Intrathecal gabapentin and clonidine synergistically inhibit allodynia in spinal nerve-ligated rats

• Published in: Life sciences (1973) Vol. 87; no. 17; pp. 565 - 571
• Main Authors: Yamama, Yoshihiro, Nishikawa, Kiyonobu, Funao, Tomoharu, Mori, Takashi, Asada, Akira
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 23.10.2010
• Subjects: Amines - administration & dosage; Anesthesia; Animal models; Animals; Catheters; Clonidine; Clonidine - administration & dosage; Cyclohexanecarboxylic Acids - administration & dosage; Disease Models, Animal; Dose-response relationship; Dose-Response Relationship, Drug; Drug interaction; Drug interactions; Drug Synergism; Drug Therapy, Combination; Drugs; Filaments; gabapentin; Gamma-aminobutyric acid; gamma-Aminobutyric Acid - administration & dosage; Injections, Spinal; Ligation; Male; Mechanical stimuli; Neuralgia - drug therapy; Neuralgia - physiopathology; Neuralgia - prevention & control; Neuropathy; Pain Measurement - drug effects; Pain perception; Pain threshold/drug effects; Rat; Rats; Rats, Sprague-Dawley; Sevoflurane; Spinal cord/drug effects/pathology; Spinal nerves; Spinal Nerves - drug effects; Spinal Nerves - injuries; Spinal nerves/physiology; Sprague-Dawley; Sprague-Dawley; Spinal nerves/physiology; Ligation; Rat; Drug interactions; Pain measurement/drug effects; Dose-response relationship; Spinal cord/drug effects/pathology; Gamma-aminobutyric acid; Pain threshold/drug effects; Clonidine; Drug synergism
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2010.09.017

The objective of this study was to elucidate the interaction between intrathecally administered gabapentin and clonidine on neuropathic pain associated with allodynia in the spinal nerve ligation model in the rat. Thresholds for hind paw responses to mechanical stimuli were determined by delivering von Frey filaments to the plantar surface. The left L5 spinal nerve was ligated and a fine catheter was intrathecally implanted at the L3–4 interspace under sevoflurane anesthesia. After confirmation of the established allodynia, gabapentin at 10, 30, 60 and 100 μg or clonidine at 5, 15, 30 and 50 μg was injected as a monotherapy in conscious rats through the intrathecal catheter to obtain the dose–response curve of %MPE (maximum possible effect) of the antiallodynic effect and its ED 50. Gabapentin and clonidine were concomitantly administered in a fixed-dose ratio proportional to the predetermined ED 50 of these drugs, thereby obtaining a dose–response curve for the drug combination and its ED 50. The profile of the interaction between these drugs was analyzed using an isobolographic analysis. The ED 50 for gabapentin and clonidine were 57.3 ± 4.0 and 20.2 ± 1.0 μg, respectively (mean ± SEM). However, the co-administration of gabapentin and clonidine at a ratio of 20:7 contributed to a much smaller experimental ED 50 values (gabapentin 10.1 ± 1.1 μg, and clonidine 3.6 ± 0.3 μg) compared with their theoretical ED 50s on the additive line in the isobologram. In the L5 spinal nerve-ligated rats, the intrathecal co-administration of gabapentin and clonidine exerted a synergistic action on the mechanical antiallodynic effect.