Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats.
Spinal gamma-aminobutyric acid (GABA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been implicated in the mechanisms of neuropathic pain after nerve injury; however, how these two receptors interact at the spinal level remains unclear. Here we show that intrathecal midazolam through activation of spinal GABAA receptors attenuated the expression and function of spinal AMPA receptors in rats following peripheral nerve injury. Thermal hyperalgesia and mechanical allodynia induced by chronic constriction nerve injury (CCI) in rats were attenuated by the short-acting benzodiazepine midazolam (20=10>5 mug>vehicle) administered intrathecally once daily for 7 postoperative days. CCI-induced upregulation of AMPA receptors within the spinal cord dorsal horn was also significantly reduced by the intrathecal midazolam (10, 20 mug) treatment. The inhibitory effects of midazolam (10, 20 mug) on neuropathic pain behaviors and AMPA receptor expression were prevented by co-administration of midazolam with the GABAA receptor antagonist bicuculline (3 mug), whereas intrathecal treatment with bicuculline (1 or 3 mug) alone in naive rats induced the upregulation of spinal AMPA receptor expression and nociceptive responses, indicating a tonic regulatory effect from endogenous GABAergic activity on the AMPA receptor expression and spinal nociceptive processing. These results indicate that modulation of spinal AMPA receptor expression and function by the GABAergic activity may serve as a mechanism contributory to the spinal nociceptive processing.
Lim
Jeongae
J
Department of Anesthesia and Pain Medicine, Konkuk University, Seoul, Korea.
Lim
Grewo
G
Sung
Backil
B
Wang
Shuxing
S
Mao
Jianren
J
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000008:administration & dosage; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D008874:Midazolam / Q000008:administration & dosage*; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D018757:GABA Modulators; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D008874:Midazolam