Spinal a2-Adrenoceptor-mediated Analgesia in Neuropathic Pain Reflects Brain-derived Nerve Growth Factor and Changes in Spinal Cholinergic Neuronal Function

• Published in: Anesthesiology (Philadelphia) 2010-08, Vol.113 (2), p.406-412
• Main Authors: Hayashida, K-I, Eisenach, J C
• Format: Article
• Language: English
• ISSN: 0003-3022
• DOI: 10.1097/ALN.0b013e3181de6d2c

Introduction: Spinal alpha 2-adrenoceptor stimulation produces analgesia in neuropathic pain states, and this effect in animals is blocked by the inhibitors of brain-derived neurotrophic factor (BDNF) function. In rats, alpha 2-adrenoceptor stimulation normally inhibits acetylcholine release, but it excites release after nerve injury. The authors examined the roles of BDNF and excitatory Gs-protein in this change. Methods: Male rats underwent L5-L6 spinal nerve ligation (SNL), and their lumbar spinal dorsal horns with or without spinal BDNF infusion were used for either synaptosome preparation for acetylcholine release or immunostaining for choline acetyltransferase. Results: SNL did not alter spontaneous release from synaptosomes or choline acetyltransferase immunoreactivity in the spinal dorsal horn, but it reduced KCI-evoked acetylcholine release. Dexmedetomidine inhibited KCI-evoked acetylcholine release in synaptosomes from normal rats, but it excited KCI-evoked release in synaptosomes from SNL rats, and both effects were blocked by the alpha 2-adrenoceptor antagonist idazoxan. Spinal infusion of an antibody to BDNF reduced choline acetyltransferase immunoreactivity in the spinal dorsal horn in both normal and SNL rats and abolished facilitation of KCI-evoked acetylcholine release by dexmedetomidine in SNL rats. Dexmedetomidine facilitation of acetylcholine release was also blocked by the inhibitors of Gs function. Discussion: The increased reliance of spinal alpha 2 adrenoceptors on cholinergic stimulation to cause analgesia after nerve injury reflects in part a shift from direct inhibition to direct excitation of spinal cholinergic neurons. The authors' results suggest that this shift relies on an interaction with Gs-proteins and BDNF.