Oral gabapentin activates spinal cholinergic circuits to reduce hypersensitivity after peripheral nerve injury and interacts synergistically with oral donepezil.
BACKGROUND
Gabapentin administration into the brain of mice reduces nerve injury-induced hypersensitivity and is blocked by intrathecal atropine and enhanced by intrathecal neostigmine. The authors tested the relevance of these findings to oral therapy by examining the efficacy of oral gabapentin to reduce hypersensitivity after nerve injury in rats and its interaction with the clinically used cholinesterase inhibitor, donepezil.


METHODS
Male rats with hypersensitivity after spinal nerve ligation received gabapentin orally, intrathecally, and intracerebroventricularly with or without intrathecal atropine, and withdrawal threshold to paw pressure was determined. The effects of oral gabapentin and donepezil alone and in combination on withdrawal threshold were determined in an isobolographic design.


RESULTS
Gabapentin reduced hypersensitivity to paw pressure by all routes of administration, and was more potent and with a quicker onset after intracerebroventricular than intrathecal injection. Intrathecal atropine reversed the effect of intracerebroventricular and oral gabapentin. Oral gabapentin and donepezil interacted in a strongly synergistic manner, with an observed efficacy at one tenth the predicted dose of an additive interaction. The gabapentin-donepezil combination was reversed by intrathecal atropine.


CONCLUSIONS
Although gabapentin may relieve neuropathic pain by actions at many sites, these results suggest that its actions in the brain to cause spinal cholinergic activation predominate after oral administration. Side effects, particularly nausea, cannot be accurately determined on rats. Nevertheless, oral donepezil is well tolerated by patients in the treatment of Alzheimer dementia, and the current study provides the rationale for clinical study of combination of gabapentin and donepezil to treat neuropathic pain.
Hayashida
Ken-ichiro
K
Department of Anesthesiology and Center for Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1009, USA.
Parker
Renée
R
Eisenach
James C
JC
D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage / Q000627:therapeutic use*; D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D000077265:Donepezil; D004357:Drug Synergism; D000077206:Gabapentin; D006930:Hyperalgesia; D007189:Indans / Q000008:administration & dosage / Q000627:therapeutic use*; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000188:drug therapy*; D059348:Peripheral Nerve Injuries; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000627:therapeutic use*
D000588:Amines; D000700:Analgesics; D002800:Cholinesterase Inhibitors; D003509:Cyclohexanecarboxylic Acids; D007189:Indans; D010880:Piperidines; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000077265:Donepezil