Opioid-Modulated Receptor Localization and Erk1/2 Phosphorylation in Cells Coexpressing µ-Opioid and Nociceptin Receptors.

We attempted to examine the alterations elicited by opioids via coexpressed µ-opioid (MOP) and nociceptin/orphanin FQ (NOP) receptors for receptor localization and Erk1/2 (p44/42 MAPK) in human embryonic kidney (HEK) 293 cells. Through two-photon microscopy, the proximity of MOP and NOP receptors was verified by fluorescence resonance energy transfer (FRET), and morphine but not buprenorphine facilitated the process of MOP-NOP heterodimerization. Single-particle tracking (SPT) further revealed that morphine or buprenorphine hindered the movement of the MOP-NOP heterodimers. After exposure to morphine or buprenorphine, receptor localization on lipid rafts was detected by immunocytochemistry, and phosphorylation of Erk1/2 was determined by immunoblotting in HEK 293 cells expressing MOP, NOP, or MOP+NOP receptors. Colocalization of MOP and NOP on lipid rafts was enhanced by morphine but not buprenorphine. Morphine stimulated the phosphorylation of Erk1/2 with a similar potency in HEK 293 cells expressing MOP and MOP+NOP receptors, but buprenorphine appeared to activate Erk1/2 solely through NOP receptors. Our results suggest that opioids can fine-tune the cellular localization of opioid receptors and phosphorylation of Erk1/2 in MOP+NOP-expressing cells.

Reduced mortality in patients with extended duration of methadone maintenance treatment: a five-year retrospective nationwide study.

BACKGROUND: The retention of patients under methadone maintenance treatment (MMT) is an indication for the effectiveness of the therapy. We aimed to explore the relation between mortality and the cumulative MMT duration. METHODS: A retrospective cohort analysis was performed using Taiwan Illicit Drug Issue Database (TIDID) and National Health Insurance Research Database (NHIRD) during 2012-2016. We included 9149 and 11 112 MMT patients as the short and long groups according to the length of their cumulative MMT duration, 1-364 and ⩾365 days, respectively. The risk of mortality was calculated by Cox proportional hazards regression model with time-dependent exposure to MMT, and the survival probability was plotted with the Kaplan-Meier curve. RESULTS: The mortality rates were 2.51 and 1.51 per 100 person-years in the short and long cumulative MMT duration groups, respectively. After adjusting for on or off MMT, age, sex, marital status, education level, maximum methadone dose, and comorbidities (human immunodeficiency virus, depression, hepatitis C virus, hepatitis B virus, alcoholic liver disease, and cardiovascular disease), the long group had a lower risk of death (hazard ratio = 0.67; 95% confidence interval 0.60-0.75) than the short group. Increased risk was observed in patients with advanced age, being male, unmarried, infected by HIV, HCV, and HBV, and diagnosed with depression, ALD, and CVD. Causes of death were frequently related to drug and injury. CONCLUSIONS: Longer cumulative MMT duration is associated with lower all-cause and drug-related mortality rate.

Risk of psychosis in illicit amphetamine users: a 10 year retrospective cohort study.

QUESTION: Amphetamine use is a risk factor for psychosis, which imposes a substantial burden on society. We aimed to investigate the incidence of psychosis associated with illicit amphetamine use and whether rehabilitation treatments could influence the psychosis risk. STUDY SELECTION AND ANALYSIS: A retrospective cohort study was conducted using the population based Taiwan Illicit Drug Issue Database (TIDID) and the National Health Insurance Research Database (NHIRD), from 2007 to 2016. We identified 74 601 illicit amphetamine users as the amphetamine cohort and 2 98 404 subjects as the non-amphetamine cohort. The incidence rate of newly diagnosed psychosis was the main outcome. Cox proportional hazards models were applied to assess the effects of amphetamine, and the Kaplan-Meier method was used to estimate the cumulative psychosis incidence curves. FINDINGS: Illicit amphetamine users were 5.28 times more likely to experience psychosis than those without illicit drug use records. The risk was higher for subjects with multiple arrests for amphetamine use. A greater hazard ratio (HR) magnitude was observed in female patients. We also observed a significant decrease in the risk of psychosis in patients receiving rehabilitation treatments during deferred prosecution (adjusted HR 0.74, 95% CI 0.61 to 0.89). CONCLUSIONS: Illicit amphetamine use was associated with an increased incidence of psychosis. The risk was identified across all age groups, particularly in women and in those arrested multiple times, and was inversely correlated with rehabilitation treatments for amphetamine misuse.

Augmentation in Healthcare Utilization of Patients with Opioid Use Disorder After Methadone Maintenance Treatment: A Retrospective Nationwide Study.

INTRODUCTION: The health benefits of entering methadone maintenance treatment (MMT) for opioid-dependent persons may not be merely limited to therapy of opioid use disorder. We aimed to compare the healthcare utilization of MMT patients before and after MMT. METHODS: A retrospective analysis was performed using the Taiwan Illicit Drug Issue Database and the National Health Insurance Research Database (NHIRD) between 2014 and 2016. We included 1255 newly enrolled MMT patients in 2015 and randomly selected 5020 patients from NHIRD matched by age and gender as the comparison group. Changes in healthcare utilization 1 year before and 1 year after the date of the index date (MMT initiation) were compared within and between MMT and comparison groups. RESULTS: During the 1-year period following MMT, the hospitalization length was considerably decreased, while the number of outpatient visits, emergency department (ED) visits, and ED expenditure significantly increased in MMT patients. Multivariable linear regression with the difference-in-difference approach revealed that all the categories of healthcare utilization increased, except for a minor increase of outpatient expenditure and a slight decrease of hospitalization length for the MMT group relative to the comparison group. Increases in utilization of the departments of psychiatry and infectious diseases of the MMT patients were considerable. CONCLUSION: MMT is associated with increased healthcare utilization, and departments of psychiatry and infectious diseases play substantial roles. Policy-makers should warrant access for all who need healthcare by ensuring the availability of the treatment for drug dependence.

Antidepressants and risk of dementia in migraine patients: A population-based case-control study.

To ascertain the relationship between receipt of antidepressant agents and the risk of subsequent dementia in migraine patients. A population-based case-control analysis, using the Taiwan National Health Insurance Research Database. We identified 1774 patients with dementia and 1774 matched nondementia controls from migraine patients enrolled in the Taiwan National Health Insurance program between 2005 and 2011. The proportional distributions of exposure to three classes of antidepressant were compared between dementia and nondementia groups. Univariable and multivariable logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of dementia based on antidepressant exposure. The proportions of subjects taking tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and new-generation antidepressants (NGAs) in dementia versus nondementia groups are 52.3 vs 51.2%, 25.5 vs 30.7%, and 18.8 vs 6.26%, respectively. The adjusted ORs of dementia were 1.02 (95% CI=0.89, 1.17; P=0.56) for TCAs, 0.58 (95% CI=0.50, 0.69; P<0.001) for SSRIs, and 4.23 (95% CI=3.34, 5.37; P<0.001) for NGAs. Treatment with SSRIs was associated with a decreased risk of dementia in migraine patients. TCAs showed no association with dementia risk, and NGAs showed increased risk. Given the possibility of confounding by indication, additional prospective trials and basic research are needed before drawing conclusions about the population-level risks for dementia onset conferred by antidepressant medications.

Risk of sepsis in patients with amyotrophic lateral sclerosis: a population-based retrospective cohort study in Taiwan.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and sepsis is a frequent cause of death in hospitalised patients. We investigated the relationship between ALS and the subsequent risk of sepsis. DESIGN: A retrospective cohort analysis. SETTING: Patients with ALSs diagnosed between 2000 and 2010 in Taiwan National Health Insurance Research Database. PARTICIPANTS: We included 701 and 2804 patients as the ALS and the non-ALS groups, respectively. OUTCOME MEASURES: The risk of sepsis was calculated by Cox proportional hazards regression model. RESULTS: During the follow-up period, the incidence density rates were 77.8 and 11.1 per 1000 person-years in the ALS and non-ALS groups, respectively. After adjusting for sex, age, Charlson comorbidity index score, life-support measures, and ß2-adrenoceptor agonists treatment, the ALS group had a higher risk of sepsis (HR=3.42; 95% CI 2.60 to 4.50) than the non-ALS group. An increase of the risk was observed in patients with ALS receiving life support treatment measures, whereas a decrease of the risk was associated with treatment of ß2-adrenoceptor agonists. CONCLUSIONS: The risk of sepsis is associated with a prior ALS diagnosis, and may be increased by the use of life support measures and decreased by ß2-adrenoceptor agonists.

Atrial Fibrillation is Associated With Morphine Treatment in Female Breast Cancer Patients: A Retrospective Population-Based Time-Dependent Cohort Study.

We investigated the relationship between morphine treatment and the risk of atrial fibrillation (AF) in female patients with breast cancer. We identified a malignancy cohort of 73,917 female breast cancer patients without an AF history before the date of breast cancer diagnosis between 2000 and 2010 by using the Longitudinal Health Insurance Database for Catastrophic Illness Patients in Taiwan. This malignancy cohort was divided into morphine and comparison cohorts comprising 18,671 and 55,246 patients, respectively, and the incidences of newly diagnosed AF were calculated. We used the Cox proportional hazard model with time-dependent exposure covariates to estimate the risk of AF. The effect of morphine was assessed through multivariable Cox proportional hazard regression controlling for age, the Charlson comorbidity index (CCI) score, and the use of bisphosphonates and paclitaxel. Compared with nonmorphine users, patients who received morphine exhibited a 4.37-fold (95% CI = 3.56-5.36) increase in the risk of developing AF. The risk of AF increased as the CCI score increased, but decreased in patients with tamoxifen treatment. This risk is especially significant in current morphine users of all ages and with low CCI score. AF risk increased as the duration of morphine use lengthened (P for trend <0.0001). The incidence of AF in female breast cancer patients in Taiwan is associated with morphine, but prevented by tamoxifen treatment.

Antidepressant treatment and risk of dementia: a population-based, retrospective case-control study.

OBJECTIVE: We investigated the relationship between antidepressant use and the risk of subsequent dementia development. METHOD: A population-based retrospective case-control analysis was conducted using the Taiwan National Health Insurance Research Database. From patients enrolled in the National Health Insurance program between 2005 and 2011, we identified 2 subsets: 5,394 cases, who had major depression in 1997-2004 and subsequently were diagnosed with dementia (ICD-9-CM code 290) in 2005-2011, and 5,232 controls, who had major depression in 2005-2011 but no dementia history. The proportional distributions of antidepressant use and comorbidities in the dementia case and nondementia control groups were compared. Univariable and multivariable logistic regression analyses were used to estimate the odds ratios (ORs) and 95% CIs for the association between dementia and antidepressant use. RESULTS: The dementia patients were more likely to have diabetes, hypertension, stroke, and head injury. The adjusted OR for dementia was 0.24 (95% CI, 0.22-0.27) in patients using tricyclics . By contrast, the use of selective serotonin reuptake inhibitors (SSRIs) (OR = 2.48; 95% CI, 2.27-2.71), monoamine oxidase inhibitors (MAOIs) (OR = 1.86; 95% CI, 1.47-2.36), heterocyclic antidepressants (OR = 1.44; 95% CI, 1.32-1.57), and other antidepressants (OR = 2.05; 95% CI, 1.85-2.27) was associated with an increased risk of dementia. Furthermore, as the cumulative dose was increased, tricyclic antidepressants reduced the risk of dementia, whereas SSRIs, MAOIs, heterocyclic antidepressants, and other antidepressants increased the risk of dementia. CONCLUSIONS: The incidence of dementia in patients is associated with antidepressant medication use. Treatment with tricyclic antidepressants was associated with a reduced risk of dementia, whereas treatment with SSRIs, MAOIs, heterocyclic antidepressants, and other antidepressants was associated with an increased risk of dementia.

Increased osteoporosis risk in dermatomyositis or polymyositis independent of the treatments: a population-based cohort study with propensity score.

We investigated the relationship between dermatomyositis/polymyositis (DM/PM) and the risk of subsequent osteoporosis development. A population-based retrospective cohort analysis was conducted using the National Health Insurance Research Database and the Catastrophic Illness Patients Database of Taiwan. We included 1179 patients and 4716 patients from 1999 to 2008 as the DM/PM cohort and the comparison cohort, respectively, and calculated the incidence rates of newly diagnosed osteoporosis. We used Cox proportional hazards models stratified on matched pair to assess the effect of DM/PM. The Kaplan-Meier method was applied to estimate the cumulative osteoporosis incidence curves. Patients with DM/PM were 2.99 times more likely to experience osteoporosis than those without DM/PM. The risk for osteoporosis in DM/PM patients was higher than comparisons in different propensity score quartiles. DM/PM cohort, no matter treated with or without corticosteroids and immunosuppressant, had a higher risk than the comparison cohort. The incidence of osteoporosis in Taiwan is associated with a priori DM/PM history. This risk was independent of the corticosteroids and immunosuppressant treatment.

Risk of type 2 diabetes mellitus in female breast cancer patients treated with morphine: A retrospective population-based time-dependent cohort study.

AIMS: We aimed to examine whether morphine treatment is associated with type 2 diabetes mellitus (T2DM) in female breast cancer patients. METHODS: We conducted a retrospective cohort analysis of the Longitudinal Health Insurance Database for Catastrophic Illness Patients in Taiwan. A total of 31,112 women with breast cancer without T2DM history during the period 2000-2005 were identified, divided into morphine and non-morphine users (8071 and 23,041 patients, respectively), and the hazard ratios of newly diagnosed T2DM during the period 2005-2010 were calculated. We used a Cox proportional hazard model with time-dependent exposure covariates to estimate the risk of T2DM. The dosage of morphine was counted as defined daily dose and its effect was assessed by multivariable Cox proportional hazard regression controlling age, Charlson comorbidity index, outpatient department visits, antipsychotics, and breast cancer drugs. RESULTS: Morphine users were 1.24 times more likely to suffer from T2DM than non-morphine users (95% CI=1.04-1.49). Risk increased slightly with the morphine dosage, in patients aged 35-49 years, and with tamoxifen, aromatase inhibitors, and antipsychotics treatment. CONCLUSIONS: The incidence of T2DM is associated with morphine treatment in female breast cancer patients. A higher risk was observed in patients aged 35-49 years using higher dose of morphine, and may be increased by tamoxifen and aromatase inhibitors.

Buprenorphine-elicited alteration of adenylate cyclase activity in human embryonic kidney 293 cells coexpressing κ-, µ-opioid and nociceptin receptors.

Buprenorphine, a maintenance drug for heroin addicts, exerts its pharmacological function via κ- (KOP), µ-opioid (MOP) and nociceptin/opioid receptor-like 1 (NOP) receptors. Previously, we investigated its effects in an in vitro model expressing human MOP and NOP receptors individually or simultaneously (MOP, NOP, and MOP+NOP) in human embryonic kidney 293 cells. Here, we expanded this cell model by expressing human KOP, MOP and NOP receptors individually or simultaneously (KOP, KOP+MOP, KOP+NOP and KOP+MOP+NOP). Radioligand binding with tritium-labelled diprenorphine confirmed the expression of KOP receptors. Immunoblotting and immunocytochemistry indicated that the expressed KOP, MOP and NOP receptors are N-linked glycoproteins and colocalized in cytoplasmic compartments. Acute application of the opioid receptor agonists- U-69593, DAMGO and nociceptin- inhibited adenylate cyclase (AC) activity in cells expressing KOP, MOP and NOP receptors respectively. Buprenorphine, when applied acutely, inhibited AC activity to ~90% in cells expressing KOP+MOP+NOP receptors. Chronic exposure to buprenorphine induced concentration-dependent AC superactivation in cells expressing KOP+NOP receptors, and the level of this superactivation was even higher in KOP+MOP+NOP-expressing cells. Our study demonstrated that MOP receptor could enhance AC regulation in the presence of coexpressed KOP and NOP receptors, and NOP receptor is essential for concentration-dependent AC superactivation elicited by chronic buprenorphine exposure.

Depression and risk of venous thromboembolism: a population-based retrospective cohort study.

OBJECTIVE: This study investigated the relationship between depression and the risk of subsequent venous thromboembolism (VTE) development. METHODS: We conducted a population-based retrospective cohort analysis by using data for the period of 2000 to 2011 from the Longitudinal Health Insurance Database 2000 of Taiwan. A depression cohort comprising 35,274 patients and a nondepression cohort comprising 70,548 patients matched according to sex, age, and index year with no history of VTE were evaluated. Cox proportional hazard regression analysis was used to assess the effects of depression and comorbidities, and the Kaplan-Meier method was applied to estimate the cumulative VTE incidence curves. RESULTS: Compared with individuals without depression, depressed patients had a 1.38-fold greater risk (95% confidence interval = 1.09-1.73) of developing VTE. This risk was significantly higher in male and younger (≤49 years) patients. In addition, patients with comorbidities such as hypertension, diabetes, heart failure, and cancer had a higher risk of depression-associated VTE that was attenuated, although nonsignificantly, by antidepressant use. CONCLUSIONS: The incidence of VTE in Taiwan is higher in depressed patients than in nondepressed patients. Moreover, men, people 49 years or younger, and patients with comorbidities have a significantly greater risk of VTE after depression.

Increased risk of osteoporosis in patients with depression: a population-based retrospective cohort study.

OBJECTIVE: To investigate the relationship between depression and risk of subsequent osteoporosis development. PARTICIPANTS AND METHODS: A population-based retrospective cohort analysis was conducted using the Longitudinal Health Insurance Database 2000 of Taiwan. We included 32,978 patients in the depression cohort and 131,912 patients in the no-depression cohort between January 1, 1998, and December 31, 2008, and calculated the incidence rates of newly diagnosed osteoporosis. We used Cox proportional hazards models to assess the effects of depression. The Kaplan-Meier method was applied to estimate the cumulative osteoporosis incidence curves. RESULTS: Patients with depression were 1.30 times more likely to experience osteoporosis than those without depression. The risk was higher for patients with severe depression and mild depression than for those without depression. A greater hazard ratio magnitude was observed in patients aged 35 to 49 years. We also observed a significant decrease in osteoporosis risk in patients with depression treated with antidepressant agents. CONCLUSION: The incidence of osteoporosis in Taiwan is associated with an a priori depression history. The risk was identified in both men and women, particularly in patients aged 35 to 49 years, and was inversely correlated with antidepressant drug treatment.

Pulmonary embolism is associated with current morphine treatment in patients with deep vein thrombosis.

OBJECTIVES: This study investigates the relationship between current morphine use and the risk of pulmonary embolism (PE) development in deep vein thrombosis (DVT) patients. METHODS: We conducted a population-based nested case-control retrospective analysis using the Longitudinal Health Insurance Database 2000 of Taiwan. A DVT cohort of 3668 patients with no history of PE from 1998 to 2010 and the other cohort of 174 patients who subsequently developed PE were evaluated. Morphine use was designated as 'current' if the prescription duration covered the index date or ended within 30 days before the index date. Logistic regression was used to estimate the odds ratios and 95% confidence intervals (CI), and the multivariable model was applied to control for age. RESULTS: Compared with non-morphine users, DVT patients who received morphine within 30 days of the index date had a 4.54-fold (95% CI = 2.30-8.97) chance of developing PE. The risk of PE development increased with an increase in cumulative dosage and in the average dosage of morphine. CONCLUSION: The incidence of PE in DVT patients in Taiwan is associated with current morphine treatment (≤30 days) and is dependent on dosage.

Subdural haemorrhage is associated with recent morphine treatment in patients with cancer: a retrospective population-based nested case-control study.

BACKGROUND: This study investigated the relationship between recent morphine use and risk of subdural haemorrhage (SDH) in patients with cancer. METHODS: This study identified a malignancy cohort of 25,322 patients who had never received morphine treatment. In this malignancy cohort, 200 patients who subsequently developed SDH were designated as the SDH group. Control-group patients without SDH were selected from the malignancy cohort and were matched ∼4:1 to each SDH case for age, sex, year of cancer diagnosis and index year. Morphine use was designated as 'recent' if the prescription duration covered the index date or ended within 6 months before the index date. Logistic regression was used to estimate odds ratios and 95% confidence intervals and a multivariable model was applied to control for age, sex and cerebrovascular disease. RESULTS: Compared with non-morphine users, patients with cancer who received morphine within 6 months of the index date exhibited a 2.58-fold (95% CI = 1.23-5.39) increase in the risk of developing SDH. The risk of SDH development increased as the duration of morphine treatment increased. CONCLUSION: The incidence of SDH in patients with cancer in Taiwan is associated with recent morphine treatment (≤6 months) and is dependent on the duration of morphine use.

Modest increase in risk of acute coronary syndrome associated with morphine use in cancer patients: a population-based nested case-control study.

BACKGROUND: Morphine is widely used for pain management in cancer patients. Use of heroin, a morphine derivative, is a risk factor for acute coronary syndrome (ACS). OBJECTIVE: This study investigates the risk of ACS associated with morphine use by comparing the incidence of ACS in cancer patients treated with and without morphine. METHODS: This is a population-based nested case-control study using the Longitudinal Health Insurance Database 2000 in Taiwan. In total, 31,384 patients on the database were diagnosed with cancer without prior history of ACS during 1998-2010. In this cohort, 499 patients subsequently developed ACS and 30,885 patients did not. The 499 patients were designated as the ACS group; controls were selected from the remaining 30,885 patients and matched 3:1 to each case for age, sex, year of cancer diagnosis, and index year. Logistic regression was used to estimate the odds ratios and 95% confidence intervals, and the multivariable model was applied to control for age, sex, and Charlson comorbidity score. RESULTS: Cancer patients who received morphine had a 32% higher risk of developing ACS than non-morphine users. This increase in risk was significant when evaluating the overall cancer patients, but non-significant when evaluating any specific cancer type. The risk of ACS increased significantly with increasing morphine dosage (to ≥65 mg/y). CONCLUSION: Morphine treatment is associated with a modest increase in risk of ACS in patients with malignancy, but this association displays low significance in specific cancer types.

Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors.

Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators.

Association of intensive morphine treatment and increased stroke incidence in prostate cancer patients: a population-based nested case­control study.

OBJECTIVES: We address the potential problem of stroke induced by morphine exposure by comparing the incidence of stroke in cancer patients treated with and without morphine. METHODS: We performed a population-based nested case­control retrospective analysis on the Longitudinal Health Insurance Database 2000 and Registry for Catastrophic Illness Patients of Taiwan. This study is based on a malignancy cohort of 31 611 patients without a history of stroke, and 1208 patients who subsequently developed stroke served as the stroke group. Four controls of matched age, sex, entry year and entry month for each case were selected from the malignancy cohort from the non-stroke group. We used logistic regression to estimate the odds ratios and 95% confidence intervals, and applied the multivariable model to control for age, sex, hypertension, diabetes, hyperlipidemia and cardiovascular disease. RESULTS: Cancer patients who received morphine had a 12% higher risk of developing stroke than non-morphine users. However, the difference was nonsignificant. A significant difference only appears in prostate cancer patients, where morphine users have a 3.02-fold (4.24- and 2.90-fold for hemorrhagic and ischemic strokes, respectively) higher risk of suffering from stroke. The risk increased significantly as the morphine dosage increased to 170 mg/year of treatment. CONCLUSIONS: Intense morphine treatment may be associated with an increased stroke incidence in patients with malignancy, and the association is particularly significant for prostate cancer patients.

Pharmacological Profiles of Oligomerized µ-Opioid Receptors.

Opioids are widely prescribed pain relievers with multiple side effects and potential complications. They produce analgesia via G-protein-protein coupled receptors: µ-, δ-, κ-opioid and opioid receptor-like 1 receptors. Bivalent ligands targeted to the oligomerized opioid receptors might be the key to developing analgesics without undesired side effects and obtaining effective treatment for opioid addicts. In this review we will update the biological effects of µ-opioids on homo- or hetero-oligomerized µ-opioid receptor and discuss potential mechanisms through which bivalent ligands exert beneficial effects, including adenylate cyclase regulation and receptor-mediated signaling pathways.