A Leptin-Mediated Central Mechanism in Analgesia-Enhanced Opioid Reward in Rats

Abstract

Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1␤ in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management.

Abnormal trigeminal sensory processing in obese mice

“…Leptin has a variety of functions beyond energy homeostasis and has been recently implicated in pain modulation peripherally and centrally. 21,22,24,49 ob/ob mice fail to develop neuropathic pain following nerve injury, which has been attributed to impaired macrophage mobilization to the injured nerve and lack of leptin-mediated upregulation of NMDA and IL-beta in the spinal cord. 22,24 The differences between the two models of obesity may be related to several inherent characteristics, such as the congenital lack of leptin and potential effects on development, the more rapid and severe weight gain in the ob/ob mice, and the presence of other metabolic and immune-related abnormalities in the ob/ob mice.…”

Association between obesity and asthma – epidemiology, pathophysiology and clinical profile

“…Human and animal studies suggest that adiposity-induced leptin increase and subsequent leptin resistance would affect these transmitters, causing or worsening asthma symptoms. This relates both to orexigenic neuropeptides such as neuropeptide Y (114)(115)(116)(117)(118)(119)(120) , endocannabinoids (121,122) , endogenous opioids (123)(124)(125)(126) ; and anorexigenic neuropeptides such as tachykinins and its most studied members substance P (127)(128)(129)(130)(131)(132) , α-melanocyte-stimulating hormone (133)(134)(135) , corticotropin-releasing factor (136)(137)(138)(139)(140)(141) and serotonin (142)(143)(144)(145)(146)(147)(148)(149)(150) . Altogether, it suggests that these peptides can modulate asthmatic inflammation among obese patients.…”

Obesity and Chronic Pain

“…For example, morphine administration increases leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens. 117 Furthermore, the morphinesatisfying effect is obstructed in leptin-deficient experimental animals or by neutralizing leptin and IL-1β in the same nucleus without diminishing morphine-induced analgesia. These findings provide evidence for an interface between opioid analgesia and opioid rewarding and may contribute to the understanding of opioid dependency and hyperalgesia tolerance phenomena.…”

“…These findings provide evidence for an interface between opioid analgesia and opioid rewarding and may contribute to the understanding of opioid dependency and hyperalgesia tolerance phenomena. 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.…”

“…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. For example, the cyclooxygenase 2-selective anti-inflammatory drug celecoxib may exhibit antidepressant effects, and some mood stabilizers have anti-inflammatory as well as weight-reducing properties.…”