Radiotherapy Suppresses Bone Cancer Pain through Inhibiting Activation of cAMP Signaling in Rat Dorsal Root Ganglion and Spinal Cord

Abstract

Radiotherapy is one of the major clinical approaches for treatment of bone cancer pain. Activation of cAMP-PKA signaling pathway plays important roles in bone cancer pain. Here, we examined the effects of radiotherapy on bone cancer pain and accompanying abnormal activation of cAMP-PKA signaling. Female Sprague-Dawley rats were used and received tumor cell implantation (TCI) in rat tibia (TCI cancer pain model). Some of the rats that previously received TCI treatment were treated with X-ray radiation (radiotherapy). Thermal hyperalgesia and mechanical allodynia were measured and used for evaluating level of pain caused by TCI treatment. PKA mRNA expression in dorsal root ganglion (DRG) was detected by RT-PCR. Concentrations of cAMP, IL-1β, and TNF-α as well as PKA activity in DRG and the spinal cord were measured by ELISA. The results showed that radiotherapy significantly suppressed TCI-induced thermal hyperalgesia and mechanical allodynia. The level of PKA mRNA in DRG, cAMP concentration and PKA activity in DRG and in the spinal cord, and concentrations of IL-1β and TNF-α in the spinal cord were significantly reduced by radiotherapy. In addition, radiotherapy also reduced TCI-induced bone loss. These findings suggest that radiotherapy may suppress bone cancer pain through inhibition of activation of cAMP-PKA signaling pathway in DRG and the spinal cord.

Cyclic nucleotide signaling in sensory neuron hyperexcitability and chronic pain after nerve injury

“…Repetitive spinal administration of the PKA inhibitor in early- and late- phases following TCI significantly delays or attenuates TCI-induced thermal hyperalgesia and mechanical allodynia. This provides direct evidence that activation of the cAMP-PKA pathway in DRG and spinal cord may mediate the development of bone cancer pain (Zhu et al, 2016). cAMP-dependent DRG neuron hyperexcitability (Huang et al, 2012) may be mediated by the phosphorylation of sodium and calcium channels (Rathee et al, 2002, England et al, 1996, Blackstone et al, 1994, Fraser and Scott, 1999).…”

“…Activated cAMP-PKA pathway also promotes the synthesis of presynaptic neurotransmitters and vesicular transport by phosphorylating key transcription factors such as cAMP response element-binding protein (CREB) and synaptic vesicle proteins such as snapin (Koppert, 2004, King et al, 2005, Tumati et al, 2011). Studies have demonstrated the involvement of cAMP-PKA pathway in inflammatory pain (Malmberg et al, 1997, Hingtgen et al, 1995, Lewin and Walters, 1999), neuropathic pain (Song et al, 2006, Zheng et al, 2007, Huang et al, 2012) and bone cancer pain (Zhu et al, 2014, Zhu et al, 2016).…”

“…These long-lasting patterns of molecular changes are corresponding to the painful behaviors observed in TCI rats. TCI treatment results in an increased concentration of cGMP in DRG and activity of cGKs in DRG and the spinal cord, as well as an increased level of cGKI messenger ribonucleic acid and protein in DRG (Zhu et al, 2016, Liu et al, 2014). These findings suggest that cAMP activation in DRG and the spinal cord and activation of cGMP-cGKI pathway in DRG may contribute to the development of bone cancer pain.…”

“…After treatment with the inhibitors of cAMP-PKA and cGMP-PKG pathways, the bone destruction can be greatly prevented or alleviated (Wu et al, 2007, Son et al, 2010). In addition, radiotherapy can remarkably relieve TCI-induced bone destruction and bone loss, which is indicated by the decreased bone destruction score and increased bone structure integrity (Zhu et al, 2014, Zhu et al, 2016).…”

“…However, mechanisms underlying the analgesic effects of radiotherapy in bone cancer remains unclear. Given the evidence that the activation of cAMP-PKA pathway in DRG and the spinal cord plays important roles in bone cancer pain, studies have shown that radiotherapy can relieve bone cancer pain through inhibiting the activation of cAMP-PKA pathway in DRG and the spinal cord (Zhu et al, 2016). A single dose of X-radiation (6 Gy) can produce a significant, weeks-long inhibition of TCI-induced thermal hyperalgesia and mechanical allodynia in TCI rats.…”