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Oral gabapentin activates spinal cholinergic circuits to reduce hypersensitivity after peripheral nerve injury and interacts synergistically with oral donepezil.
Anesthesiology. 2007 Jun; 106(6):1213-9.A

Abstract

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17525597

Citation

Hayashida, Ken-ichiro, et al. "Oral Gabapentin Activates Spinal Cholinergic Circuits to Reduce Hypersensitivity After Peripheral Nerve Injury and Interacts Synergistically With Oral Donepezil." Anesthesiology, vol. 106, no. 6, 2007, pp. 1213-9.
Hayashida K, Parker R, Eisenach JC. Oral gabapentin activates spinal cholinergic circuits to reduce hypersensitivity after peripheral nerve injury and interacts synergistically with oral donepezil. Anesthesiology. 2007;106(6):1213-9.
Hayashida, K., Parker, R., & Eisenach, J. C. (2007). Oral gabapentin activates spinal cholinergic circuits to reduce hypersensitivity after peripheral nerve injury and interacts synergistically with oral donepezil. Anesthesiology, 106(6), 1213-9.
Hayashida K, Parker R, Eisenach JC. Oral Gabapentin Activates Spinal Cholinergic Circuits to Reduce Hypersensitivity After Peripheral Nerve Injury and Interacts Synergistically With Oral Donepezil. Anesthesiology. 2007;106(6):1213-9. PubMed PMID: 17525597.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oral gabapentin activates spinal cholinergic circuits to reduce hypersensitivity after peripheral nerve injury and interacts synergistically with oral donepezil. AU - Hayashida,Ken-ichiro, AU - Parker,Renée, AU - Eisenach,James C, PY - 2007/5/26/pubmed PY - 2007/6/29/medline PY - 2007/5/26/entrez SP - 1213 EP - 9 JF - Anesthesiology JO - Anesthesiology VL - 106 IS - 6 N2 - 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. SN - 0003-3022 UR - https://www.unboundmedicine.com/medline/citation/17525597/Oral_gabapentin_activates_spinal_cholinergic_circuits_to_reduce_hypersensitivity_after_peripheral_nerve_injury_and_interacts_synergistically_with_oral_donepezil_ L2 - https://pubs.asahq.org/anesthesiology/article-lookup/doi/10.1097/01.anes.0000267605.40258.98 DB - PRIME DP - Unbound Medicine ER -