Neuroimmunological complications arising from chemotherapy‐induced gut toxicity and opioid exposure in female dark agouti rats

• Published in: Journal of neuroscience research Vol. 100; no. 1; pp. 237 - 250
• Main Authors: Bajic, Juliana Esma, Howarth, Gordon Stanley, Mashtoub, Suzanne, Whittaker, Alexandra Louise, Bobrovskaya, Larisa, Hutchinson, Mark Rowland
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2022
• Subjects: 5-Fluorouracil; Adaptation; Analgesics; Analgesics, Opioid - toxicity; Animals; Antineoplastic Agents; Astrocytes - metabolism; Brain; Buprenorphine; Cancer; CD11b antigen; Chemotherapy; Clusters; Cognitive ability; Complications; Dasyproctidae; Digestive system; Female; Gastrointestinal tract; glia; Glial fibrillary acidic protein; Hippocampus; Humans; Inflammation; Interleukin 1; mucositis; Narcotics; Neuroglia - metabolism; Neuromodulation; Neuronal-glial interactions; Opioids; Pain; Rats; Reactivity; RRID:AB_10015282; RRID:AB_2129384; RRID:AB_2340709; RRID:AB_2340771; RRID:AB_305808; RRID:AB_308765; RRID:AB_476693; Side effects; Signaling; Thorax; Toxicity; Tramadol; western blot; RRID:AB_2129384; mucositis; 5-Fluorouracil; RRID:AB_476693; RRID:AB_305808; RRID:AB_2340709; RRID:AB_2340771; RRID:AB_308765; western blot; RRID:AB_10015282; glia; opioids
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.24959

Cancer patients may experience symptom clusters, including chemotherapy‐induced (CI) gut toxicity (CIGT) and cognitive impairment. Analgesic selection for pain associated with CIGT is difficult as opioids induce glial reactivity and unwanted side effects. This study quantified central glial reactivity and proinflammatory effects in rats with CIGT using three mechanistically different analgesics. Regional adaptations were indicative of immune‐to‐brain signaling routes. Utilizing a 5‐fluorouracil‐induced GT (5IGT) rat model and analgesic intervention (carprofen (CAR), buprenorphine (BUP), and tramadol (TRAM)), spinal and brain neuroimmune modulation was examined via microglial, astrocyte, and proinflammatory (cluster of differentiation molecule 11b; CD11b, glial fibrillary associated protein; GFAP, and interleukin‐1 beta; IL1β) reactivity marker expression changes by western blot analysis. 5IGT significantly increased thoracic GFAP (p < 0.05) and IL‐1β (p < 0.0001) expression, CAR and BUP ameliorated these effects. BUP and TRAM with 5‐FU synergistically increased hippocampal GFAP expression. CAR administered with 5IGT significantly elevated hippocampal and thoracic CD11b expression levels (p < 0.05). The neuroimmune responses observed in this study suggest activation of peripheral‐to‐central immune signaling pathways. We speculate that the opioid‐induced hippocampal changes inferred a humorally mediated mechanism, whereas thoracic neuroimmune modifications indicated activation of an indirect neural route. Although TRAM ameliorated 5IGT‐intestinal inflammation, this opioid presents complications relating to bodyweight and regional glial dysregulation (neuroinflammation) and may not be optimal in the management of pain associated with 5IGT. The chemotherapy‐induced gut‐derived neuroimmune consequences observed suggest a potential mechanistic contribution to central components of the cancer symptom cluster experience, while the opioid‐related glial changes have implications for optimal pain management in this setting warranting further investigation. 5‐Fluorouracil‐induced gut toxicity resulted in a main neuroimmunological effect in the thoracic region with carprofen ameliorating this effect. Buprenorphine and tramadol increased astrocyte reactivity marker expression, yet decreased thoracic IL‐1beta expression. Understanding the peripheral‐to‐central complications arising in chemotherapy‐induced toxicities and analgesic treatments may elucidate potential mechanisms contributing to the central complications arising from chemotherapy.