected by the method of qRT-PCR. The infiltration of immune cells of psoriasis were quantified and detected by flow cytometry. Results A total of 146 common genes were identified between psoriasis and normal controls. They were significantly enriched in IL-17, chemokine, and NOD-like receptor (NLR) signaling pathway. Ten key genes were selected with bigger degree of connectivity through PPI network, and ARG1 and CXCL2 had better predictive ability based on ROC curves. Increased expression of ARG1 and CXCL2 in psoriasis patients were verified by qRT-PCR method. In addition, a lot of immune cells were upregulated in psoriasis compared to healthy controls through ssGSEA and flow cytometry. Conclusion biomarkers and potential therapy ARG1 and CXCL2 may serve as for psoriasis. This may be related to the immune response and NLR pathway.

Opioids are available for the management of severe and chronic pain. However, long-term use of high-dose opioids could lead to physiologic tolerance, hyperalgesia, gastrointestinal immobility, addiction, respiratory depression, tumor progression, and inhibition of the immune system. It seems some of these adverse effects of opioids might be induced by TLR-4 signaling.

The spinal mechanisms of visceral hypersensitivity are poorly understood, particularly when there is an interaction with somatic systems. Recently we demonstrated that rats which were pretreated with neonatal bladder inflammation (NBI) and subsequently pretreated as adults with bladder re-inflammation had augmented reflex and neuronal responses to urinary bladder distension via a corticotropin-releasing factor receptor type 2 (CRFR2) mechanism. Another insult producing similar augmented responses is somatic inflammation induced by Complete Freund's Adjuvant (CFA) in the hindlimb. Using neurochemical measures and both reflex and neuronal responses to urinary bladder distension as endpoints, the present study probed the role of CRFR2-related mechanisms in bladder hyperalgesia secondary to NBI and CFA-induced hindlimb inflammation. ELISA measures of the lumbosacral spinal cord demonstrated increased CRFR2 protein following pretreatment with NBI+CFA. Intrathecal CRFR2 antagonists blocked the augmentation of visceromotor responses to distension following pretreatment with both NBI+CFA. Lumbosacral dorsal horn neuronal responses to bladder distension in rats pretreated with NBI+CFA were attenuated by the spinal topical administration of a CRFR2 antagonist. These findings are the first demonstration of a somatovisceral interaction working via CRFR2 receptors and support the therapeutic value of these agents in the treatment of painful bladder disorders, particularly when triggered by somatic events. (Word Count 199) PERSPECTIVE: Bladder hypersensitivity occurs following neonatal cystitis and an adult insult such as somatic inflammation. This paper demonstrates that CRFR2-related mechanisms are associated with this hypersensitivity. This supports the therapeutic value of these agents in the treatment of painful bladder disorders, particularly when triggered by somatic events.