Abstract
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.
Highlights
Breast cancer is the most frequent type of cancer diagnosed in women and the major cause of cancer-associated mortalities in the world (DeSantis et al, 2015)
While the profile of the endogenous ligand somatostatin-14 was non-selective between somatostatin receptor types (Figure 1A), J-2156 displayed a strong affinity in the nanomolar range for the SST4 receptor only, with low affinity for the other somatostatin receptor types (Figure 1B)
We confirmed that J-2156 is a SST4 receptor-selective agonist with over ∼300-fold selectivity for this receptor compared to other receptor types of the somatostatin family, consistent with a previous report by others (Engström et al, 2005)
Summary
Breast cancer is the most frequent type of cancer diagnosed in women and the major cause of cancer-associated mortalities in the world (DeSantis et al, 2015). Cancer cells in the bones locally stimulate as well as induce the release of inflammatory mediators (Lozano-Ondoua et al, 2013; Esquivel-Velázquez et al, 2015; Kane et al, 2015). Cancer-induced bone pain has a very complex pathophysiology as it is underpinned by both inflammatory and neuropathic components, along with an interplay of cancer-specific factors (Cao et al, 2010). It involves pathobiological alterations of peripheral tissues and nerve fibers as well as characteristic neurochemical changes at the level of the spinal cord (Falk and Dickenson, 2014)
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