Excitatory amino acid receptor antagonists and electroacupuncture synergetically inhibit carrageenan-induced behavioral hyperalgesia and spinal fos expression in rats

The interaction between electroacupuncture and an N-methyl-D-aspartic acid (NMDA) receptor antagonist, (DL-2-amino-5-phosphonopentanoic acid; AP5), or an (+/-)-alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainite (AMPA/KA) receptor antagonist, (6,7-dinitroquinoxaline-2,3 (1H,4H); DNQX) administered intrathecally on carrageenan-induced thermal hyperalgesia and spinal c-Fos expression was investigated. The latency of paw withdrawal (PWL) from a thermal stimulus was used as a measure of hyperalgesia in awake rats. Intrathecal (i.t.) injection of I and 10 nmol AP5, but not DNQX, markedly increased the PWL of the carrageenan-injected paw. At a dose of 100 nmol, either AP5 or DNQX significantly increased the PWL of carrageenan-injected paw, with AP5 being more potent. The PWLs of the non-injected and normal saline (NS)-injected paws were not detectably affected by the administration of NMDA or AMPA/KA receptor antagonists at the doses tested. Unilateral electroacupuncture stimulation of the 'Zu-San-Li' (St 36) and 'Kun-Lun' (UB 60) acupuncture points (60 and 2 Hz alternately, 1-2-3 mA) contralateral to the carrageenan-injected paw significantly elevated the PWLs of carrageenan-and NS-injected paws. Although neither i.t. injection of 0.1 nmol AP5 nor I nmol DNQX alone had an effect on the PWL of the carrageenan-and NS-injected paws, both significantly potentiated electroacupuncture-induced analgesia in carrageenan-injected rats, especially 0.1 nmol AP5. Fos expression evoked by intraplantar (i.pl.) injection of carrageenan was examined in the spinal cord with immunohistochemical methods. Three hours after i.pl. injection of carrageenan, the number of Fos-like immunoreactive (Fos-LI) neurons was significantly increased in all the layers of the ipsilateral spinal cord at L4-5, with the highest density in laminae I-II and V-VI. Intrathecally pre-administered AP5 (10 nmol) or DNQX (100 nmol) significantly reduced the total number of carrageenan-induced Fos-LI neurons. The reduction was most apparent in laminae I-II and IV-V. Similarly, following bilateral electroacupuncture stimulation of the 'Zu-San-Li' and 'Kun-Lun' acupuncture points, the numbers of carrageenan-induced Fos-LI neurons in laminae I-H and V-VI were also markedly reduced. When a combination of electroacupuncture with 10 nmol AP5 or 100 nmol DNQX was used, the level of Fos expression in the spinal cord induced by carrageenan was significantly lower than electroacupuncture or i.t. injection of AP5 or DNQX alone. These results demonstrate that electroacupuncture and NMDA or AMPA/KA receptor antagonists have a synergetic, anti-nociceptive action against inflammatory pain. Furthermore, this study supports the idea that both NMDA and AMPA/KA receptors are involved in spinal nociceptive transmission in carrageenan-inflamed rats, with the former more preferentially mediating transmission of nociceptive information from cutaneous tissue. (C) 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.