In the majority of patients with
breast cancer in the advanced stages, skeletal
metastases are common, which may cause excruciating
pain. Currently available
drug treatments for relief of
breast cancer-induced bone
pain (BCIBP) include non-steroidal anti-inflammatory drugs and strong
opioid analgesics along with inhibitors of osteoclast activity such as
bisphosphonates and
monoclonal antibodies such as
denosumab. However, these medications often lack efficacy and/or they may produce serious dose-limiting side effects. In the present study, we show that
J-2156, a
somatostatin receptor type 4 (
SST4 receptor) selective agonist, reverses
pain-like behaviors in a rat model of BCIBP induced by unilateral intra-tibial injection of Walker 256
breast cancer cells. Following intraperitoneal administration, the ED50 of
J-2156 for the relief of
mechanical allodynia and
mechanical hyperalgesia in the ipsilateral hindpaws was 3.7 and 8.0 mg/kg, respectively. Importantly, the vast majority of somatosensory neurons in the dorsal root ganglia including small diameter C-fibers and medium-large diameter fibers, that play a crucial role in
cancer pain hypersensitivities, expressed the
SST4 receptor.
J-2156 mediated
pain relief in BCIBP-rats was confirmed by observations of a reduction in the levels of phosphorylated
extracellular signal-regulated kinase (pERK), a
protein essential for central sensitization and persistent
pain, in the spinal dorsal horn. Our results demonstrate the potential of the
SST4 receptor as a pharmacological target for relief of BCIBP and we anticipate the present work to be a starting point for further mechanism-based studies.