Adenosine A1 receptors in mouse pontine reticular formation modulate nociception only in the presence of systemic leptin

Abstract

Human obesity is associated with increased leptin levels and pain, but the specific brain regions and neurochemical mechanisms underlying this association remain poorly understood. This study used adult male C57BL/6J (B6, n = 14) mice and leptin-deficient, obese B6.Cg-Lepob/J (obese, n = 10) mice to evaluate the hypothesis that nociception is altered by systemic leptin levels and by adenosine A1 receptors in the pontine reticular formation. Nociception was quantified as paw withdrawal latency (PWL) in s after onset of a thermal stimulus. PWL was converted to percent maximum possible effect (%MPE). After obtaining baseline PWL measures, the pontine reticular formation was microinjected with saline (control), three concentrations of the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA), or super-active mouse leptin receptor antagonist (SMLA) followed by SPA 15 min later, and PWL was again quantified. In obese, leptin-deficient mice, nociception was quantified before and during leptin replacement via subcutaneous osmotic pumps. SPA was administered into the pontine reticular formation of leptin-replaced mice and PWL testing was repeated. During baseline (before vehicle or SPA administration), PWL was significantly (p = 0.0013) lower in leptin-replaced obese mice than in B6 mice. Microinjecting SPA into the pontine reticular formation of B6 mice caused a significant (p = 0.0003) concentration-dependent increase in %MPE. SPA also significantly (p < 0.05) increased %MPE in B6 mice and in leptin-replaced obese mice, but not in leptin-deficient obese mice. Microinjection of the mouse super-active leptin antagonist (SMLA) into the pontine reticular formation before SPA did not alter PWL. The results show for the first time that pontine reticular formation administration of the adenosine A1 receptor agonist SPA produced antinociception only in the presence of systemic leptin. The concentration-response data support the interpretation that adenosine A1 receptors localized to the pontine reticular formation significantly alter nociception.

Obesity and Chronic Pain

“…117,118 Further exploration has shown that some reticular formation receptors routinely involved in pain regulation do not work without leptin. 119 The administration of ibuprofen decreased glial activation with no effect on leptin expression in nucleus accumbens in the experimental setting. 117 These findings suggest that better understating of inflammation can create a platform for further developing the interchangeability of some drugs used for pain, behavioral disorders, and obesity.…”

Leptin status alters buprenorphine-induced antinociception in obese mice with dysfunctional leptin receptors

“…As noted previously [37] the relationship between leptin and obesity adds to the complexity of determining the degree to which leptin status and/or obesity alter nociception. The Fig.…”

“…Given that leptin is produced by adipocytes, differentiating the extent to which nociception is modulated by leptin per se versus obesity is not trivial [37]. In an effort to evaluate the contributions of obesity and/or leptin to buprenorphine-induced antinociception, the present study used mice that share the obesity phenotype but differ in leptin signaling.…”

“…Closed claims analyses reveal that being female and obese are the greatest risk factors for opiate-related adverse events [18]. Obesity is co-morbid with increased reports of pain in humans [2, 24] and with altered nociception in mice [29, 34, 37]. …”

“…Adipocytes secrete leptin, a proinflammatory cytokine that also functions to signal satiety [3]. Nociceptive processing is altered in obese mice [26, 27, 33] and previously we have shown that leptin replacement can restore thermal nociception in obese, leptin-deficient mice [34, 37]. We are aware of no comparable data from mice determining whether the antinociceptive effects of buprenorphine are altered by obesity and/or sex.…”