Opioid receptor–triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia

Abstract

The development of opioid-induced analgesic tolerance and hyperalgesia is a clinical challenge for managing chronic pain. Adaptive changes in protein translation in the nervous system are thought to promote opioid tolerance and hyperalgesia; however, how opioids drive such changes remains elusive. Here, we report that mammalian target of rapamycin (mTOR), which governs most protein translation, was activated in rat spinal dorsal horn neurons after repeated intrathecal morphine injections. Activation was triggered through μ opioid receptor and mediated by intracellular PI3K/Akt. Spinal mTOR inhibition blocked both induction and maintenance of morphine tolerance and hyperalgesia, without affecting basal pain perception or locomotor functions. These effects were attributed to the attenuation of morphine-induced increases in translation initiation activity, nascent protein synthesis, and expression of some known key tolerance-associated proteins, including neuronal NOS (nNOS), in dorsal horn. Moreover, elevating spinal mTOR activity by knocking down the mTOR-negative regulator TSC2 reduced morphine analgesia, produced pain hypersensitivity, and increased spinal nNOS expression. Our findings implicate the μ opioid receptor-triggered PI3K/Akt/mTOR pathway in promoting morphine-induced spinal protein translation changes and associated morphine tolerance and hyperalgesia. These data suggest that mTOR inhibitors could be explored for prevention and/or reduction of opioid tolerance in chronic pain management. IntroductionChronic pain is a major public health problem. About 116 million Americans (approximately 30% of the population) live with this disorder. The economic impact of chronic pain is equally large, at around $100 billion annually (1). Although recent advances have been made in the therapeutic management of chronic pain, opioids are still the gold standard for its pharmacological treatment in the clinical setting. However, long-term use of these drugs is often limited by the development of analgesic tolerance and hyperalgesia, phenomena observed in both laboratory animals and patients (2). Opioid tolerance is characterized by a progressive lack of response to opioids that can be overcome by escalating doses to achieve equivalent pain relief. In contrast, opioid-induced hyperalgesia is a sensitization process in which opioids paradoxically produce pain hypersensitivity. These undesirable manifestations, along with other adverse effects caused by escalating doses (e.g., oversedation, respiratory depression, and constipation), significantly decrease quality of life in patients with chronic pain.Despite intensive research into the neurobiological mechanisms of opioid-induced tolerance and hyperalgesia in the past decades, opioid-induced tolerance and hyperalgesia are still ineffectively managed by current drugs, in part because these drugs target a single mechanism and/or produce several side effects. It is well docu-

Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice

“…For instance, tolerance develops to respiratory depression and euphoria but not to constipation in humans and animals (Freye and Latasch, 2003). Furthermore, the spinal versus supraspinal mechanisms underlying the development of morphine tolerance differ in regard to which opioid or other receptor types are involved (Porreca et al, 1987;Xu et al, 2014). It has been shown that the mammalian target of rapamycin (mTOR) mediates the induction and maintenance of tolerance to morphine's antinociceptive effects in the tailflick assay, but mTOR does not affect morphine tolerance as related to locomotor function (Xu et al, 2014).…”

“…Furthermore, the spinal versus supraspinal mechanisms underlying the development of morphine tolerance differ in regard to which opioid or other receptor types are involved (Porreca et al, 1987;Xu et al, 2014). It has been shown that the mammalian target of rapamycin (mTOR) mediates the induction and maintenance of tolerance to morphine's antinociceptive effects in the tailflick assay, but mTOR does not affect morphine tolerance as related to locomotor function (Xu et al, 2014). The interaction of mTOR and Tat has been previously reported, with mTOR being involved in Tat-induced neurotoxicity (Fields et al, 2015).…”

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

“…Western blotting was performed according to our published procedures [30,31]. Briefly, the animals were sacrificed by decapitation and the L4-5 spinal dorsal horns were harvested and placed temporarily in liquid nitrogen.…”

Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: Involvement of PI3k/Akt signaling pathway

“…Additionally, it was reported that blockade on PI3k/Akt signaling pathway attenuated ephrinB-caused pain . Furthermore, a recently published reported that chronic intrathecal morphine treatments-induced mTOR activation contributed to the development of morphine tolerance, which was also mediated by PI3k/Akt signaling activation (Xu et al, 2014).…”