Rats with Features of Metabolic Syndrome Exhibit Sex-specific Differences in Nociception

Introduction: Pain processing is polygenically modulated and varies as a function of sex, body habitus, modality, and genotype. Human pain has been positively correlated with obesity (J Pain 8: 430, 2007) and both pain processing and self-reports of pain vary between men and women (J Pain 13: 228, 2012; J Pain 101: 259, 2003). Rats selectively bred to have features of metabolic syndrome (Science 307: 418, 2005) may provide an animal model that can help elucidate the underlying neurochemical mechanisms contributing to differences in pain that are sex-specific and associated with obesity/metabolic syndrome (Anesthesiology 113: 1176, 2010). As an initial step prior to pharmacological studies of chronic pain, this experiment is testing the hypothesis that rats with features of metabolic syndrome exhibit sex-specific differences in nociception. Materials and methods: To date we have used multimodal pain testing to evaluate nociceptive responses in male (n = 3) and female (n = 3) rats with features of metabolic syndrome. The experiments quantified hind paw withdrawal latency to a heat stimulus using the Hargreaves method (Pain 32: 77, 1988). Gram-equivalent responses to mechanical stimuli were quantified using the up-down method (J Neurosci Methods 53: 55, 1994). Duration of response to the acetone spray test was used to characterize the response to a cold thermal stimulus (Anesth Analg 101: 457, 2005). Results: Responses were quantified (mean ± SD) for male and female rats on each of the three pain modalities tested. Paw withdrawal latencies (PWL) in seconds for females (7.26 ± 1.45) and males (5.98 ± 1.51) differed by 21.4%. Responses to mechanical stimuli (in grams) for females (8.66 ± 6.35) and males (5.40 ± 5.21) differed by 60.4%. Duration of response to the acetone spray test in seconds for females (0.5 ± 0) and males (0.67 ± 0.26) differed by 33.3%. Discussion: Previous studies found that lean rats selectively bred for enhanced aerobic fitness had higher thresholds for heat nociception than did rats bred to promote features of metabolic syndrome (Neurosci Lett 443: 37, 2008). Lean/fit rats also recover more rapidly from neuropathic pain caused by chronic constriction injury of the sciatic nerve (Anesthesiology 113: 1176, 2010). The present results indicate that in obese rats with features of metabolic syndrome the females had a longer PWL, a greater threshold for mechanical nociception, and a longer duration of response to the acetone test. These data imply a lower pain threshold in the obese, male rats. The preliminary results also suggest that rats selectively bred to enhance the polygenic modulation of obesity/metabolic syndrome offer a unique resource for studies aiming to elucidate mechanisms contributing to sex-specific differences in nociceptive processing.