&lt;p&gt;Evaluating the Role of CXCR3 in Pain Modulation: A Literature Review&lt;/p&gt;

Deng

et al. 2023

Cells

Autophagy is a cellular catabolic process in the evolutionarily conservative turnover of intracellular substances in eukaryotes, which is involved in both immune homeostasis and injury repairment. CXCR3 is an interferon-induced chemokine receptor that participates in immune regulation and inflammatory responses. However, CXCR3 regulating intestine injury via autophagy along with the precise underlying mechanism have yet to be elucidated. In the current study, we employed an LPS-induced inflammatory mouse model and confirmed that CXCR3 knockout significantly attenuates intestinal mucosal structural damage and increases tight junction protein expression. CXCR3 knockout alleviated the LPS-induced increase in the expression of inflammatory factors including TNF-α, IL-6, p-65, and JNK-1 and enhanced autophagy by elevating LC3II, ATG12, and PINK1/Parkin expression. Mechanistically, the function of CXCR3 regarding autophagy and immunity was investigated in IPEC-J2 cells. CXCR3 inhibition by AMG487 enhanced autophagy and reduced the inflammatory response, as well as blocked the NF-κB signaling pathway and elevated the expression of the tight junction protein marker Claudin-1. Correspondingly, these effects were abolished by autophagy inhibition with the selective blocker, 3-MA. Moreover, the immunofluorescence assay results further demonstrated that CXCR3 inhibition-mediated autophagy blocked p65 nuclear translocation, and the majority of Claudin-1 was located at the tight junctions. In conclusion, CXCR3 inhibition reversed LPS-induced intestinal barrier damage and alleviated the NF-κB signaling pathway via enhancing autophagy. These data provided a theoretical basis for elucidating the immunoregulatory mechanism by targeting CXCR3 to prevent intestinal dysfunction.

Section: Introductionmentioning

confidence: 99%

CXCR3 Inhibition Blocks the NF-κB Signaling Pathway by Elevating Autophagy to Ameliorate Lipopolysaccharide-Induced Intestinal Dysfunction in Mice

Deng

et al. 2023

Cells

“…Such is the case for the promoter of the genes encoding for the chemokine receptor 3 (CXCR3) [ 65 ] or G Protein-Coupled Receptor 151 (GPR151) [ 66 ], which were both found to be less methylated in the spinal nerve ligation (SNL) mouse model of neuropathic pain. CXCR3 is a key player in the pathophysiological process of many inflammatory conditions and associated to pain modulation in DRG and spinal cord [ 67 ]. GPR151 has been associated to DRG hyperexcitability in neuropathic chronic pain [ 68 ].…”

Section: Epigenetic Mechanisms In Chronic Painmentioning

confidence: 99%

Role of Epigenetic Mechanisms in Chronic Pain

Mauceri

2022

Cells

Pain is an unpleasant but essential-to-life sensation, usually resulting from tissue damage. When pain persists long after the injury has resolved, it becomes pathological. The precise molecular and cellular mechanisms causing the transition from acute to chronic pain are not fully understood. A key aspect of pain chronicity is that several plasticity events happen along the neural pathways involved in pain. These long-lasting adaptive changes are enabled by alteration in the expression of relevant genes. Among the different modulators of gene transcription in adaptive processes in the nervous system, epigenetic mechanisms play a pivotal role. In this review, I will first outline the main classes of epigenetic mediators and then discuss their implications in chronic pain.

“…The expression, signalling and desensitisation of opioid receptors is affected by their interactions with other G-protein—coupled receptors (GPCRs) such as chemokine receptors, which play a major role in many processes including inflammation through altering immune cell migration. 69,70 Opioid peptides activate ACKR3 (a member of the atypical chemokine receptor family and formerly known as CXCR7), which appears to be a negative regulator of opioid peptide (mainly dynorphin) function and is proposed as an opioid scavenger receptor. 69 Understanding of its role in opioid action is still very much in its infancy but does highlight the likelihood that future drug development of pain therapeutics will include an array of drugs targeting receptors often not considered important, particularly in the field of chemokine pharmacology.…”

Section: Other Opioid Receptorsmentioning

confidence: 99%

New pharmacological perspectives and therapeutic options for opioids: Differences matter

Somogyi

Musolino

Barratt

2022

Anaesth Intensive Care

Opioids remain the major drug class for the treatment of acute, chronic and cancer pain, but have major harmful effects such as dependence and opioid-induced ventilatory impairment. Although no new typical opioids have come onto the market in the past almost 50 years, a plethora of new innovative formulations has been developed to meet the clinical need. This review is intended to shed light on new understanding of the molecular pharmacology of opioids, which has arisen largely due to the genomic revolution, and what new drugs may become available in the coming years. Atypical opioids have and are being developed which not only target the mu opioid receptor but other targets in the pain pathway. Biased mu agonists have been developed but remain ‘unbiased’ clinically. The contribution of drugs targeting non-mu opioid receptors either alone or as heterodimers shows potential promise but remains understudied. That gene splice variants of the mu opioid receptor produce multiple receptor isoforms in different brain regions, and may change with pain chronicity and phenotype, presents new challenges but also opportunities for precision pain medicine. Finally, that opioids also have pro-inflammatory effects not aligned with mu opioid receptor binding affinity implicates a fresh understanding of their role in chronic pain, whether cancer or non-cancer. Hopefully, a new understanding of opioid analgesic drug action may lead to new drug development and better precision medicine in acute and chronic pain relief with less patient harm.