Mammalian Target of Rapamycin Signaling in the Spinal Cord Is Required for Neuronal Plasticity and Behavioral Hypersensitivity Associated With Neuropathy in the Rat

The protein kinase mammalian target of rapamycin (mTOR) regulates mRNA translation and is inhibited by rapamycin Signaling pathways involving mTOR are implicated in physiological and pathophysiological processes We determined the spinal effects of the rapamycin analogue cell cycle inhibitor (CCI)-779 on neuronal responses and behavioral hypersensitivity in a model of persistent neuropathic pain We also assessed the anatomical distribution of spinal mTOR signaling pathways Specifically we ligated rat spinal nerves 15 and L6 to produce a model of neuropathic pain After confirming neuropathy with behavioral testing, we obtained in vivo single-unit extracellular stimulus-evoked recordings from deep dorsal horn spinal neurons We applied CCI-779 spinally in electrophysiological and behavioral studies and assessed its effects accordingly We also used immunohistochemistry to probe for mTOR signaling pathways in dorsal root ganglia (DRG) and the spinal cord We found that spinally administered CCI-779 rapidly attenuated calibrated mechanically but not thermally evoked neuronal responses and mechanically evoked behavioral responses Immunohistochemistry showed presence of mTOR signaling pathways in nociceptive-specific C-fiber DRG and in neurons of inner lamina II of the spinal cord We conclude that alterations in the activity of spinal mTOR signaling pathways are crucial to the full establishment of spinal neuronal plasticity and behavioral hypersensitivity associated with nerve injury Perspective This study is consistent with growing evidence implicating mTOR signaling pathways as important modulators of persistent pain, providing novel insights into the molecular mechanisms of pain maintenance and potential for novel approaches into treating chronic pain (C) 2010 by the American Pain Society