Complete Freund’s adjuvant (CFA) has been used to develop the arthritic or inflammatory condition in the animal, but there is a lack of information concerning high CFA doses on nociceptive behaviour and inflammatory parameters. This study aimed to compare the effects of different high doses of CFA in rat to closely mimic nociceptive and inflammatory parameters of rheumatoid arthritis (RA) in humans. Twenty-four male Sprague-Dawley rats were randomly divided into four groups (n = 6): Control (C), CFA-induced polyarthritic groups at 5.0 mg/mL (CFA 5.0), 7.5 mg/mL (CFA 7.5) and 10.0mg/mL (CFA 10.0). The rats’ right hindpaw was inoculated with CFA intradermally and developed into a polyarthritic state within 20 days. Nociceptive behavioural assessments, including von Frey and hot plate tests and spontaneous activities, were conducted on day 0, 7, 15 and 20. Bilateral ankle joints diameter and circumference, full blood count, joints and paw histological examinations were also conducted throughout the study period. Based on the results, CFA 5.0 and CFA 7.5 groups showed a significant increase in spontaneous activities and development of thermal hyperalgesia but no change in body weight and food intake, no development of tactile allodynia and haematological indices, and no significant morphological changes of joints histology. Meanwhile, CFA 10.0 group demonstrated significant and constant changes in all nociceptive and inflammatory parameters investigated. In conclusion, CFA at the dose of 10mg/mL has the most potential and reliable dosage to develop polyarthritis in a rat model to mimic RA condition in humans.
Arthritis-induced adjuvant (AIA) is an established animal model reflecting several clinical manifestations of human arthritis. It provides more understanding of pathogenesis and pathways involved in arthritic development and for testing various treatment modalities. Complete Freund’s adjuvant (CFA) is one of the most known algogenic agents used to develop AIA rodent model. Its wide application increases understanding of CFA effects locally and systemically following adjuvant-containing mycobacterium exposure in-vivo. This study aims to review possible factors involved in producing a successful CFA-induced arthritic rat model. We conducted a review of previous studies to determine critical factors to be emphasized. Since arthritis can be classified as gout, osteoarthritis, and rheumatoid arthritis, among others, factors that should be assessed include different dosage and volume, injection site, remission, arthritic and animal gender, and strain selections to successfully develop an arthritic rat model.
Pain derived from rheumatoid arthritis (RA) is the most debilitating symptom suffered by patients although inflammation is successfully controlled. It is the main concern that is frequently overlooked due to unclear understandings of its occurrence. Medications to alleviate pain are limited and produce severe side effects. This study aimed to uncover possible involvement of nociceptive signalling N-methyl-D-aspartate-2B receptor (NMDAR-2B) or P2X4 receptor (P2X4R)-induced microglial activation at thalamus of chronic polyarthritis rat mimicking RA upon CORM-2 (selective P2X4R antagonist) and ifenprodil (non-competitive NMDAR-2B antagonist) administrations. Eighty Sprague-Dawley male rats were randomly assigned into five groups (n = 16): non-arthritic control(C), arthritic control(A), arthritic rats treated with either diclofenac (positive control) (A + Diclofenac), CORM-2 (A + CORM-2), or ifenprodil (A + Ifenprodil). The rat was induced with complete Freund’s adjuvant into chronic polyarthritis state for 15 days. Treatment of either sodium diclofenac, ifenprodil, CORM-2 or saline (as vehicle) was performed for seven days intrathecally. Bilateral ankle joint diameter and spontaneous behaviour activity (mobility) were evaluated to assess oedema-induced pain responses. Thalamus tissue was collected for qRT-PCR and immunohistochemistry analyses. Results revealed a significant reduction in ankle joint diameter and improved mobility in groups treated with CORM-2 and ifenprodil. The treatments significantly attenuated mRNA level and protein expression of thalamic P2X4R and activated microglia of arthritic rats. This study deduced possible contribution of thalamic NMDAR-2B-P2X4R-induced microglial activation in pathogenesis of RA pain. It also provides insights to understand the pathogenesis of RA pain and suggests CORM-2 and ifenprodil as possible new therapeutics in RA pain management.
The role of carbon monoxide (CO) has evolved albeit controversial disputes on its toxicity. This biological gasotransmitter participates in the endogenous regulation of neurotransmitters and neuropeptides released in the nervous system. Exogenous CO gas inhalation at a lower concentration has been the subject of investigations, which have revealed its biological homeostatic mechanisms and protective effects against many pathological conditions. This therapeutic procedure of CO is, however, limited due to its immediate release, which favours haemoglobin at a high affinity with the subsequent generation of toxic carboxyhaemoglobin in tissues. In order to address this problem, carbon monoxide releasing molecule-2 (CORM-2) or also known as tricarbonyldichlororuthenium II dimer is developed to liberate a controlled amount of CO in the biological systems. In this review, we examine several potential mechanisms exerted by this therapeutic compound to produce the anti-nociceptive effect that has been demonstrated in previous studies. This review could shed light on the role of CORM-2 to reduce pain, especially in cases of chronic and neuropathic pain.
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