Peripheral NMDA Receptors Are Involved In Spinal Astrocytes Activation And Long-term Hyperalgesia Induced By CFA Injection

Peripheral inflammation including peripheral injection of complete Freund's adjuvant (CFA) induces central sensitization characterized by the development of allodynia and hyperalgesia to mechanical and thermal stimuli. Recent evidence suggests that activation of glial cells including microglia and astrocytes contributes to the development of behavioral hypersensitivity after nerve injury or peripheral inflammation. Evidence showed that microglial activation preceded astrocytic activation following peripheral inflammation, and this led to the hypothesis that activation of microglia is involved in the initiation phase and astrocytes in maintaining long term hyperalgesia. It has been proved that peripheral NMDA receptors activation contributes significantly to the mechanical sensitivity and heat sensitization that accompanies persistent inflammation. In the present study, following intraplantar administration of CFA into the rat hind paw, the paw withdrawal latency (PWL) induced by a thermal stimulus in awake rats and the GFAP (glial fibrillary acidic protein), the astroglial marker were measured. The aim of the study was to investigate if peripheral NMDA receptors were involved in long-term hyperalgesia (LTH) and activation of astrocytes.Animals were divided into 2 groups (n=30 in each) and all animals received injections of CFA into the plantar aspects of two hind paws. In pre-CFA treatment group, MK-801 (50 nmol, 25μl) was injected into the left hind paw 15 min before CFA injection with the same volumes of NS being injected into the right side of animals, and the drug or NS injections were carried out repetitively in 4 consecutive days, respectively. In post-CFA treatment group, MK-801 (50 nmol) was injected into the left hind paw on day 4 after CFA injection and continued for another 4 days, and the contralateral right hind paw received same volumes of saline. PWL in response to a thermal stimulus was tested at 1d before CFA injection as a control and 8h, 1d, 4d, 8d and 14d post CFA injection. Rats of each group were randomly killed for immunocytochemical assay at 8h, 1, 4, 8 and 14 d after CFA injection..The results of experiments are as follows: 1) peripheral injection of CFA induced long-term hyperalgesia lasting more than 14 days, and activation of spinal astrocytes lasted the same period as LTH; 2) peripheral administration of MK-801 produced a significant suppression of the LTH and activation of astrocytes induced by CFA injection; 3) pre-CFA peripheral administration of...