Studies suggest that astrocytes and microglia in the spinal cord are involved in the development of persistent pain induced by tissue inflammation and nerve injury. However, the role of glial cells in bone cancer pain is not well understood. The present study evaluated the spinal glial activation in a novel rat model of bone cancer pain produced by injecting AT-3.1 prostate cancer cells into the unilateral tibia of male Copenhagen rats. The structural damage to the tibia was monitored by radiological analysis. The thermal hyperalgesia, mechanical hyperalgesia and allodynia, and spontaneous flinch were measured. The results showed that: (1) inoculation of prostate cancer cells, but not the vehicle Hank's solution, induced progressive bone destruction at the proximal epiphysis of the tibia from day 7-20 post inoculation; (2) the inoculation also induced progressive thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia, and spontaneous flinches; (3) astrocytes and microglia were significantly activated in the spinal cord ipsilateral to the cancer leg, characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglial marker); (4) IL-1beta was up-regulated in the ipsilateral spinal cord, evidenced by an increase of IL-1beta immunostained astrocytes. These results demonstrate that injection of AT-3.1 prostate cancer cells into the tibia produces progressive hyperalgesia and allodynia associated with the progression of tibia destruction, indicating the successful establishment of a novel male rat model of bone cancer pain. Further, bone cancer activates spinal glial cells, which may release IL-1beta and other cytokines and contribute to hyperalgesia.

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It has been shown that interleukin-1beta (IL-1beta) facilitates nociception during neuropathic and inflammatory pain, but its involvement in bone cancer pain and its mechanisms have not previously been established. This study is an investigation of IL-1beta spinal expression and the N-methyl-D-aspartate (NMDA) receptor (NMDAR) NR1 subunit phosphorylation during cancer pain, co-localization of IL-1 receptor type I (IL-1RI) and NMDAR in the spinal cord, and the effects of IL-1 receptor antagonist (IL-1ra) on NMDAR1 (NR1) phosphorylation and hyperalgesia in a rat model of bone cancer pain. Cancer was induced by injecting AT-3.1 prostate cancer cells into the tibia of the male Copenhagen rat. Phosphorylation of NR1, an essential subunit of the NMDAR, is known to modulate NMDAR activity and facilitate pain. Mechanical hyperalgesia, established by a decrease in paw withdrawal pressure threshold (PWPT), was measured at baseline and 2 h after IL-1ra treatment. IL-1ra was given (i.t.) daily for 7 days between days 13 and 19 after the cancer cell inoculation. Spinal cords were removed for Western blot to measure IL-1beta and NR1 phosphorylation and for double immunostaining of IL-1RI and NR1. The data showed that 1) spinal IL-1beta was up-regulated and NR1 phosphorylation was increased, 2) IL-1ra at 0.1 mg/rat significantly (P<0.05) inhibited mechanical hyperalgesia, increasing PWPT on day 14 from 71.1+/-3.1-85.3+/-4.6 g and on day 19 from 73.5.0+/-3.5-87.1+/-3.7 g, and inhibited NR1 phosphorylation compared with saline control, and 3) IL-1RI is localized in NR1-immunoreactive neurons within the spinal cord. The results suggest that spinal IL-1beta enhances NR1 phosphorylation to facilitate bone cancer pain.

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