The Somatostatin Receptor-4 Agonist J-2156 Alleviates Mechanical Hypersensitivity in a Rat Model of Breast Cancer Induced Bone Pain

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.

Transcriptomic characterisation of the optimised rat model of Walker 256 breast cancer cell‐induced bone pain

“…Using μCT scans, histological assessment with H&E staining, and immunohistochemical staining against Cytokeratin 18 in tibial bones, we have demonstrated that cancer cells were present in the bones and pathological changes associated with metastatic lesions such as osteolytic bone degradation was evident. This was the case both during the period when pain behaviour (< day 21) was evident and also during the period when pain behaviour was apparently resolved (> day 21), as reported in detail in our previous studies . Group of rats inoculated with live W256 cells developed significant ( P ≤ .05) mechanical hypersensitivities in the bilateral hindpaws at days 7–10 post‐inoculation (pain behaviours present), when compared to group of rats inoculated with HK W256 cells (Figure ).…”

“…It is necessary that we understand the gene level changes occurring in the neural tissues that underpin the pathophysiology of pain in the preclinical models used in the drug discovery processes. Previous works from our laboratory have established that the Walker 256 breast cancer cell‐induced bone pain model in rats is a research tool that mimics key features of the human BCIBP condition and can be very useful in investigating the mechanisms of BCIBP and in discovery of novel analgesics against this debilitating pain condition . However, there is insufficient information on global gene expression changes at the level of dorsal root ganglia (DRGs) and the spinal cord, occurring in the pathophysiology of BCIBP.…”

Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains

“…Activation of SST 4 in the central nervous system leads to M-current augmentation and epileptiform activity inhibition in hippocampal CA1 pyramidal cells [ 10 ]. In addition, SST 4 activation increases potassium conductance via GIRK channels leading to consequent suppression of voltage-sensitive calcium channels in primary sensory neurons of the dorsal root ganglia (DRG) [ 18 ].…”

Assessment of the anti‐hyperalgesic efficacy of J‐2156, relative to clinically available analgesic/adjuvant agents in a rat model of mild to moderate chronic mechanical low back pain (LBP)

“…This highlights an unmet medical need for the discovery of efficacious and well‐tolerated novel analgesic agents. Hence, we assessed the SST 4 receptor agonist, J‐2156, 14 in our LBP‐5X rat model to determine its potential as a novel pharmacotherapeutic treatment for cLBP.…”

“…This unmet medical need is driving research aimed at discovery of new molecules that are efficacious and well‐tolerated. Of interest, J‐2156, an investigational small molecule somatostatin type 4 (SST4) receptor agonist has been shown by our laboratory to alleviate prostate cancer‐induced bone pain in rats 14 as well as chronic mechanical LBP in a moderately severe (LBP‐10X) rat model 15 . However, its efficacy in a mild to moderate rat model of chronic mechanical LBP remains to be assessed.…”