Abstract
Poor postoperative pain (POP) control increases perioperative morbidity, prolongs hospitalization days, and causes chronic pain. However, the specific mechanism(s) underlying POP is unclear and the identification of optimal perioperative treatment remains elusive. Akt and mammalian target of rapamycin (mTOR) are expressed in the spinal cord, dorsal root ganglion, and sensory axons. In this study, we explored the role of Akt and mTOR in pain-related behaviors induced by plantar incision in mice. Plantar incision activated spinal Akt and mTOR in a dose-dependent manner. Pre-treatment with Akt inhibitors intrathecally prevented the activation of mTOR dose-dependently. In addition, blocking the Akt-mTOR signaling cascade attenuated pain-related behaviors and spinal Fos protein expression induced by plantar incision. Our observations demonstrate that Akt-mTOR might be a potential therapeutic target for the treatment of POP.
Highlights
Surgery is a first-line treatment option for many diseases and can be associated with numerous complications including, but not limited to, acute postoperative pain (POP)
Recent evidence indicates that mammalian target of rapamycin kinase (mTOR) is expressed within the spinal cord and in sensory axons (Geranton et al, 2009; Obara et al, 2011; Cui et al, 2014) and that blocking of mTOR alleviated pain-related behaviors associated with local inflammation or neuropathic pain (JimenezDiaz et al, 2008; Geranton et al, 2009). Given that both trauma and inflammatory factors are involved in POP and that Akt plays a role in synaptic plasticity and memory (Klann and Dever, 2004; Costa-Mattioli et al, 2009) we explored whether Akt-related signaling may play an important role in POP
Compared to mice treated with dimethyl sulfoxide (DMSO), PWL was significantly elevated by Akt IV treatment (Figure 1B1: 0.2 μg at 0.5–2 h; 1 μg at 0.5–8 h) and by MK2206 treatment (Figure 1E1: 1 μg at 0.5–4 h; 5 μg at 0.5–12 h) (P< 0.05)
Summary
Surgery is a first-line treatment option for many diseases and can be associated with numerous complications including, but not limited to, acute postoperative pain (POP). Poor POP control increases perioperative sickness, prolongs hospitalization days, and causes chronic pain (Reddi and Curran, 2014), all of which incur a significant cost to society in terms of subsequent healthcare costs (Turk, 2002). Patients often experience pain as a result of surgical trauma and it is difficult to reduce perioperative opioid use. Recent studies indicate that activation of the serine/threonine protein kinase, Akt ( known as PKB), contributes to pain-related behaviors induced by various kinds of stimuli, including capsaicin, BDNF, and chronic nerve constriction (Sun et al, 2006, 2007; Xu et al, 2007, 2011; Guedes et al, 2008; Choi et al, 2012; Duan et al, 2012; Kay et al, 2013; Li et al, 2013; Hung et al, 2014; Xu B. et al, 2014; Zhang et al, 2014). Akt is widely expressed in the spinal cord, in the dorsal root ganglia (DRG) and laminae I-IV
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