Effects of Tyrosine Kinase Inhibitors on Blood Pressure in Patients with Unresectable or Advanced Recurrent Renal Cell Carcinoma-Bayes-Mixed Treatment Comparison Meta-Analysis.

Although cytokine therapy has been a common drug therapy for renal cell carcinoma for long since the 1980s, the evidence for the rationale of this therapy has been limited. Currently, 7 molecular targeted drugs(ie, sorafenib, sunitinib, axitinib, pazopanib, cabozantinib, everolimus, and temsirolimus)are available in Japan. Among these molecular targeted drugs, we clinically evaluated 5 tyrosine kinase inhibitors(ie, sorafenib, sunitinib, axitinib, pazopanib, and cabozantinib)in terms of their effects on blood pressure and the response rate by Bayes-mixed treatment comparison meta-analysis(Bayes- MTC analysis)to develop the decision-making model for the optimal treatment selection. Cabozantinib and axitinib exerted the greatest effect on blood pressure, and their probability of affecting blood pressure was 1.7 to 2 times higher than the probability of sunitinib. Among the 5 tyrosine kinase inhibitors, the effects of sunitinib and sorafenib on blood pressure were small. According to the results of clinical trials in Japan, hypertension was observed in 27.5% of patients treated with sorafenib, 51.0% with sunitinib, and 75.7% with axitinib. Our analysis also showed similar results. This study demonstrated that Bayes-MTC analysis is a useful tool enabling not only direct evaluation but also indirect evaluation.

Effects of (+)-pentazocine on the antinociceptive effects of (-)-pentazocine in mice.

Previous studies have shown that sigma-1 receptor chaperone (Sig-1R) ligands can regulate pain-related behaviors, and Sig-1R itself can regulate µ-opioid receptor functions as well as signal transduction. Even though (±)-pentazocine has been used clinically for the treatment of pain through opioid receptors, (+)-pentazocine is known to be a selective Sig-1R agonist. To the best of our knowledge, there is no information available regarding the involvement of Sig-1R agonistic action in the antinociceptive effects of (±)-pentazocine. Therefore, the present study was designed to investigate the effects of (+)-pentazocine on the antinociceptive effects of (-)-pentazocine in mice. Both and (-)-pentazocine induced biphasic antinociceptive effects as measured by the warm-plate test. The early phase, but not the delayed phase, of the antinociceptive effects induced by (-)-pentazocine, which are mediated by the activation of µ-opioid receptors, were suppressed by pretreatment with (+)-pentazocine. These results suggest that the innate antinociceptive action of (±)-pentazocine could be marginally reduced by the effects of (+)-pentazocine, but (+)-pentazocine can suppress the antinociceptive effects of (-)-pentazocine at certain time points.

Involvement of µ- and δ-opioid receptor function in the rewarding effect of (±)-pentazocine.

Most opioid receptor agonists have abuse potential, and the rewarding effects of opioids can be reduced in the presence of pain. While each of the enantiomers of pentazocine has a differential pharmacologic profile, (±)-pentazocine has been used clinically for the treatment of pain. However, little information is available regarding which components of pentazocine are associated with its rewarding effects, and whether the (±)-pentazocine-induced rewarding effects can be suppressed under pain. Therefore, the present study was performed to investigate the effects of pain on the acquisition of the rewarding effects of (±)-pentazocine, and to examine the mechanism of the rewarding effects of (±)-pentazocine using the conditioned place preference paradigm. (±)-Pentazocine and (-)-pentazocine, but not (+)-pentazocine, produced significant rewarding effects. Even though the rewarding effects induced by (±)-pentazocine were significantly suppressed under pain induced by formalin, accompanied by increase of preprodynorphin mRNA levels in the nucleus accumbens, a high dose of (±)-pentazocine produced significant rewarding effects under pain. In the normal condition, (±)-pentazocine-induced rewarding effects were blocked by a low dose of naloxone, whereas the rewarding effects induced by high doses of pentazocine under pain were suppressed by naltrindole (a δ-opioid receptor antagonist). Interestingly, (±)-pentazocine did not significantly affect dopamine levels in the nucleus accumbens. These findings suggest that the rewarding effects of (-)-pentazocine may contribute to the abuse potential of (±)-pentazocine through µ- as well as δ-opioid receptors, without robust activation of the mesolimbic dopaminergic system. We also found that neural adaptations can reduce the abuse potential of (±)-pentazocine under pain.

Reinforcement of pimobendan with guideline-directed medical therapy may reduce the rehospitalization rates in patients with heart failure: retrospective cohort study.

BACKGROUND: Pimobendan reportedly improves the subjective symptoms of heart failure. However, evidence of improved prognosis is lacking. This study aimed to determine whether reinforcing guideline-directed medical therapy (GDMT) improved rehospitalization rates for worsening heart failure in patients administered pimobendan. METHODS: A total of 175 patients with heart failure who were urgently admitted to our hospital for worsening heart failure and who received pimobendan between January 2015 and February 2022 were included. Of the 175 patients, 44 were excluded because of in-hospital death at the time of pimobendan induction. The remaining 131 patients were divided into two groups, the reduced ejection fraction (rEF) (n = 93) and non-rEF (n = 38) groups, and further divided into the GDMT-reinforced and non-reinforced groups. RESULTS: In patients with rEF, the rate of rehospitalization for heart failure was significantly lower in the GDMT-reinforced group than in the non-reinforced group (log-rank test, P = .04). However, the same trend was not observed in the non-rEF group. CONCLUSIONS: Reinforcing GDMT may reduce the heart failure rehospitalization rate in patients with pimobendan administration and rEF. However, multicenter collaborative research is needed. TRIAL REGISTRATION: IRB Approval by the Nippon Medical School Hospital Ethics Committee B-2021-433 (April 10, 2023).

Impact of polypharmacy on 3-year mortality in patients with heart failure: a retrospective study.

BACKGROUND: Guideline-directed medical therapy (GDMT) is important in heart failure management; however, polypharmacy itself may impact heart failure. Although measures against polypharmacy are needed, current discussion on unilateral drug tapering (including the drugs that should be tapered) is insufficient. In this study, we investigated the relationship between the number of prescribed GDMT drugs and prognosis in patients with heart failure. METHODS: In this single-centre retrospective study, 3,146 eligible patients with heart failure were included and divided into four groups based on the median number of prescribed GDMT drugs and the median number of drugs not included in the GDMT (ni-GDMT) at the time of hospital discharge. The definition of GDMT was based on various Japanese guidelines. The primary outcome was all-cause mortality within 3 years of hospital discharge. RESULTS: A total of 252 deaths were observed during the 3-year follow-up period. Kaplan-Meier analysis revealed that groups with GDMT drug count ≥ 5 and ni-GDMT drug count < 4 had the lowest mortality, and those with GDMT drug count < 5 and ni-GDMT drug count ≥ 4 had the highest mortality (log-rank, P < 0.001). Cox regression analysis revealed a significant association between ni-GDMT drug count and all-cause mortality, even after adjustment for number of GDMT medications, age, male, left ventricular ejection function < 40%, hemoglobin, albumin levels, and estimated glomerular filtration rate [HR = 1.06 (95% CI: 1.01-1.11), P = 0.020]. Conversely, the GDMT drug count was not associated with increased mortality rates. CONCLUSIONS: The ni-GDMT drug count was significantly associated with 3-year mortality in patients with heart failure. Conversely, the GDMT drug count did not worsen the prognosis. Polypharmacy measures should consider ni-GDMT drug quantity to improve the prognosis and outcomes in patients with heart failure.

Prescription factors influencing baloxavir prescription during the 2018/2019 and 2019/2020 seasons: a administrative database study in Japan.

BACKGROUND: We aimed to evaluate the factors associated with baloxavir prescription in Japanese hospitals using a health insurance claim-based database (MDV analyzer), during the 2018/2019 and 2019/2020 influenza seasons. The MDV analyzer contains anonymized claims data from approximately 420 Diagnosis Procedure Combination hospitals, and does not contain data from clinics. METHODS: Data were collected for influenza patients treated with anti-influenza drugs during the 2018/2019 and 2019/2020 influenza seasons. Multivariate analysis was used to identify factors associated with baloxavir prescription. RESULTS: During the study period, 322,063 influenza patients were included for analyses. In multivariate analysis, children, female sex, inpatient, hospital bed capacity, and private hospitals were negatively associated with baloxavir prescription. Compared to elderly patients, the adjusted odds ratio (OR) for baloxavir prescription was 0.612 (95% confidence interval (CI), 0.587-0.637) in children aged 6-11 years, and 0.119 (95% CI, 0.111-0.128) in children aged 0-5 years. Compared to small hospitals (bed capacity, 20-299), the adjusted OR for baloxavir prescription was 0.559 (95% CI, 0.540-0.578) in large hospitals (bed capacity, ≥ 500). CONCLUSION: Children, female sex, inpatient, hospital bed capacity, and private hospitals were negatively associated with baloxavir prescription.

Acetaminophen-induced hypotension in sepsis.

BACKGROUND: Acetaminophen-induced hypotension has been reported in critically ill patients; however, it remains unclear whether mannitol, present as a stabilizing compound in acetaminophen formulations, affects hemodynamic changes. The objectives of this study were to clarify the direct effect of acetaminophen on blood pressure by comparing blood pressure changes after acetaminophen and intravenous immunoglobulin (IVIG) administration, both containing mannitol, in patients with sepsis and understand the risk factors for reduced blood pressure following acetaminophen administration. METHODS: This was a retrospective cohort study. Adult patients who were diagnosed with sepsis at Nippon Medical School Hospital, and who were undergoing continuous arterial blood pressure measurement and received intravenous acetaminophen or IVIG, were included. RESULTS: Overall, 185 patients were included, with 92 patients in the IVIG group and 93 in the acetaminophen group. The incidence of hypotension was 36.9% in the IVIG group (34 of 92 patients) and 58.0% in the acetaminophen group (54 of 93 patients) (OR = 8.26, p = 0.004). In a propensity score-matched cohort, 80 matched patients were selected. The incidence of hypotension was 37.5% in the IVIG group (15 of 40 patients) and 67.5% in the acetaminophen group (27 of 40 patients) (OR = 7.21, p = 0.007). CONCLUSIONS: Acetaminophen induced substantially greater hypotension than IVIG in patients with sepsis, with both containing mannitol. Further studies are needed to clarify the effects on hemodynamics of mannitol contained in acetaminophen formulations.

[Cost-effectiveness analysis comparing carboplatin and weekly paclitaxel with cisplatin and docetaxel in the treatment of advanced non-small cell lung carcinoma].

Carboplatin plus weekly paclitaxel (CBDCA/wPTX) and cisplatin plus docetaxel (CDDP/DTX) are the standard regimens used in the first-line treatment of advanced non-small cell lung carcinoma (NSCLC), with no significant difference in efficacy between the two. However, because there has been no study of the cost-effectiveness of CBDCA/wPTX versus CDDP/DTX to data, we compared these two regimens in the present study. Expected costs were calculated based on data from patients with Stage III b/IV NSCLC who were treated with either CBDCA/wPTX or CDDP/DTX in the Nippon Medical School Hospital. Efficacy (1-year survival rate) was determined by pooled analysis of studies extracted from the database. The cost-effectiveness ratio was calculated from expected costs and 1-year survival rates for both the CBDCA/wPTX and CDDP/DTX regimens. The expected costs per patient of the CBDCA/wPTX and CDDP/DTX regimens were ¥2, 847, 514 and ¥3, 513, 195, respectively, with 1-year survival rates of 38.6% and 42.5%, respectively. Thus, the cost-effectiveness ratio for the CBDCA/wPTX and CDDP/DTX regimens is ¥6, 750, 863 and ¥8, 329, 054, respectively. These findings clearly suggest that, CBDCA/wPTX is a more cost-effective regimen than CDDP/DTX.

Anticoagulant activity of apixaban can be estimated by multiple regression analysis.

BACKGROUND: Information on apixaban anticoagulant activity is required to prevent major bleeding or thrombosis during its use. METHODS: We enrolled 194 patients with nonvalvular atrial fibrillation (NVAF) in whom warfarin was replaced with apixaban: 105 (54.1%) received the standard dose of apixaban (5 mg twice daily [BID]; 5 mg group) and 89 (45.9%) received a reduced dose (2.5 mg BID; 2.5 mg group). Multiple regression analysis was performed to predict the prothrombin time of apixaban (PTa) based on factors including age, body weight (BW), serum creatinine, and CHA2DS2-VASc score. RESULTS: PTa and PT of warfarin (PTw) were significantly correlated in both groups (correlation coefficient R = 0.239 [P = .014] in the 5 mg group; R = 0.248 [P = .019] in the 2.5 mg group). PTa in the 5 mg group was predicted as follows: 16.952-0.036 × BW +0.299 × CHA2DS2-VASc score (P < .0004; R = 0.378). However, in the 2.5 mg group, PTa could not be predicted. The mean of the predicted and measured PTa values in the 5 mg group was 15.6 s, which was similar to the mean measured PTa of 15.5 s in the 2.5 mg group. CONCLUSIONS: PT can be predicted by a formula including simple clinical parameters in patients receiving the standard dose of apixaban. This simple predictive formula may help to stratify bleeding and thrombosis risks in patients treated with apixaban.

A Self-Check Program Targeting Quality Improvement in a Hospital-Based Palliative Care Consultation Team, Japanese Society for Palliative Medicine: Issues Regarding Team Activities Identified through the Plan-Do-Check-Act Cycle.

Background: The number of hospital-based palliative care consultation teams (PCCTs) has increased in Japan, and quality improvement (QI) of PCCTs is an issue. The Japanese Society for Palliative Medicine is building a framework for continuous QI of PCCT activities. Objective: The objective of this study was to develop a program to support QI for PCCTs, and to describe the initial experience with the program. Design: The report details the development of a self-check program, followed by a one-year follow-up observational survey. Methods: We developed a self-check program using the concept of the Plan-Do-Check-Act (PDCA) cycle and a multidisciplinary expert panel. A total of 114 PCCTs entered the program in the first year. Results: We developed three forms for the CHECK, ACT-PLAN, and DO phases aligned with the PDCA cycle. The forms consisted of 34 items across 8 domains. A total of 83 PCCTs (729 members) returned the CHECK, ACT-PLAN forms, and 41 PCCTs returned the DO forms after one year. Overall, 213 high priority issues were identified in the ACT phase. The issues of many PCCTs were "Sharing goals of care is inadequate within the PCCT (33%)" and "Sharing goals of care is inadequate between patient/family or primary team and the PCCT (28%)." Improvements in identified issues were: "achieved" 23% and "almost achieved" 48% after one year. Conclusions: We developed a self-check program to support QI efforts for hospital-based PCCTs. The priority issues among PCCTs and improvement goals with examples were identified. These results will support ongoing efforts to develop a continuous improvement model for QI of PCCTs.

Acute Kidney Injury in Non-Intensive Care and Intensive Care Patients Treated with Vancomycin and Piperacillin-Tazobactam.

BACKGROUND: We investigated the incidence of acute kidney injury (AKI) and risk factors associated with vancomycin (VAN) and piperacillin-tazobactam (TZP) combination therapy in non-intensive care unit (ICU) and ICU settings. METHODS: In this single-center retrospective cohort study, adults who received VAN for ≥48 h during the period from 1 January 2016 through 31 December 2017 were included. The primary endpoint was incidence of AKI. RESULTS: Data from 593 adults were analyzed. The incidence of AKI was 10.6% overall, 8.0% in the non-TZP group, and 19.8% in the TZP group. In univariate analysis, the odds ratio (OR) for AKI was higher in the TZP group than in the non-TZP group (2.84, 95% CI = 1.64-4.90). In both the non-ICU and ICU settings, the OR for AKI was higher in the TZP group than in the non-TZP group (non-ICU: OR = 3.04, 95% CI = 1.52-6.09; ICU: OR = 2.51, 95% CI = 1.03-6.08). Furthermore, in propensity score analysis, the OR for AKI was higher in the TZP group than in the non-TZP group (OR = 2.81, 95% CI = 1.52-5.17). In both the non-ICU and ICU settings, the OR for AKI was higher in the TZP group than in the non-TZP group (non-ICU: OR = 2.57, 95% CI = 1.17-5.64; ICU: OR = 3.51, 95% CI = 1.05-11.6). CONCLUSIONS: Combined use of TZP in patients receiving VAN increased AKI incidence in non-ICU and ICU settings.

[Survey of the drugs remaining in the diskhaler and investigation of cleaning of fluticasone propionate].

When a fluticasone propionate (FP) diskhaler is used to administer inhaled corticosteroid, it has been reported that there is considerable drug residue remaining in the diskhaler after use. The internal structure of the diskhaler is complex, and it is possible that sufficient cleaning of the device is not achieved using the attached brush. In this study, the diskhaler cleaning method was examined using a patient questionnaire. In response to the question on cleaning, 56.3% of patients responded "Having done", and 66.7% responded to the question on the frequency of the cleaning, "When I use it". Furthermore, cleaning by a healthy volunteer was examined using Rotadisk for inhalation practice. When the group that did not perform cleaning was compared with the group that performed cleaning with the brush, the amount of the lactose adhesion was significantly lower in the cleaning group. When the no-cleaning group was compared with the group that shook off the excess residue from the tray and the main body of the diskhaler, the group that shook off the diskhaler components showed a significantly lower amount of lactose adhesion. It was confirmed that drug residue were able to accumulate, and the shaking off method appeared to have an effect equal to that of cleaning with the brush. It seems that providing patients with guidance not only about the method of inhaling with the diskhaler but also about cleaning of the device is an important area of pharmacy patient management.

[Cost-effective analysis of rotation from sustained-release morphine tablet to transdermal fentanyl of matrix type or sustained-release oxycodone tablet].

The present study was undertaken to determine the pharmacoeconomics of switching from sustained-release morphine tablet to matrix type (MT) of transdermal fontanel or sustained-release Oxycodone tablet. Cost-effective analysis was performed using a simulation model along with decision analysis. The analysis was done from the payer's perspective. The cost-effective ratio/patient of transdermal MT fontanel (22, 539 yen)was lower than that of sustained -release Oxycodone tablet (23, 630 yen), although a sensitivity analysis could not indicate that this result was reliable. These results suggest the possibility that transdermal MT fontanel was much less expensive than a sustained-release Oxycodone tablet.

Pharmacokinetic and pharmacodynamic studies of pregabalin suppositories based on pharmacological research.

OBJECTIVES: As commercially available pregabalin preparations are limited to oral administration, it is impossible to use it as an adjuvant analgesic for neuropathic cancer-related pain in terminally ill cancer patients with oral feeding difficulties. The objective of this study was to develop a pregabalin suppository to be available at hospitals. METHODS: Pregabalin suppositories were prepared using bases comprising six different compositions of Witepsol H-15, Witepsol S-55, and Witepsol E-75. The suppository release test and stability test were performed in vitro. The pharmacokinetics and pharmacodynamics of the suppositories were assessed in rats. KEY FINDINGS: In the in vitro releasing test, the pregabalin suppositories with H-15, H-15 : S-55 = 1 : 1, H-15 : S-55 = 2 : 1, H-15 : S-55 = 1 : 2 released approximately 100% of the pregabalin within 180 min. Among these pregabalin suppositories, only the suppository with H-15 : S-55 = 2 : 1 demonstrated an equivalent AUC0-∞ with the oral administration group. Consistent with the results of the pharmacokinetic study, the pregabalin suppository with H-15 : S-55 = 2 : 1 exhibited antinociceptive effects. In addition, the pregabalin suppository with H-15 : S-55 = 2 : 1 was stable for 12 weeks when refrigerated with light shielding. CONCLUSIONS: The pregabalin suppositories prepared in this study may be applicable for pain control for terminally cancer ill patients with oral feeding difficulties.

Contributions of pharmacists through the promotion of proper drug use.

The contents of pharmacist interventions, which were carried out by the ward pharmacists in their routine pharmacy service activities, were sorted and analyzed to evaluate the contributions of pharmacists. In the ward where pharmacists were stationed, there were a total of 196 cases of pharmacist intervention. The prescription was changed in 170 cases, giving a rate of prescription change of 86.7%. The breakdown of the pharmacist intervention was as follows: "efficacy/safety", 106 cases, followed by "dosage regimen" (48 cases) and "compliance" (10 cases). Cost savings achieved during the investigation period were calculated to be 440,639 yen, and cost avoidance was valued at 1,941,847-3,883,695 yen using the Diagnosis Procedure Combination (DPC). The results of the present investigation showed that pharmacists contribute to through not only their pharmacy services, but also through the promotion of proper drug use and risk management, thereby contributing to hospital management through cost savings and avoidance.

A Drug Interaction between Crizotinib and Warfarin in Non-Small-Cell Lung Cancer: A Case Report.

We report a case of increased prothrombin time-international normalized ratio (PT-INR) when crizotinib and warfarin were co-administered. A 74-year-old Japanese woman presented to the hospital with dyspnea, and was diagnosed with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). Three years after surgical resection of the tumor, the patient started crizotinib because of the recurrence of NSCLC. She received 2 mg/day warfarin due to a medical history of cerebral infarction and chronic atrial fibrillation. Before crizotinib initiation, the patient's PT-INR was 2.60. After 7 days of daily doses of crizotinib, the patient's PT-INR increased to 3.65. This case report provides the first evidence of a drug interaction between crizotinib and warfarin.

Pregabalin prescription for terminally ill cancer patients receiving specialist palliative care in an acute hospital.

BACKGROUND: Pregabalin is recommended as an adjuvant analgesic for neuropathic cancer-related pain, and may be taken at all steps of the World Health Organization analgesic ladder. However, unlike opioids, pregabalin treatments are limited to an oral administration route. If patients have oral feeding difficulties, it is not possible to administer any drug as an adjuvant analgesic for neuropathic cancer-related pain. Therefore, the aim of the present study was to clarify the problems of pain control after pregabalin discontinuation in terminally ill cancer patients. METHODS: Our subjects comprised cancer patients who died during their hospital stay and were referred between April 2013 and October 2015 to the palliative care team of the 899-bed Cancer Hospital at the Nippon Medical School Hospital in Japan. The medical records of each patient were retrospectively reviewed, and patient characteristics were recorded. RESULTS: We obtained data on 183 patients during the study period. Thirty-eight (20.8 %) patients were treated with pregabalin. Thirty-three (86.8 %) out of 38 patients were prescribed pregabalin for neuropathic cancer-related pain. The incidence of bony metastases was significantly higher in patients administered pregabalin than in those not taking the drug (non-pregabalin group 32.4 % vs pregabalin group 57.9 %). Pregabalin was ultimately discontinued in all patients, with the main reason being oral feeding difficulties (81.6 %). After the discontinuation of pregabalin, the amount of opioid drugs administered was increased in 56.5 % of patients with oral feeding difficulties. CONCLUSION: Our results demonstrated that the amount of opioid drugs administered was increased in more than 50 % of patients following the discontinuation of pregabalin, and was repeatedly increased for some patients. A new administration route is required for cancer patients unable to take oral medication. TRIAL REGISTRATION: UMIN000022507. May 28, 2016 retrospectively registered.

Direct evidence for the involvement of the mesolimbic kappa-opioid system in the morphine-induced rewarding effect under an inflammatory pain-like state.

Recent clinical studies have demonstrated that when morphine is used to control pain in cancer patients, psychological dependence is not a major concern. The present study was undertaken to ascertain the modulation of psychological dependence on morphine under a chronic pain-like state in rats. The prototypical mu-opioid receptor agonist morphine (8 mg/kg, i.p.) induced a dose-dependent place preference. In the present study, we found that an inflammatory pain-like state following formalin injection significantly suppressed the morphine-induced rewarding effect. This effect was almost reversed by s.c. pretreatment with the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI, 5 mg/kg). Furthermore, the morphine-induced increase in dopamine (DA) turnover in the limbic forebrain was significantly inhibited by treatment with formalin. This inhibition was also suppressed by pretreatment with nor-BNI. In addition, in vivo microdialysis studies clearly showed that the morphine-induced increase in the extracellular levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in the nucleus accumbens (N.Acc.) was significantly decreased in rats that had been pretreated with formalin. This effect was in turn reversed by the microinjection of a specific dynorphin A antibody into the N.Acc. These findings suggest that the inflammatory pain-like state induced by formalin injection may have caused a sustained activation of the kappa-opioidergic system within the N.Acc., resulting in suppression of the morphine-induced rewarding effect in rats. The present study provides further evidence of the clinical usefulness of morphine in patients suffering from severe pain.

Modulation of kappa-opioidergic systems on mecamylamine-precipitated nicotine-withdrawal aversion in rats.

The present study was designed to examine the modulation of the kappa-opioidergic system on mecamylamine-precipitated nicotine-withdrawal aversion. The nicotinic receptor antagonist mecamylamine, which is known to pass the blood-brain barrier, produced a place aversion in rats chronically treated with nicotine using an osmotic mini-pump. This effect was significantly attenuated by pretreatment with -opioid receptor agonists U50,488H (1.0 mg/kg, s.c.) and TRK-820 (0.03 mg/kg, s.c.). The attenuation of mecamylamine-precipitated nicotine-withdrawal aversion by U50,488H was completely reversed by the combination with a selective -opioid receptor antagonist nor-binaltorphimine (10.0 mg/kg, i.p.). These results suggest that the activation of endogenous -opioidergic systems can suppress the mecamylamine-precipitated nicotine-withdrawal aversion.

Change in the expression of c-fos in the rat brain following sciatic nerve ligation.

A little or none is known about the direct evidence for the possible change in the expression of c-fos at the supraspinal level after nerve injury. Therefore, the present study was designed to investigate the level of c-fos in some brain regions following sciatic nerve ligation in the rat. Immunoblot analysis clearly showed that the levels of c-fos in the rat frontal cortex, thalamus and periaqueductal gray matter were significantly increased, whereas it was significantly decreased in the nucleus accumbens and ventral tegmental area. Under these conditions, the levels of c-fos in the rat amygdala, hippocampus and hypothalamus were not changed. These results provide direct evidence that the neuropathic pain-like state causes a substantial change in the expression of c-fos in the rat brain.