Experimental Physiology 1236 Exp Physiol 97.11 (2012) pp 1236–1245 Related Research Paper Related Research Paper Increased central and peripheral inflammation and inflammatory hyperalgesia in Zucker rat model of leptin receptor deficiency and genetic obesity Tommaso Iannitti, Annette Graham and Sharron Dolan Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK This study investigated whether sensitivity to nociceptive stimuli is altered in obese rats using established models of inflammatory pain, and using real-time PCR, profiled alterations in expression of key adipokine and inflammatory mediator mRNA (adiponectin, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, inducible nitric oxide synthase (iNOS)) in spinal cord with obesity. Responses to thermal and mechanical stimulation of the hindpaw and paw oedema were assessed in adult male Zucker fatty rats (fa/fa) and their lean littermates (fa/–; n = 6–9 per group) in the absence of inflammation (acute nociception), then in response to intradermal hindpaw injection of carrageenan (3%; 50 μl) or capsaicin (10 μg; 50 μl) or hindpaw incision. The analgesic potency of morphine (1, 2.5 or 5 mg kg -1 or vehicle; s.c.) was also assessed. Acute nociception was unaltered in obese animals, but following carrageenan- induced inflammation the obese rats were significantly more sensitive to mechanical and thermal stimulation of the inflamed paw, and displayed greater paw oedema. No difference in the capsaicin- or paw-incision-induced pain sensitivity or in the analgesic potency of morphine was observed between groups. Levels of adiponectin and inducible nitric oxide synthase mRNA were downregulated in spinal cord from obese rats, whereas tumour necrosis factor-α mRNA was upregulated; interleukin-1β and cyclo-oxygenase were unchanged. The increased pain sensitivity and inflammatory response together with changes in spinal adipokine expression in obese rats fit well with the hypothesis that obesity is a chronic low-grade inflammatory disorder, producing a state where responses to subsequent inflammatory challenge are potentiated. (Received 22 December 2011; accepted after revision 17 April 2012; first published online 20 April 2012) Corresponding author S. Dolan: Department of Biological and Biomedical Sciences, Cowcaddens Road, Glasgow Caledonian University, Glasgow G4 0BA, UK. Email: s.dolan@gcu.ac.uk In obese humans, there is a significant negative relationship between obesity and health-related quality of life scores, which include measures of pain (Yancy et al. 2002). Obese individuals are more commonly affected by chronically painful conditions, such as osteoarthritis (Grotle et al. 2008), peripheral vascular disease (Frisbee, 2007), lower back pain and a wide range of disabling muscoskeletal conditions (Patterson et al. 2004; Anandacoomarasamy et al. 2008). The increased incidence of pain with obesity is not entirely due to increased weight bearing or joint stress, as obesity has also been linked to pain in other joints, including the hand (Oliveira et al. 1999) and neck (Webb et al. 2003), and has been reported to increase the prevalence of painful conditions, such as fibromyalgia (Becker et al. 2002), migraine (Ford et al. 2008; Peterlin et al. 2010) and the severity of headache (Bigal et al. 2006; Bigal & Lipton, 2008). Furthermore, obese women are at a higher comparative risk of knee osteoarthritis than obese men (Felson & Chaisson, 1997), suggesting that factors other than body weight contribute to disease progression. In animal models, evidence points to an increase in acute pain sensitivity with obesity. For instance, obese Zucker rats were reported to be more sensitive to noxious mechanical and thermal stimulation of the tail (Roane & Porter, 1986). Increased paw oedema has also been reported in obese rats in response to intraplantar injection of Freund’s complete adjuvant, a model of arthritis (Croci & Zarini, 2007). However, in DOI: 10.1113/expphysiol.2011.064220 C  2012 The Authors. Experimental Physiology C  2012 The Physiological Society