Objective Mechanisms responsible for osteoarthritic (OA) pain remain poorly understood, and current analgesic therapies are often insufficient. This study was undertaken to characterize and pharmacologically test the pain phenotype of a noninvasive mechanical joint loading model of OA, thus providing an alternative murine model for OA pain. Methods The right knees of 12‐week‐old male C57BL/6 mice were loaded at 9N or 11N (40 cycles, 3 times per week for 2 weeks). Behavioral measurements of limb disuse and mechanical and thermal hypersensitivity were acquired before mechanical joint loading and monitored for 6 weeks postloading. The severity of articular cartilage lesions was determined postmortem with the Osteoarthritis Research Society International scoring system. To assess efficacy of various treatments for pain, 9N‐loaded mice were treated for 4 weeks with diclofenac (10 mg/kg), gabapentin (100 mg/kg), or anti–nerve growth factor (anti‐NGF) (3 mg/kg). Results Mechanical hypersensitivity and weight bearing worsened significantly in 9N‐loaded mice (n = 8) and 11N‐loaded mice (n = 8) 2 weeks postloading, compared to baseline values and nonloaded controls. Maximum OA scores of ipsilateral knees confirmed increased cartilage lesions in 9N‐loaded mice (mean ± SEM 2.8 ± 0.2; P < 0.001) and 11N‐loaded mice (5.3 ± 0.3; P < 0.001), compared to nonloaded controls (1.0 ± 0.0). Gabapentin and diclofenac restored pain behaviors to baseline values after 2 weeks of daily treatment, and gabapentin was more effective than diclofenac. A single injection of anti‐NGF alleviated nociception 2 days after treatment and remained effective for 2 weeks, with a second dose inducing stronger and more prolonged analgesia. Conclusion Our findings show that mechanical joint loading induces OA lesions in mice and a robust pain phenotype that can be reversed using analgesics known to alleviate OA pain in patients. This establishes the use of mechanical joint loading as an alternative model for the study of OA pain.
The effective management of visceral pain is a significant unmet clinical need for those affected by gastrointestinal diseases, such as inflammatory bowel disease (IBD). The rational design of novel analgesics requires a greater understanding of the mediators and mechanisms underpinning visceral pain. Interleukin-13 (IL-13) production by immune cells residing in the gut is elevated in IBD, and IL-13 appears to be important in the development of experimental colitis. What's more, receptors for IL-13 are expressed by neurons innervating the colon, though it is not known whether IL-13 plays any role in visceral nociception per se. To resolve this, we employed Ca2+ imaging of cultured sensory neurons and ex vivo electrophysiological recording from the lumbar splanchnic nerve innervating the distal colon. Ca2+ imaging revealed the stimulation of small-diameter, capsaicin-sensitive sensory neurons by IL-13, indicating that IL-13 likely stimulates nociceptors. IL-13-evoked Ca2+ signals were attenuated by inhibition of Janus (JAK) and p38 kinases. In the lumbar splanchnic nerve, IL-13 did not elevate baseline firing, nor sensitise the response to capsaicin application, but did enhance the response to distention of the colon. In line with Ca2+ imaging experiments, IL-13-mediated sensitisation of the afferent response to colon distention was blocked by inhibition of either JAK or p38 kinase signalling. Together, these data highlight a potential role for IL-13 in visceral nociception and implicate JAK and p38 kinases in pro-nociceptive signalling downstream of IL-13.
Perforated intestinal metastasis while taking the BRAF inhibitor, vemurafanibA 61-year-old man presented to our hospital with left-sided abdominal pains and fever. He had a history of primary cutaneous melanomas excised in 2003 and 2005, small bowel melanoma metastases excised in 2011 and radiologically confirmed metastases in the mediastinum, lung and liver. His tumour was BRAF V600 mutation positive. He was taking vemurafanib as part of the COMBI-V trial, resulting in dramatic reduction in volume of a palpable cervical metastasis. Vemurafanib has been shown to prolong progression-free survival in advanced melanoma by inhibiting the BRAF cell signalling pathway. 1 Abdominal computed tomography scan suggested visceral perforation with free fluid and gas in the left upper quadrant ( Fig. 1). At laparotomy, an abscess was found adjacent to perforated small bowel segment. The small bowel was resected with primary anastomosis and the patient made a good recovery. Histological findings were of multiple metastatic melanoma deposits with mucosal ulceration and serosal exudate at the area of oversewn perforation. Between melanoma deposits, the small bowel appeared microscopically normal.Small bowel metastases are found in over 25% of advanced melanoma patients undergoing autopsy. However, only 0.8-4.4% of patients with primary melanoma developed symptoms from intestinal metastases before death. 2 Many intestinal metastases are therefore occult. Intestinal melanomas may present with symptoms of partial obstruction or bleeding, but perforation itself is exceptionally rare, with only six previous cases documented in the literature. 3 Colonic perforation secondary to drug-induced colitis has been reported with other new anti-melanoma agents including ipilimumab; 4 however, our case differs as the perforation was at the site of a small bowel metastasis. As far as we are aware, our case is the first example of a perforation that occurred while the patient was taking vemurafanib. We hypothesize that vemurafanib may have contributed to visceral perforation, although drug-induced necrosis was not proven histologically. References 1. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011; 364: 2507-16. 2. Alwhouhayb M, Mathur P, Al Bayaty M. Metastatic melanoma presenting as a perforated small bowel. Turk.
Visceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut related side-effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception in disease states is required to facilitate this. The pro-inflammatory cytokine TNFα is linked to pain in patients with inflammatory bowel disease or irritable bowel syndrome and has been shown to sensitise colonic sensory neurons. Somatic, TNFα-triggered thermal and mechanical hypersensitivity is mediated by TRPV1 signalling and p38 MAPK activity respectively, downstream of TNFR1 receptor activation. We therefore hypothesised that TNFR1-evoked p38 MAPK activity may also be responsible for TNFα sensitisation of colonic afferent responses to the TRPV1 agonist capsaicin, and noxious distension of the bowel. Using Ca2+ imaging of dorsal root ganglia sensory neurons, we observed TNFα-mediated increases in intracellular [Ca2+] and sensitisation of capsaicin responses. The sensitising effects of TNFα were dependent on TNFR1 expression and attenuated by TRPV1 and p38 MAPK inhibition. Consistent with these findings, ex vivo colonic afferent fibre recordings demonstrated enhanced response to noxious ramp distention of the bowel and bath application of capsaicin following TNFα pre-treatment. Responses were reversed by p38 MAPK inhibition and absent in tissue from TNFR1 knockout mice. Our findings demonstrate a contribution of TNFR1, p38 MAPK and TRPV1 to TNFα-induced sensitisation of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in GI disease.
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