Chronic Cancer Pain: Opioids within Tumor Microenvironment Affect Neuroinflammation, Tumor and Pain Evolution

SIMPLE SUMMARY: Pain is a worrisome symptom that 60–80% of patients with cancer experience chronically. In the last twenty years, immunological and pain research have shown that cancer pain is attributable to the neuroinflammatory response driven by the cellular and soluble components of the tumor microenvironment, with features similar to that induced in many other painful chronic non-cancer diseases. Neuroinflammation leads to central sensitization and neuroplastic remodeling of the central nervous system with alteration of pain sensitivity (hyperalgesia), responsiveness (behavior), and drive (centralization). Engagement of opioid receptors by both endogenous and exogenous opioids, namely, the cornerstone of pain therapy morphine, results in modulation of pain intensity and quality, in addition to cancer growth and progression. The effects of opioids on the evolution of pain, (relief or immune-mediated hyperalgesia) and cancer (promotion or inhibition), are dual and ambiguous. This ambiguity currently represents a major limitation of long-term opioid therapy, and encourages novel immunotherapeutic strategies. ABSTRACT: Pain can be a devastating experience for cancer patients, resulting in decreased quality of life. In the last two decades, immunological and pain research have demonstrated that pain persistence is primarily caused by neuroinflammation leading to central sensitization with brain neuroplastic alterations and changes in pain responsiveness (hyperalgesia, and pain behavior). Cancer pain is markedly affected by the tumor microenvironment (TME), a complex ecosystem consisting of different cell types (cancer cells, endothelial and stromal cells, leukocytes, fibroblasts and neurons) that release soluble mediators triggering neuroinflammation. The TME cellular components express opioid receptors (i.e., MOR) that upon engagement by endogenous or exogenous opioids such as morphine, initiate signaling events leading to neuroinflammation. MOR engagement does not only affect pain features and quality, but also influences directly and/or indirectly tumor growth and metastasis. The opioid effects on chronic cancer pain are also clinically characterized by altered opioid responsiveness (tolerance and hyperalgesia), a hallmark of the problematic long-term treatment of non-cancer pain. The significant progress made in understanding the immune-mediated development of chronic pain suggests its exploitation for novel alternative immunotherapeutic approaches.