Chemotherapy-evoked painful peripheral neuropathy: Analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit

• Published in: Neuroscience 2007-01, Vol.144 (2), p.714-720
• Main Authors: Xiao, W, Boroujerdi, A, Bennett, G.J, Luo, Z.D
• Format: Article
• Language: English
• Subjects: allodynia; Amines - therapeutic use; Analgesics - therapeutic use; Animals; Antineoplastic Agents, Phytogenic; Biological and medical sciences; Blotting, Western; Calcium Channels - metabolism; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Cyclohexanecarboxylic Acids - therapeutic use; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Gabapentin; gamma-Aminobutyric Acid - therapeutic use; Gene Expression Regulation - drug effects; hyperalgesia; Male; Medical sciences; Motor Activity - drug effects; Nervous system (semeiology, syndromes); Neuralgia - chemically induced; Neuralgia - drug therapy; Neuralgia - physiopathology; Neurology; neuropathic pain; Paclitaxel; Pain Measurement - methods; Protein Subunits; Rats; Rats, Sprague-Dawley; Time Factors; Vertebrates: nervous system and sense organs; Vincristine
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2006.09.044

Abstract Chemotherapeutics in the taxane and vinca-alkaloid classes sometimes produce a painful peripheral neuropathy for which there is no validated treatment. Experiments with rat models of paclitaxel- and vincristine-evoked pain suggest that these conditions may not respond to all of the analgesics that have efficacy in other models of painful peripheral neuropathy. We tested gabapentin as a potential analgesic for paclitaxel- and vincristine-evoked pain. We used a repeated dosing paradigm because there are precedents showing that repeated drug exposure may be necessary to demonstrate analgesia in neuropathic pain models. Gabapentin is believed to work via binding to voltage-gated calcium channels that contain the alpha-2-delta type-1 (α2 δ-1) subunit, and the expression of this subunit is known to be increased in some painful peripheral neuropathy models. Thus we also examined whether the paclitaxel-evoked pain syndrome was accompanied by an α2 δ-1 increase, and whether gabapentin had any effect on subunit expression. We found that the paclitaxel- and vincristine-evoked mechano-allodynia and mechano-hyperalgesia were significantly reduced by gabapentin, but only with repeated dosing. Paclitaxel-evoked painful peripheral neuropathy was associated with an increased expression of the α2 δ-1 subunit in the spinal dorsal horn, but not in the dorsal root ganglia. The spinal cord increase was normalized by repeated gabapentin injections. Together, these findings suggest that repeated dosing with gabapentin may be beneficial in patients with chemotherapy-evoked painful peripheral neuropathy and that gabapentin’s mechanisms of action may include normalization of the nerve injury-evoked increase in calcium channel α2 δ-1 subunit expression.