Neuropathic pain remains an unmet medical need, despite recent advances in our understanding of the pathophysiology of central and peripheral sensitization. But nerve injury can also increase the analgesic efficacy of some drugs, including spinally administered 12-adrenoceptor agonists. In exploring the mechanisms underlying this increased efficacy, we have discovered that peripheral nerve injury results in sprouting of noradrenergic fibers in the spinal cord at the dermatomes receiving inputs from injury. Preliminary data suggest that spinal noradrenergic sprouting after peripheral nerve injury is due to brain derived growth factor (BDNF), and Specific Aim 1 will examine mechanisms for bilateral sprouting of spinal noradrenergic fibers at the segments of peripheral nerve injury, with focus on glia as a source of BDNF and TrkB signaling as a cause of sprouting. Few therapies are effective to treat neuropathic pain, and most of these mimic or augment the activity of the release of norepinephrine in the spinal cord. Preliminary data demonstrate that neuropathic pain is associated with a novel action of spinal norepinephrine to activate local spinal cholinergic circuits for analgesia.
Specific Aim 2 will examine mechanisms for novel excitatory actions of 12-adrenoceptors on spinal cholinergic neurons after peripheral nerve injury, with focus on 12-adrenoceptor subtype and G protein species activated. These changes in anatomy and circuitry of descending inhibition suggest novel approaches to the treatment of neuropathic pain. We present preliminary data which show that this pathway can be activated by gabapentin. Since norepinephrine also stimulates spinal acetylcholine release for analgesia after nerve injury, this pathway could be augmented by norepinephrine transporter and cholinesterase inhibitors. Exciting new preliminary data in humans suggests that the cholinesterase inhibitor, donepezil (Aricept.) provides analgesia and improves cognition in patients with chronic neuropathic pain.
Specific Aim 3 will test in animals and patients the therapeutic consequences of noradrenergic sprouting, using clinically available, oral drugs. These studies will improve our understanding and provide practical guidance for better treatment of neuropathic pain.

Public Health Relevance

Nerve injury, whether from cancer, diabetes, or trauma, can result in chronic pain which is difficult to treat, even with narcotics. These studies in rats and in people with chronic pain will explore new ways to use medicines to help the body's own pain relieving system to work better to relieve pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Porter, Linda L
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Wake Forest University Health Sciences
Schools of Medicine
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Kimura, Masafumi; Hayashida, Ken-ichiro; Eisenach, James C et al. (2013) Relief of hypersensitivity after nerve injury from systemic donepezil involves spinal cholinergic and ýý-aminobutyric acid mechanisms. Anesthesiology 118:173-80
Eisenach, James C; Pan, Peter; Smiley, Richard M et al. (2013) Resolution of pain after childbirth. Anesthesiology 118:143-51
Hayashida, Ken-ichiro; Kimura, Masafumi; Yoshizumi, Masaru et al. (2012) Ondansetron reverses antihypersensitivity from clonidine in rats after peripheral nerve injury: role of ?-aminobutyric acid in ?2-adrenoceptor and 5-HT3 serotonin receptor analgesia. Anesthesiology 117:389-98
Yoshizumi, Masaru; Eisenach, James C; Hayashida, Ken-ichiro (2012) Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes. Eur J Pharmacol 677:87-92
Yoshizumi, Masaru; Parker, Renee A; Eisenach, James C et al. (2012) Gabapentin inhibits ýý-amino butyric acid release in the locus coeruleus but not in the spinal dorsal horn after peripheral nerve injury in rats. Anesthesiology 116:1347-53
Hayashida, Ken-Ichiro; Peters, Christopher M; Gutierrez, Silvia et al. (2012) Depletion of endogenous noradrenaline does not prevent spinal cord plasticity following peripheral nerve injury. J Pain 13:49-57
Hobo, Shotaro; Eisenach, James C; Hayashida, Ken-ichiro (2011) Up-regulation of spinal glutamate transporters contributes to anti-hypersensitive effects of valproate in rats after peripheral nerve injury. Neurosci Lett 502:52-5
Hayashida, Ken-ichiro; Eisenach, James C (2011) A tropomyosine receptor kinase inhibitor blocks spinal neuroplasticity essential for the anti-hypersensitivity effects of gabapentin and clonidine in rats with peripheral nerve injury. J Pain 12:94-100
Boada, M Danilo; Gutierrez, Silvia; Houle, Timothy et al. (2011) Developmental differences in peripheral glabrous skin mechanosensory nerve receptive field and intracellular electrophysiologic properties: phenotypic characterization in infant and juvenile rats. Int J Dev Neurosci 29:847-54
Hayashida, Ken-ichiro; Parker, Renee A; Eisenach, James C (2010) Activation of glutamate transporters in the locus coeruleus paradoxically activates descending inhibition in rats. Brain Res 1317:80-6

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