Introduction

Chronic pain and its related sequelae represent a severe public health challenge affecting nearly 30 % of the population [1]. In addition to its impact on quality of life, chronic pain has an economic impact, costing over $560 billion annually [2]. Opioids have been the mainstay of chronic pain treatment for many decades despite a host of shortcomings including tolerance and hyperalgesia, which ultimately limit the efficacy of these medications [3, 4]. Tolerance is the diminishing response to medication, requiring escalating doses to achieve the same pain relief. Increasing the dose of opioids increases the possibility of adverse side effects including constipation, respiratory depression, and nausea [5, 6]. Conversely, hyperalgesia is hypersensitivity to pain and also can be caused by the administration of opioid medication [6]. The therapeutic limitations of opioid medications in chronic pain management show a clear need to understand the molecular mechanisms which underpin the biologic processes governing chronic pain, tolerance to pharmacologic medicine, and hyperalgesia.

Neuroplasticity in the form of adaptive changes in protein transcription and translation may contribute to the development of chronic pain, opioid tolerance, and its hyperalgesia [7]. Changes in the expression of neuronal nitric oxide synthase (nNOS), protein kinase C (PKC), CaMKIIα, and other proteins are associated with chronic pain conditions and opioid-induced hyperalgesia or tolerance [8–11]. The mechanisms and signaling pathways are still not fully understood, but mammalian target of rapamycin (mTOR) represents a key player in the mechanism governing neuroplasticity in chronic pain and opioid-induced hyperalgesia/tolerance disorders [12–21]. This paper reviews recent evidence regarding the role of mTOR in chronic pain, opioid tolerance, and opioid-induced hyperalgesia and discusses how mTOR participates in the development and maintenance of these disorders. Current evidence suggests that mTOR likely represents an excellent candidate target for novel pharmaceutical intervention in chronic pain, opioid tolerance, and opioid-induced hyperalgesia in patients.

mTOR inhibitors in clinical use Rapamycin, a specific inhibitor of mTOR, was discovered at Easter Island (former Rapa Nui) in a bacterial strain named Streptomyces hygroscopius [31]. Rapamycin was first found to inhibit the growth of yeast and was being developed as an antifungal drug [32]. Its antifungal use was temporally abandoned after the discovery of its potent immunosuppressive activity, which later proved beneficial for transplant patients [33, 34]. The mTOR inhibitor and some of its derivatives also showed anti-proliferative activity which was found useful in the treatment of certain cancers [31, 35–37]. Studies have shown hyperactivity of mTOR in gliomas [38] as well as nonglial brain tumors [39]. The specificity by which rapamycin and its analogues bind to and inhibit mTORC1 activity thereby abrogating the proliferation of these cancers has prompted clinical trials to investigate the efficacy of rapamycin and its analogues “Rapalogs” as novel treatments in cancer therapy and their approval for specific indications [34, 40, 41]. Rapamycin was recently shown to prolong the life of mice [42], whether this effect occurs in humans is unknown and remains to be determined.

mTOR expression in pain-related regions mTOR is expressed and distributed in pain-related central nervous system regions. Xu et al. used immunofluorescence to analyze the distribution of mTOR, 4E-BP1/2, S6K and their phosphorylated counterparts in dorsal root ganglia (DRG) and spinal cord dorsal horn [43]. mTOR was found in approximately 26.1 % of DRG neurons and S6K was found in about 19.1 % of DRG neurons, with most of small diameter [43]. 4E-BP1 was exclusively found in DRG satellite glial cells, but it co-localized in dorsal horn with mTOR and S6K. 4E-BP1, mTOR, and S6K are highly expressed in the superficial dorsal horn [43]. Interestingly, the activated or phosphorylated forms of these proteins were virtually undetectable or at very low levels under normal conditions in the DRG and dorsal horn [43]. These findings support the behavioral observation that intrathecal administration of the mTOR inhibitor rapamycin does not affect basal pain perception, suggesting that mTOR and its downstream effectors do not play a key role in acute pain.

mTOR in chronic pain mTOR's role in cancer treatment is not simply limited to its effects on neoplastic cell survival and proliferation. Studies have shown that activation of mTOR and its downstream effectors in spinal cord (but not in DRG) are implicated in cancer pain [18, 44]. Shih et al. showed that rats injected with prostate cancer cells into the tibia, a model of bone cancer pain, experienced pain hypersensitivity [18]. This hypersensitivity was attenuated following intrathecal injection of rapamycin [18]. Rapamycin's effect is dose-dependent without affecting locomotor function and without significant systemic side effects such as immunosuppression [18]. Furthermore, they showed that levels of phosphorylated mTOR (p-mTOR) and p-S6K increased in the L4-5 dorsal horn and DRG on the side of the prostate cancer cell injection [18]. This increase in p-mTOR and p-S6K was blocked in the presence of an NMDA receptor antagonist [18]. The authors proposed that the activation of NMDA receptor-mediated spinal cord mTOR pathways contribute to the initiation, establishment, and maintenance of bone cancer-induced pain hypersensitivity [18] (Fig. 2). This conclusion is further supported by the observation that NMDA receptor subunit NR1 co-localized with mTOR and S6K in dorsal horn neurons [18]. Download Open in new tab Download in PowerPoint Spinal cord mTOR and its downstream pathway also are involved in inflammatory pain. Liang et al. showed that intraplantar injection of complete Freund's adjuvant (CFA) in a model of chronic inflammatory pain increased the levels of p-mTOR and p-S6K1 in the ipsilateral L4/5 spinal cord and DRG [16]. Behavioral testing demonstrated that CFA-induced mechanical and thermal pain hypersensitivity could be alleviated by intrathecal administered rapamycin [16]. Additionally, Xu et al., used λ-carrageenan to induce persistent peripheral inflammation in rats and found increased levels of not only p-mTOR but also upstream phosphorylated protein kinase B (Akt) in dorsal horn [20]. The downstream targets of mTOR activation, p-S6K and p-4E-BP1 were also elevated in dorsal horn [20]. More importantly, intrathecal administration of rapamycin produced anti-nociceptive effects in this persistent inflammatory pain model [20]. These anti-nociceptive effects of rapamycin were also observed in the second phase of the formalin model [20]. Selective inhibitors of PI3K (upstream of Akt), Akt, or mTORC1 attenuated phase II flinching behavior in rats that were injected with formalin [20]. Phase II of formalin-induced inflammation is known to represent spinal sensitization [45]. These findings demonstrate the potential highly targeted role of mTOR inhibitors in the treatment of inflammatory pain. Although the mechanism of mTOR-induced inflammatory pain sensitivity is relatively clear, how mTOR is involved in neuropathic pain remains elusive. Rapamycin administration in neuropathic pain models attenuates pain hypersensitivity in several studies in both rats and mice [17, 18, 46]. Géranton et al. reported that spared nerve injury (SNI)-induced mechanical allodynia was attenuated by rapamycin delivered intrathecally 6 days after surgery [47]. However, western blotting analysis of dorsal horn and dorsal roots 7 days after SNI revealed no significant changes in the expression of p-S6K [47]. Additionally, immunostaining showed no change in the percentage of peripherin-labeled fibers expressing p-mTOR [47]. Liang et al. also showed no change in the basal level of p-mTOR in spinal cord and DRG after spinal nerve ligation [16]. Conversely, Zhang et al. used the chronic constriction injury (CCI) model of neuropathic pain to analyze the role of mTOR in neuropathic pain [21]. The phosphorylated counterparts of mTOR, 4E-BP1, and S6K were upregulated in the spinal cord 7 days and 14 days after CCI [21]. Intrathecal rapamycin not only blocked this upregulation but also attenuated CCI-induced mechanical allodynia (but not thermal hyperalgesia) [21]. These data suggest that distinct types of peripheral nerve injury differentially may regulate the activation of mTOR and its downstream effectors in spinal cord and DRG. Further research into the mechanism of rapamycin antinociception in neuropathic pain is required.