Accepted

Increases in cancer diagnosis have tremendous negative impacts on patients and their families, and major societal and economic costs. The beneficial effect of chemotherapeutic agents on tumor suppression comes with major unwanted side effects such as weight and hair loss, nausea and vomiting, and neuropathic pain. Chemotherapy-induced peripheral neuropathy (CIPN), which can include both painful and non-painful symptoms, can persist 6 months or longer after the patient's last chemotherapeutic treatment. These peripheral sensory and motor deficits are poorly treated by our current analgesics with limited effectiveness. Therefore, the development of novel treatment strategies is an important preclinical research focus and an urgent need for patients. Approaches to prevent CIPN have yielded disappointing results since these compounds may interfere with the anti-tumor properties of chemotherapeutic agents. Nevertheless, the first (serotonin noradrenaline reuptake inhibitors [SNRIs], anticonvulsants, tricyclic antidepressants) and second (5% lidocaine patches, 8% capsaicin patches and weak opioids such as tramadol) lines of treatment for CIPN have shown some efficacy. The clinical challenge of CIPN management in cancer patients and the need to target novel therapies with long-term efficacy in alleviating CIPN are an ongoing focus of research. The endogenous cannabinoid system has shown great promise and efficacy in alleviating CIPN in preclinical and clinical studies. In this review, we will discuss the mechanisms through which the platinum, taxane, and vinca alkaloid classes of chemotherapeutics may produce CIPN and the potential therapeutic effect of drugs targeting the endocannabinoid system in preclinical and clinical studies, in addition to cannabinoid compounds diffuse mechanisms of action in alleviation of CIPN.

Pain is the major symptom of osteoarthritis (OA) and is an important factor in strategies to manage this disease. However, the current standard of care does not provide satisfactory pain relief for many patients. The pathophysiology of OA is complex, and its presentation as a clinical syndrome is associated with pathologies of multiple joint tissues. Inflammation is associated with both OA pain and disease outcome and is therefore a major treatment target for OA and OA pain. Unlike TNF inhibitors and IL-1 inhibitors, established drugs such as glucocorticoids and methotrexate can reduce OA pain. Although central nociceptive pathways contribute to OA pain, crosstalk between the immune system and nociceptive neurons is central to inflammatory pain; therefore, new therapies might target this crosstalk. Newly identified drug targets, including neurotrophins and the granulocyte-macrophage colony-stimulating factor (GM-CSF)-CC-chemokine ligand 17 (CCL17) chemokine axis, offer the hope of better results but require clinical validation.

Prolonged treatment of chronic severe pain with opioid analgesics is frought with problematic adverse effects including tolerance, dependence, and life-threatening respiratory depression. Though these effects are mediated predominately through preferential activation of μ opioid peptide (μOP) receptors, there is an emerging appreciation that actions at κOP and δOP receptors contribute to the observed pharmacologic and behavioral profile of μOP receptor agonists and may be targeted simultaneously to afford improved analgesic effects. Recent developments have also identified the related nociceptin opioid peptide (NOP) receptor as a key modulator of the effects of μOP receptor signaling. We review here the available literature describing OP neurotransmitter systems and highlight recent drug and probe design strategies.