Neuropathic pain reflects a myriad of changes in the periphery, spinal cord, and supra-spinal structures. Interestingly, despite this baffling array of changes, many approved treatments for neuropathic pain recruit, augment, or mimic bulbospinal inhibition including morphine, noradrenaline (NA) re-uptake inhibitors, and clonidine. Although clinical studies suggest a baseline deficit of descending inhibition in patients with neuropathic pain, we believe that activation of this pathway is a key mechanism engaged by several effective and approved treatments. Gabapentin (GBP) is commonly used for treatment of neuropathic pain but its mechanisms for analgesia are not entirely known. We recently demonstrated GBP activates locus coeruleus (LC) neurons via glutamatergic signaling and that the anti-hypersensitivity effects of GBP in rats with peripheral nerve injury relies on this activation and subsequent spinal NA release. The goals of this proposal are to identify the mechanisms by which GBP regulates glutamate release to activate the LC and also to determine whether the mechanisms of GBP on input to LC neurons apply globally or specifically to subsets involved in analgesia and adverse effects such as somnolence, reduction of attention, and memory retention. Initially, we will examine mechanisms by which GBP modulates GABA regulation of pre-synaptic glutamate release in the LC using synaptosomes and microdialysis. Secondly, we will examine mechanisms by which GBP modulates the unique astroglial-neuronal interaction in the LC to increase extracellular glutamate, using cultured astrocytes and microdialysis. Lastly, we will administrate GBP in the LC and compare NA release in the spinal cord, prefrontal cortex, ventro-lateral preoptic area of the hypothalamus, and the dorsal hippocampus by using microdialysis to test whether GBP-induced activation in the LC is a global phenomenon or selective to projections controlling pain, attention, arousal and memory. The proposed experiments will not only provide important information for understanding analgesic mechanisms of GBP but also lead to novel hypothesis regarding the treatment of neuropathic pain.

Public Health Relevance

Gabapentin is widely used to treat chronic pain, but how it works is not well understood. In this proposal, we will study how gabapentin stimulates a natural pain-relief mechanism to reduce pain but also to cause side effects.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sorensen, Roger
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Schools of Medicine
United States
Zip Code
Hayashida, Ken-Ichiro; Kimuram, Masafumi; Eisenach, James C (2018) Blockade of ?2-adrenergic or metabotropic glutamate receptors induces glutamate release in the locus coeruleus to activate descending inhibition in rats with chronic neuropathic hypersensitivity. Neurosci Lett 676:41-45
Kimura, Masafumi; Eisenach, James C; Hayashida, Ken-Ichiro (2016) Gabapentin loses efficacy over time after nerve injury in rats: role of glutamate transporter-1 in the locus coeruleus. Pain 157:2024-32
Peters, Christopher M; Hayashida, Ken-Ichiro; Suto, Takashi et al. (2015) Individual differences in acute pain-induced endogenous analgesia predict time to resolution of postoperative pain in the rat. Anesthesiology 122:895-907
Kimura, Masafumi; Suto, Takashi; Morado-Urbina, Carlos E et al. (2015) Impaired Pain-evoked Analgesia after Nerve Injury in Rats Reflects Altered Glutamate Regulation in the Locus Coeruleus. Anesthesiology 123:899-908
Kimura, Masafumi; Suto, Takashi; Eisenach, James C et al. (2015) Down-regulation of astroglial glutamate transporter-1 in the locus coeruleus impairs pain-evoked endogenous analgesia in rats. Neurosci Lett 608:18-22
Suto, Takashi; Eisenach, James C; Hayashida, Ken-Ichiro (2014) Peripheral nerve injury and gabapentin, but not their combination, impair attentional behavior via direct effects on noradrenergic signaling in the brain. Pain 155:1935-42
Suto, Takashi; Severino, Amie L; Eisenach, James C et al. (2014) Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms. Neuropharmacology 81:95-100
Yoshizumi, Masaru; Eisenach, James C; Hayashida, Ken-ichiro (2013) Valproate prevents dysregulation of spinal glutamate and reduces the development of hypersensitivity in rats after peripheral nerve injury. J Pain 14:1485-91
Kimura, Masafumi; Hayashida, Ken-ichiro; Eisenach, James C et al. (2013) Relief of hypersensitivity after nerve injury from systemic donepezil involves spinal cholinergic and ?-aminobutyric acid mechanisms. Anesthesiology 118:173-80
Hayashida, Ken-ichiro (2013) Substance P-saporin for bone cancer pain in dogs: can man's best friend solve the lost in translation problem in analgesic development? Anesthesiology 119:999-1000

Showing the most recent 10 out of 16 publications