Spinal alpha 2-adrenoceptor-mediated analgesia in neuropathic pain reflects brain-derived nerve growth factor and changes in spinal cholinergic neuronal function.
BACKGROUND
Spinal alpha2-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, alpha2-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 KCl-evoked acetylcholine release. Dexmedetomidine inhibited KCl-evoked acetylcholine release in synaptosomes from normal rats, but it excited KCl-evoked release in synaptosomes from SNL rats, and both effects were blocked by the alpha2-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 KCl-evoked acetylcholine release by dexmedetomidine in SNL rats. Dexmedetomidine facilitation of acetylcholine release was also blocked by the inhibitors of Gs function.


CONCLUSIONS
The increased reliance of spinal alpha2 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.
Hayashida
Ken-ichiro
K
Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA.
Eisenach
James C
JC
D000109:Acetylcholine / Q000378:metabolism; D000698:Analgesia / Q000379:methods*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002799:Cholinergic Fibers / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009437:Neuralgia / Q000503:physiopathology* / Q000628:therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D018341:Receptors, Adrenergic, alpha-2; D000109:Acetylcholine