Analgesic tolerance to morphine is regulated by PPARγ

Abstract

BACKGROUND AND PURPOSEOpioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice. EXPERIMENTAL APPROACHWe monitored analgesia on alternate days using the tail immersion test. , bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance. KEY RESULTS Daily administration of morphine (30 mg·kg− CONCLUSIONS AND IMPLICATIONSOverall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse.

PPARs and pain

“…The role of PPAR signalling in the development or modulation of other chronic pain conditions, such as osteoarthritis, cancer pain and migraine requires further study, as does the interaction of PPAR signalling with other well‐characterized endogenous pain control systems and currently prescribed analgesics. On this latter point, the PPARγ agonist pioglitazone has been shown to attenuate tolerance to morphine in a rat model of inflammatory pain (Ghavimi et al ., , Ghavimi et al ., ) and in the mouse tail immersion test (de Guglielmo et al ., ). Similar potential synergistic antinociceptive interactions with the cannabinoid (Russo et al ., ) and TRPV1 (Ambrosino et al ., ) signalling systems have been reported.…”

Effects of extremely low frequency magnetic field on the development of tolerance to the analgesic effect of morphine in rats

“…Therefore, exposure to MF 30 min after injection of morphine could not maintain the analgesic effect of morphine. Thermal hyperalgesia could be caused, in part, through postreceptor processes followed by repeated morphine injection, including opioid receptor downregulation, internalization [Guglielmo et al, ], downregulation of spinal glutamate transporters [Mao et al, ], reduction of µ‐opioid receptor signaling [Johnson et al, ], and the increase of nitric oxide [Jeong et al, ]. However, exposure to MF was unable to restore these changes in Exp.…”

“…Opioid drugs are highly effective analgesics for the treatment of pain. However, chronic use for 7–9 days leads to the development of tolerance, drug dependence, and addiction [Guglielmo et al, ; Shokraviyan et al, ]. Opioid tolerance is a complex phenomenon, and multiple mechanisms are responsible for the development of tolerance to the analgesic effect of morphine.…”

“…Opioid tolerance is a complex phenomenon, and multiple mechanisms are responsible for the development of tolerance to the analgesic effect of morphine. It has been shown that chronic exposure to opioid agonists can cause opioid receptor downregulation, internalization [Bailey and Connor, ], phosphorylation of activated receptors by G‐protein‐coupled receptor kinases, subsequent binding of beta‐arrestins [Guo et al, ; Guglielmo et al, ], activation of the N‐methyl D‐aspartate (NMDA) receptor, downregulation of spinal glutamate transporters [Mao et al, ], reduction of µ‐opioid receptor signaling in sensory neurons and brainstem nuclei [Johnson et al, ], reduction of beta‐endorphin and methionine‐enkephalin levels in the brain [Gudehithlu et al, ], and elevation of cyclic adenosine monophosphate (cAMP) [Al‐Hasani and Bruchas, ].…”

The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users

“…PPARγ agonists have been shown to inhibit the expression of cytokines by monocytes/macrophages and microglia (36). Preclinical research further showed that PPARγ activation by pioglitazone (PIO) attenuated development of opioid tolerance (38) reduced heroin self-administration under a fixed-ratio and progressive-ratio schedule of reinforcement and heroin-induced increases in extracellular dopamine in the nucleus accumbens (39). …”