Faculty Bibliography

The primary molecular target for clinically used opioids is the mu-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with beta2-adrenergic receptors (beta2-ARs) through an interaction with the fifth and sixth helices of beta2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective beta2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and beta2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with beta2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by beta2-AR antagonists, providing a new avenue for opioid therapy.

The pharmacological effect of opioids originates, at the cellular level, by their interaction with the mu-opioid receptor (mOR) resulting in the regulation of voltage-gated Ca2+ channels and inwardly rectifying K+ channels that ultimately modulate the synaptic transmission. Recently, an alternative six trans-membrane helix isoform of mOR, (6TM-mOR) has been identified, but its function and signaling are still largely unknown. Here, we present the structural and functional mechanisms of 6TM-mOR signaling activity upon binding to morphine. Our data suggest that despite the similarity of binding modes of the alternative 6TM-mOR and the dominant seven trans-membrane helix variant (7TM-mOR), the interaction with morphine generates different dynamic responses in the two receptors, thus, promoting the activation of different mOR-specific signaling pathways. We characterize a series of 6TM-mOR-specific cellular responses, and observed that they are significantly different from those for 7TM-mOR. Morphine stimulation of 6TM-mOR does not promote a cellular cAMP response, while it increases the intracellular Ca2+ concentration and reduces the cellular K+ conductance. Our findings indicate that 6TM-mOR has a unique contribution to the cellular opioid responses. Therefore, it should be considered as a relevant target for the development of novel pharmacological tools and medical protocols involving the use of opioids.

Oral cancers are often severely painful and clinically difficult to manage. Few researchers have investigated the neurobiologic factors responsible for cancer pain; however, the study of oral cancer pain might inform us about the fundamental biology of cancer. The purpose of the present report was to summarize the clinical challenges inherent in oral cancer pain management, oral cancer pain mechanisms and mediators, and the convergence of the investigation of carcinogenesis and pain.

PURPOSE/OBJECTIVES: To assess the effects of high blood sugar at the levels of diabetic or prediabetic states during cancer treatment because patients undergoing chemotherapy (CTX) experience multiple symptoms that vary among individuals and may be affected by glucose levels. DESIGN: Descriptive, cross-sectional. SETTING: Two comprehensive cancer centers, one Veterans Affairs hospital, and four community-based oncology programs. SAMPLE: 244 outpatients with breast, gastrointestinal, gynecologic, and lung cancers. METHODS: Patients completed demographic and symptom questionnaires. Glycosylated hemoglobin A1c (HbA1c) was evaluated to determine diabetic state. Descriptive statistics and one-way analyses of variance were used in the analyses. MAIN RESEARCH VARIABLES: HbA1c, symptom severity scores, patient and clinical characteristics (e.g., age, gender, comorbidities, sociodemographic information, body mass index [BMI], lifestyle factors). FINDINGS: HbA1c results showed 9% of the sample in the diabetic and 26% in the prediabetic state. Patients in the diabetic state reported a higher number of comorbid conditions and were more likely to be African American. Patients in the prediabetic state were older aged. Patients in the diabetic and prediabetic states had a higher BMI compared to nondiabetic patients. No differences in symptom severity or quality-of-life (QOL) scores were found among the three diabetic states. CONCLUSIONS: This study is the first to evaluate for associations between diabetic states and symptom severity and QOL scores in patients receiving CTX. This study confirmed that older age, as well as having higher BMI and having multiple comorbidities, were associated with increased mean glycemic levels. IMPLICATIONS FOR NURSING: Clinicians should assess and identify patients with diabetes or prediabetes undergoing treatment for cancer. Patients who are older aged, those with a high BMI, and those with multiple comorbid conditions may be at increased risk for higher glycemic states.

More than half of all cancer patients have significant pain during the course of their disease. The strategic localization of TMPRSS2, a membrane-bound serine protease, on the cancer cell surface may allow it to mediate signal transduction between the cancer cell and its extracellular environment. We show that TMPRSS2 expression is not only dramatically increased in the primary cancers of patients but TMPRSS2 immunopositivity is also directly correlated with cancer pain severity in these patients. TMPRSS2 induced proteolytic activity, activated trigeminal neurons, and produced marked mechanical hyperalgesia when administered into the hind paw of wild-type mice but not PAR2-deficient mice. Coculture of human cancer cells with murine trigeminal neurons demonstrated colocalization of TMPRSS2 with PAR2. These results point to a novel role for a cell membrane-anchored mediator in cancer pain, as well as pain in general.

CONTEXT: Fatigue is the most common symptom in oncology patients during chemotherapy (CTX). Little is known about the predictors of interindividual variability in initial levels and trajectories of morning fatigue severity in these patients. OBJECTIVES: An evaluation was done to determine which demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of morning fatigue and to compare findings with our companion paper on evening fatigue. METHODS: A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N=586) completed demographic and symptom questionnaires a total of six times over two cycles of CTX. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling (HLM) was used to answer the study objectives. RESULTS: A large amount of interindividual variability was found in the morning fatigue trajectories. A piecewise model fit the data best. Patients with higher body mass index (BMI), who did not exercise regularly, with a lower functional status, and who had higher levels of state anxiety, sleep disturbance and depressive symptoms, reported higher levels of morning fatigue at enrollment. Variations in the trajectories of morning fatigue were predicted by the patients' ethnicity and younger age. CONCLUSION: The modifiable risk factors that were associated with only morning fatigue were BMI, exercise, and state anxiety. Modifiable risk factors that were associated with both morning and evening fatigue included functional status, depressive symptoms, and sleep disturbance. Using this information, clinicians can identify patients at higher risk for more severe morning fatigue and evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors.

CONTEXT: Fatigue is a distressing, persistent sense of physical tiredness that is not proportional to a person's recent activity. Fatigue impacts patients' treatment decisions and can limit their self-care activities. While significant interindividual variability in fatigue severity has been noted, little is known about predictors of interindividual variability in initial levels and trajectories of evening fatigue severity in oncology patients receiving chemotherapy (CTX). OBJECTIVES: To determine whether demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of evening fatigue. METHODS: A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N=586) completed demographic and symptom questionnaires a total of six times over two cycles of CTX. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling (HLM) was used to answer the study objectives. RESULTS: A large amount of interindividual variability was found in the evening fatigue trajectories. A piecewise model fit the data best. Patients who were White, diagnosed with breast, gynecological, or lung cancer, and who had more years of education, child care responsibilities, lower functional status, and higher levels of sleep disturbance and depression reported higher levels of evening fatigue at enrollment. CONCLUSION: This study identified both non-modifiable (e.g., ethnicity) and modifiable (e.g., child care responsibilities, depressive symptoms, sleep disturbance) risk factors for more severe evening fatigue. Using this information, clinicians can identify patients at higher risk for more severe evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors.