Cannabinoid receptor type 2 (CB2) agonists display potential
analgesic effects in acute and
neuropathic pain. However, its complex cellular and molecular mechanisms in
bone cancer pain remain unclear. And less relevant reports concerned its time-dependent effects on the long-lasting modifications of behavior, spinal inflammatory
cytokines levels, astrocytes activity induced by
bone cancer pain. A rat model of
bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland
carcinoma cells was utilized.
Pain behaviors at different time points were assessed by ambulatory
pain scores and paw withdrawal mechanical threshold (PWMT). Pro-inflammatory
cytokines, such as
interleukin (IL)-1β,
IL-6,
IL-18, and
tumor necrosis factor alpha (TNF-α), were quantitated by Western blots. Glial activity was assessed by immunohistochemistry. Intra-tibia inoculation of Walker 256 mammary gland
carcinoma cells induced progressive
bone cancer pain; a long-term up-regulation of IL-1β,
IL-6,
IL-18, and TNF-α; and the activation of glia in spinal cord. Activation of microglia was first evident on day 4 after surgery and reached to a peak on day 7 while activation of astrocytes was on day 10. A single
intrathecal injection of
JWH-015 attenuated
bone cancer induced spontaneous
pain and
mechanical allodynia, reduced the expression of pro-inflammatory
cytokines, and inhibited the activity of astrocytes. All the modifications were transient and peaked at 24 h after
JWH-015 administration. Furthermore, the protective effects of
JWH-015 were reversed in the presence of CB2-selective antagonist
AM630. Overall, our results provided evidences for the persistent participation of
inflammation reaction in the progression of
bone cancer pain, and demonstrated that
JWH-015 reduced the expression of IL-1β,
IL-6,
IL-18, and TNF-α and inhibited astrocytes activation in a time-dependent manner, thereby displaying an
analgesic effect.