endothelin-1 and Pain--Intractable

Cancer pain is an ever-present public health concern. With innovations in treatment, cancer patients are surviving longer, but uncontrollable pain creates a poor quality of life for these patients. Oral cancer is unique in that it causes intense pain at the primary site and significantly impairs speech, swallowing, and masticatory functions. We propose that oral cancer pain has underlying biologic mechanisms that are generated within the cancer microenvironment. A comprehensive understanding of key mediators that control cross-talk between the cancer and peripheral nervous system, and possible interventions, underlies effective cancer pain management. The purpose of this review is to explore the current studies on oral cancer pain and their implications in clinical management for cancer pain in general. Furthermore, we will explore the endogenous opioid systems and novel cancer pain therapeutics that target these systems, which could solve the issue of opiate tolerance and improve quality of life in oral cancer patients.

Topics: Analgesics, Opioid; Animals; Carcinoma, Squamous Cell; Drug Tolerance; Endothelin-1; Facial Pain; Humans; Mouth Neoplasms; Nerve Growth Factor; Nociceptors; Opioid Peptides; Pain Management; Pain, Intractable; Palliative Care; Quality of Life; Receptors, Proteinase-Activated

Endothelin-1 (ET-1) exists in endothelial cells as well as a variety of other cell types. The presence of ET-1 and its receptors in neurons suggests its possible role as a neurotransmitter and/or neuromodulator. Studies utilizing exogenous ET-1 have suggested that ET-1 affects pain transmission. This study was designed to examine the possible role(s) of neuronal ET-1 in pain processing. We produced neuron-specific ET-1 knockout mice using the Cre/loxP system with a synapsin I promoter and examined the effects produced by the lack of neuronal ET-1 on pain behavior using common pain models and a model of stress-induced analgesia. In acute nociceptive pain models, paw withdrawal thresholds to radiant heat and mechanical stimuli applied with von Frey hairs were significantly lower in the knockout mice compared with control. This indicated that the absence of neuronal ET-1 leads to greater sensitivity to acute nociceptive stimuli. After inflammation was produced by intraplantar injection of carrageenan, there was a significantly greater degree of thermal hyperalgesia and mechanical allodynia in the knockout mice even after the difference in baseline values was compensated. Furthermore, in a neuropathic pain model produced by spinal nerve ligation, there was also a greater degree of mechanical allodynia in the knockout mice. Finally, in a swim-stress model, the magnitude of stress-induced analgesia was less in the knockout mice, indicating the involvement of neuronal ET-1 in stress-induced analgesia. The results suggest that there is a basal release of ET-1 from neurons that affect baseline pain thresholds as well as an additional release during persistent pain states that acts to suppress the pain. The involvement of neuronal ET-1 in stress-induced analgesia further suggests its role in endogenous pain inhibitory systems. To confirm that ET-1 is released in persistent pain states and to determine which part of the CNS is involved, we measured the concentrations of ET-1 before and after inducing peripheral inflammation in different parts of the CNS involved in endogenous pain inhibitory systems in normal mice. We found that ET-1 was increased in the hypothalamus while no significant increase was observed in the midbrain, medulla and spinal cord. The results of the present study suggest that neuronal ET-1 is involved in endogenous pain inhibitory control likely via pathways through the hypothalamus.

Topics: Acute Disease; Animals; Disease Models, Animal; Endothelin-1; Hyperalgesia; Hypothalamus; Mice; Mice, Knockout; Neural Inhibition; Neural Pathways; Neurons; Pain; Pain Measurement; Pain Threshold; Pain, Intractable; Peripheral Nervous System Diseases; Physical Stimulation; Promoter Regions, Genetic; Reaction Time; Stress, Physiological; Synapsins