ABCB1 genetic polymorphisms affect opioid requirement by altering function of the intestinal P-glycoprotein.

The association between polymorphisms of the human ATP binding cassette subfamily B member 1 (ABCB1) gene and opioid response has attracted intense attention recently. As the ABCB1 gene encodes for the transporter P-glycoprotein in the brain and intestine involved in the pharmacokinetics of opioids, we investigated the effects of ABCB1 genetic polymorphisms on doses of opioids for pain relief and determined which pharmacokinetic process was affected in cancer pain patients. Sixty-eight cancer pain patients admitted for intrathecal therapy (ITT) were included. The association between ABCB1 genetic polymorphisms (C3435T, C1236T, G2677T/A and A61G) and systemic doses of opioids before ITT were investigated. Concentrations of oxycodone in plasma and cerebrospinal fluid (CSF) were determined by HPLC-MS/MS in 17 patients treated with oral oxycodone before ITT, and the influences of ABCB1 genetic polymorphisms on plasma-concentration to oral-dose ratios and CSF-concentration to plasma-concentration ratios of oral oxycodone were further analyzed. ABCB1 C3435T and G2677T/A polymorphisms were significantly associated with systemic doses of opioids before ITT, which coincided with the influences of ABCB1 C3435T and G2677T/A polymorphisms on the ratios of plasma-concentration to oral-dose. However, no significant difference was found in ratios of CSF-concentration to plasma-concentration among ABCB1 SNP genotypes. The present study provided the first evidence that ABCB1 C3435T and G2677T/A polymorphisms affect opioid requirement in cancer pain patients via altering transportation function of P-glycoprotein in the intestine, which will further expand our knowledge about pharmacokinetics of opioids and could contribute to the individualization of opioids use.

Pain Physicians' Attitudes and Experiences Regarding Clinical Pharmacy Services in China: A National Cross-Sectional Survey.

Purpose: Pharmacists are key members of the pain management interdisciplinary team in many developed countries. However, the implementation of clinical pharmacy services in pain management is impeded by the imbalance between the pain physicians and clinical pharmacists specializing in pain management in China. The purpose of this study was to elucidate the perceptions, expectations and current experience of Chinese pain physicians regarding clinical pharmacy services. Patients and Methods: An anonymous, self-administered questionnaire was designed according to previously published studies with minor modifications and distributed online to 1100 pain physicians selected randomly in hospitals across all 31 provinces of mainland China in 2021. Data were analyzed using descriptive and inferential statistics. Results: A total of 1071 valid questionnaires were included for analysis. The pain physicians were from all 31 provinces of mainland China and most of them were from tertiary hospitals holding an undergraduate degree. Among listed kinds of clinical pharmacy services, pain physicians were less comfortable with pharmacists treating minor illnesses (p < 0.001). Pain physicians' experiences with clinical pharmacy services were far less than their expectations (p < 0.001), which is in line with the results that most of pain physicians (65.9%) interacted with pharmacists at a frequency of less than once a week. Significant differences in the experiences were found among ages (p < 0.01) and among years of work experience (p < 0.05) of pain physicians. Pain physicians' expectations of pharmacists were positively correlated with their experiences with clinical pharmacy services (p < 0.001). Conclusion: Pain physicians in China had positive perceptions and high expectations, but relatively low experiences regarding clinical pharmacy services. Expanding clinical pharmacist pain management credentialing and increasing pain physicians' exposure to clinical pharmacy services are favourable to support the interdisciplinary collaboration in pain management in China.

Comparison of external system and implanted system in intrathecal therapy for refractory cancer pain in China: A retrospective study.

INTRODUCTION: Intrathecal therapy (ITT) via an implanted system was demonstrated for the treatment of refractory cancer pain for decades. Recently, the dissemination of ITT is enhanced in an external system way in Asia for a lower implantation cost. This study compares the efficacy, safety, and cost of the two ITT systems in refractory cancer pain patients in China. METHODS: One hundred and thirty-nine cancer pain patients who underwent implantation of the ITT system were included. One hundred and three patients received ITT via the external system (external group), while 36 patients received ITT via the implanted system (implanted group). A 1:2 propensity score matching procedure was used to yield a total of 89 patients for the final analysis. Medical records of included patients were retrospectively reviewed and pain scores, incidences of complications, and costs were compared. RESULTS: ITT via the external system provided pain relief as potent as ITT via the implanted system but was less time-consuming in the implantation phase (13 vs. 19 days, p < .01). Nausea/vomiting and urinary retention were the most frequent adverse events in both external and implanted groups (32.14%, 16.07% vs. 36.36%, 21.21%). No significant difference was found in the incidences of all kinds of complications. Compared to the implanted group, the external group cost less for the initial implantation (7268 vs. 26,275 US dollar [USD], p < .001) but had a significant higher maintenance cost (606.62 vs. 20.23 USD calculated monthly, p < .001). CONCLUSIONS: ITT via the external system is as effective and safe as that via the implanted system and has the advantage of being cheap in the upfront implantation but costs more during the maintenance process in China.

Pharmacist-led olaparib follow-up service for ambulatory ovarian cancer patients: A prospective study in a tertiary specialized cancer hospital in China.

Purpose: To establish a pharmacist-led olaparib follow-up program for ovarian cancer patients, provide patient education, get information on adverse drug reactions (ADRs), and identify and manage drug-related problems. Methods: Ambulatory adult patients with ovarian cancer receiving olaparib were enrolled. At least one follow-up session was conducted by clinical pharmacists. Pharmacists collected data on the type and grade of ADRs, drug adherence, olaparib dosing, concomitant medications, and pharmacists' suggestions. Results: 83 patients were enrolled with the median age of 58. The average number of the follow-up sessions provided to each patient was 1.31, and the average duration of each follow-up was 17.78 min. The olaparib starting dose for most patients (97.59%) was 600 mg/d. 36.14% of the patients had missed olaparib doses and 27.71% of the patients had dose adjustments due to ADRs. The most common ADRs (incidence≥10%) were: fatigue (40.96%), anemia (36.14%), leukopenia (36.14%), nausea (28.92%), thrombocytopenia (16.87%), anorexia (16.87%), dyspepsia (15.66%). The tolerability profiles were generally similar between patients treated for "first-line maintenance" and those treated for "recurrence maintenance" (p > .05). There were 42% of the patients who were concomitantly taking medications without exact chemical contents (such as formulated Chinese medicines and Chinese decoctions), and common types of concomitant medications with exact drug names were antihypertensive, anti-hyperglycemic, and anti-hyperlipidemic medications. The pharmacists identified 4 clinically significant drug-drug interactions (DDIs) in two patients. Pharmacists made 196 suggestions mainly related to rational use of the medications and management of ADRs. Conclusion: The study provides the first report about pharmacist-led follow-up service for olaparib. The types of ADRs were similar to those previously observed in clinical trials, and the profiles of ADRs in different types of patients (first-line maintenance vs. recurrence maintenance) were also similar. Pharmacists identified drug-related problems (such as adherence, DDIs and management of ADRs) and offer suggestions for the patients.

Effect of Continuing Nursing Education on the Quality of Nursing Management of Cancer Pain in China.

BACKGROUND: Limited knowledge and poor attitudes toward pain are major barriers to nursing management of cancer pain. This study investigated the effect of continuing nursing education (CNE) on the management of cancer pain. METHOD: Annual CNE was provided from 2016 to 2019, and evaluation of nursing management of cancer pain was conducted every 2 years. The effect of CNE was determined based on the evaluation results. RESULTS: After annual CNE, the participating hospitals showed significant improvement in nursing management of cancer pain. Annual CNE significantly increased subscores in all domains except the domain of initial pain assessment. In terms of hospital levels, nursing management of cancer pain was significantly improved only for tertiary A hospitals. CONCLUSION: Annual CNE significantly improved nursing management of cancer pain. [J Contin Educ Nurs. 2021;52(11):535-540.].

Clinical profile of acute pancreatitis following treatment with protease inhibitors: a real-world analysis of post-marketing surveillance data.

BACKGROUNDS: Acute pancreatitis (AP) has been reported in patients treated with protease inhibitors (PIs), but there are few real-world studies comparing the occurrence and characteristics of AP after different PI regimens. RESEARCH DESIGN AND METHODS: Disproportionality analysis and Bayesian analysis were utilized for data mining of the Food and Drug Administration's Adverse Event Reporting System (FAERS) database for suspected adverse events involving AP after PI. The times to onset and fatality rates of AP following different PI regimens were also compared. RESULTS: Based on 33,832 reports related to PIs, 285 cases were associated with AP, involving with 12 out of the 15 studied PIs. Of all the reported AP events related to PIs, 64.56% occurred in men and the median time to onset of AP was 103 (IQR: 26-408) days after the initiation of PI treatment with a fatality rate of 14.02%. Among all PI therapies, indinavir was notably associated with AP, and ritonavir and lopinavir/ritonavir-induced AP cases appeared to be associated with a higher risk of death. CONCLUSIONS: Most of PIs were associated with AP-related adverse events, among which indinavir has a stronger association with AP but there is no significant difference in fatality rates.

Impact of Continuing Medical Education for Physicians on the Quality of Cancer Pain Treatment in China.

CONTEXT: The management of cancer pain has gained attention in China since the proposal of the three-step analgesic ladder in 1986 and has been further improved after the Chinese Ministry of Health launched the campaign for "Good Pain Management Ward" in 2011. The Beijing Pain Management Center for Quality Control and Improvement was formed with the intent to improve the quality of pain management by various means such as providing continuing medical education (CME) and conducting evaluation in Beijing, the capital of China. OBJECTIVES: The objective of this study was to investigate the impact of CME on cancer pain treatment in hospitals in Beijing, China. METHODS: The Beijing Pain Management Center for Quality Control and Improvement carried out annual CME on cancer pain treatment for physicians in Beijing in February from 2016 to 2019. The quality of cancer pain treatment in these hospitals was evaluated in August 2015, 2017 and 2019 by using an evaluation instrument containing eight domains. The evaluation results were retrospectively reviewed to assess the impact of CME. RESULTS: After annual CME for four successive years, a significant increase in evaluation scores for cancer pain treatment was observed in the participating hospitals. The increased trend varied widely both among the levels of hospitals (secondary and two tiers of tertiary hospitals) and among evaluation domains. These hospitals scored lowest in domains related to opioid tolerance, ongoing care, and risk of nonsteroidal anti-inflammatory drugs in the last evaluation. CONCLUSION: CME significantly improved the quality of cancer pain treatment in the participating hospitals. Thus, standard CME courses may be adopted to improve the quality of cancer pain treatment by other regions in China and other countries.

Possible mechanism and potential application of anti-opioid effect of diazepam-binding inhibitor.

AIMS: Our previous study has demonstrated that porcine diazepam-binding inhibitor (pDBI) and its active fragments, pDBI-16 and pDBI-19, have inhibition effect on morphine analgesia in mice. The present study aimed to investigate the underlying mechanism and potential application of this anti-opioid effect. MATERIALS AND METHODS: Effect of DBI on morphine analgesia was examined by the tail electric stimulation vocalization test. Complementary peptides and antiserum were used to further confirm the effect of DBI in morphine tolerance and dependence. Pharmacological and microinjection methods were used to investigate the underlying mechanism. KEY FINDINGS: Firstly, pDBI administered either intracerebroventricularly or intravenously dose-dependently inhibited morphine analgesia, while blocking DBI-16 or DBI-19 by the complementary peptides for DBI-16 (CP-DBI-16) or DBI-19 (CP-DBI-19) potentiated it in mice. Secondly, explicit immunoexpression of DBI in the lateral habenular (LHb) was observed in naive rats, and intra-LHb injection of pDBI dose-dependently abolished analgesic effect produced by intra-periaqueductal gray (PAG) injection of morphine in rats. Thirdly, pretreatment with N-Methyl-d-Aspartate receptor (NMDAR) antagonist MK-801 or nitric oxide (NO) synthase inhibitor L-NAME abolished the inhibition effect of pDBI, pDBI-16 or pDBI-19 on morphine analgesia in mice. Finally, antiserum against DBI dose-dependently reversed analgesic tolerance induced by increasing doses of morphine twice daily for 13 days in mice, while CP-DBI-16 or CP-DBI-19 significantly inhibited naloxone-precipitated morphine withdrawal jumping in mice. SIGNIFICANCE: Taken together, our results demonstrated that NMDAR/NO signaling and LHb-PAG pathway are crucially involved in the anti-opioid effect of DBI, which could provide a potential biological target for opioid tolerance and dependence.

Intrathecal Morphine Infusion Therapy via a Percutaneous Port for Refractory Cancer Pain in China: An Efficacy, Safety and Cost Utilization Analysis.

PURPOSE: Intrathecal morphine infusion therapy via a percutaneous port (IMITPP) has been used widely for its relatively low initial cost. However, there is scarce knowledge about IMITPP. In this study, we sought to evaluate efficacy, complications, and the interval required to achieve the cost equivalence of IMITPP in patients with refractory cancer pain in China. PATIENTS AND METHODS: A retrospective chart review was conducted on cancer patients who had received IMITPP at our hospital between April 2017 and April 2019. Data from the numeric pain rating scale and Karnofsky performance scores, and complications and costs related to IMITPP were collected from medical records. Daily analgesic costs before and after IMITPP were calculated based on the doses of opioids on admission and at discharge, respectively. The doses of systemic opioids before IMITPP were stratified into very high doses [VHD, oral morphine equivalent dose (OMED) >599 mg/day], high doses (HD, 300 mg/day ≤ OMED ≤ 599 mg/day), and regular doses (RD, OMED < 300 mg/day). RESULTS: Intrathecal morphine infusion therapy via a percutaneous port provided significant pain relief, but impaired activities of daily living in patients with refractory cancer pain. The commonly reported complications included nausea/vomiting and urinary retention, most of which were managed with symptomatic therapies. The median interval required to achieve cost equivalence was 11.44 months. The median intervals of VHD group and HD group were significantly shorter than that of RD group. CONCLUSION: Intrathecal morphine infusion therapy via a percutaneous port provided effective cancer pain management without causing serious complications. Patients with higher doses of systemic opioids would economically benefit from IMITPP in a shorter time.

Interlaboratory analysis of teicoplanin plasma concentration assays among Chinese laboratories.

WHAT IS KNOWN AND OBJECTIVE: Teicoplanin is widely used for the treatment of infections caused by drug-resistant Gram-positive bacteria. Since there is a good correlation between trough levels and clinical outcome, therapeutic drug monitoring (TDM) is recommended to achieve better clinical curative effects. However, TDM of teicoplanin is not routine in China. So, a programme was initiated in 2017, including both HPLC method establishment and interlaboratory quality assessment, for the measurement of teicoplanin. METHODS: A main centre and a quality control centre were set up in the study. An HPLC-based method of teicoplanin determination in plasma was developed by the main centre. Analysis was performed using a Waters Symmetry C18 column (250 mm × 4.6 mm, 5 µm). The mobile phase was NaH2 PO4 (0.01 mol/L) and acetonitrile (75:25 v/v; pH 3.3), with a flow rate of 1.0 mL/min and a detection wavelength of 215 nm. Piperacillin sodium was selected as an internal standard (IS). Twenty-six additional TDM centres were then recruited to adopt this method. Then, all the centres were asked to take part in a quality control assessment evaluated by the quality control centre. RESULTS: For all TDM centres, linearity of teicoplanin concentration ranges was between 3.125 and 100 µg/mL. Intraday and interday accuracies ranged from 87.1% to 118.4%. Intraday and interday precision ranged from 0.3% to 13.8%. Therapeutic drug monitoring centres all passed inter-room quality assessment. All samples tested met the acceptance criteria. Then, 542 samples were collected. Patients with sub-optimal (≤10 mg/L) plasma teicoplanin concentrations constituted 42% of the total study population. WHAT IS NEW AND CONCLUSIONS: For the first time, a simple, rapid and accurate HPLC method for determining teicoplanin levels was successfully applied to therapeutic drug monitoring in clinical practice for twenty-seven TDM centres in China. The results demonstrated excellent interlaboratory agreement for teicoplanin testing and provide support for clinical laboratory quality management and results inter-accreditation.

Effect of heat shock protein 70 modulators on the development of morphine analgesic tolerance in rats.

The clinical use of opioid analgesics, such as morphine, is limited by analgesic tolerance, molecular mechanism of which is not well understood. Recently, molecular chaperone heat shock protein 70 (Hsp70) has been demonstrated to play important roles in morphine-induced neuroadaptation. Here, we focused on the involvement of Hsp70 in the development of analgesic tolerance to morphine. Rats were treated with morphine (5, 10, 20 mg/kg, subcutaneously) or saline once daily for 10 consecutive days. Hsp70 modulator N-formyl-3, 4-methylenedioxybenzylidine-γ-butyrolactam [KNK437, 100 mg/kg, intraperitoneally (i.p.)], geranylgeranylacetone (500 mg/kg, i.p.) or pifithrin-µ (20 mg/kg, i.p.) was administered before morphine (10 mg/kg, subcutaneously)/saline treatment. Analgesic effect of morphine was measured using the tail-flick latency test, and Hsp70 protein expression was examined by western blot. Analgesic effect of morphine decreased gradually with the increase in the number of days of morphine injection, indicating development of analgesic tolerance. A significant increase of Hsp70 expression in the periaqueductal gray was observed during the development of analgesic tolerance after repeated morphine injections. The development of morphine analgesic tolerance was suppressed by pre-treatment with Hsp70 transcriptional inhibitor KNK437 or functional antagonist pifithrin-µ, while promoted by pre-treatment with Hsp70 transcriptional inducer geranylgeranylacetone. Our results demonstrated that the development of morphine analgesic tolerance was dual regulated by Hsp70 modulators, suggesting Hsp70 as an interesting and new target for preventing the development of opioid analgesic tolerance.

Super analgesia of intrathecal morphine may be related to ABCB1 (MDR1) gene polymorphism.

Intrathecal morphine provides superior analgesia and minimizes side effects with ~1/300th of the oral dose necessary to achieve this effect. The conversion ratios from oral route to intrathecal route vary greatly among individuals, and this may be related with polymorphisms of the ATP-binding cassette B1 (ABCB1)/multiple drug resistance 1 (MDR1) gene encoding the transporter P-glycoprotein in the blood-brain barrier. In the case presented herein, a patient with cancer pain for over 3 months was treated with oxycodone hydrochloride prolonged-release tablets (Oxycontin) and morphine hydrochloride tablets for breakthrough pain. The patient was admitted due to intolerable adverse effects of Oxycontin. During this admission, he was implanted with an intrathecal morphine pump which can deliver morphine into the cerebrospinal fluid. To our surprise, intrathecal morphine at a dose of ~1/540th of oral morphine equivalent dose produced complete analgesia. Our finding revealed homogenous CC at position 3435 (C3435T) in the ABCB1/MDR1 gene in this patient, which encodes P-glycoprotein with good efflux pump functionality. As intrathecal morphine bypasses the blood-brain barrier that oral medications have to pass through, the good pump functionality may have contributed to the super analgesia of intrathecal morphine in this case. Genetic analysis of ABCB1/MDR1 gene polymorphisms can be useful for personalized pain management in patients with intrathecal morphine pump.

Changes in intestinal microbiota affect metabolism of ginsenoside Re.

Ginsenoside Re, an active ingredient in Panax ginseng, is widely used as a therapeutic and nutriment. The intestinal microbiota plays crucial roles in modulating the pharmacokinetics and pharmacological actions of ginsenoside Re. The aim of this study was to explore the relationship between bacterial community variety and the metabolic profiles of ginsenoside Re. We developed two models with intestinal dysbacteriosis: a pseudo-germ-free model induced by a nonabsorbable antimicrobial mixture (ATM), and Qi-deficiency model established via over-fatigue and acute cold stress (OACS). First, the bacterial community structures in control, ATM and OACS rats were compared via 16S ribosomal RNA amplicon sequencing. Then, the gut microbial metabolism of ginsenoside Re was assessed qualitatively and quantitatively in the three groups by UPLC-Q-TOF/MS and HPLC-TQ-MS, respectively. Ten metabolites of ginsenoside Re were detected and tentatively identified, three of which were novel. Moreover, owing to significant differences in bacterial communities, deglycosylated products, as the main metabolites of ginsenoside Re, were produced at lower levels in ATM and OACS models. Importantly, the levels of these deglycosylated metabolites correlated with alterations in Prevotella, Lactobacillus and Bacteroides populations, as well as glycosidase activities. Collectively, biotransformation of ginsenoside Re is potentially influenced by regulation of the composition of intestinal microbiota and glycosidase activities.

Context- and time-dependent neurobiological and behavioral sensitization induced by a single morphine exposure in mice.

RATIONALE: Drug-induced sensitization in the mesocorticolimbic systems is thought to play an important role in certain aspects of drug addiction, including the involvement of drug-associated cues and environments in mediating drug-seeking behaviors. Our previous studies have identified the significance of heat shock protein 70 (Hsp70) in the development of a single morphine exposure-induced behavioral sensitization. OBJECTIVES: The present study expands upon these findings by investigating the effect of environment on the expression of behavioral sensitization induced by a single morphine exposure, and the potential involvement of Hsp70 protein levels in these effects. METHODS: Mice were pretreated with a single morphine injection in test chambers (morphine-paired) or home cages (morphine-unpaired) on day 1 and challenged on day 2 or 8, in test chambers. Hsp70 expression in the nucleus accumbens (NAc) was analyzed after the challenge. RESULTS: The expression of single morphine exposure-induced behavioral sensitization was accompanied by a significant increase in Hsp70 expression in NAc. In contrast, the unpaired morphine-treated group failed to exhibit behavioral sensitization or higher Hsp70 expression. Additionally, by adding a habituation process prior to the challenge, we demonstrated that conditioned hyperactivity, which was not accompanied by an increased expression of Hsp70, is not essential for behavioral sensitization. CONCLUSIONS: Behavioral sensitization induced by a single morphine exposure in mice exhibits context and time dependency, with environmental context likely functioning via an inhibitory conditioning mechanism. Furthermore, alterations in Hsp70 expression in the NAc may represent a neurobiological sensitization mechanism mediating context- and time-dependent behavioral sensitization.

Efficiency of individual dosage of digoxin with calculated concentration.

BACKGROUND: Digoxin is a frequently prescribed drug, particularly in the elderly population, in which there is an increased prevalence of atrial fibrillation and cardiac failure. With its complex pharmacokinetic profile and narrow therapeutic index, use of digoxin requires regular monitoring of blood levels. Recent evidence suggests that a lower concentration range (0.4-1.0 ng/mL) is preferable in patients with congestive heart failure and a higher range (0.8-2.0 ng/mL) is needed in patients with atrial tachyarrhythmia. The Konishi equation is widely used to predict the serum digoxin concentration (SDC) in Japan. This study assessed the correlation between SDC predicted by the Konishi equation and that actually measured in Chinese patients and investigated the impact of renal function on SDC. METHODS: The study subjects comprised 72 patients with cardiac failure or/and atrial tachyarrhythmia seen at our hospital from January 2012 to December 2013. The patients were divided into five groups according to Kidney Diseases Outcome Quality Initiative guidelines. SDCs were measured using the Abbott Architect i1000 immunology analyzer. The correlations between measured SDCs and calculated SDCs and between clearance of digoxin and creatinine clearance rate were assessed retrospectively. RESULTS: The correlation between measured and predicted SDC calculated by the Konishi equation was significant (r=0.655, P<0.001) for the 72 patients overall; however, correlations within the different stages of renal function were nonsignificant, with a correlation found only in patients with stage 3 (30 mL per minute < creatinine clearance <60 mL per minute). With regard to the correlation between clearance of digoxin and creatinine clearance, our results show that although there was a significant correlation between clearance of digoxin and creatinine clearance in the group overall, correlations were not evident within the different stages of renal function. CONCLUSION: The results of this study indicate that clearance of digoxin and the creatinine clearance rate cannot be explained by renal function alone and that the validity of the Konishi equation for individualizing the digoxin dosage in Chinese patients is limited, being applicable only in stage 3 renal disease. Further research in larger numbers of patients across all stages of renal function will be required in the future to verify the original Konishi model.

Chaperone heat shock protein 70 in nucleus accumbens core: a novel biological target of behavioural sensitization to morphine in rats.

Drug addiction is a major public health issue, yet the underlying adaptation of neural networks by drugs of abuse is not fully understood. We have previously linked chaperone heat shock protein 70 (Hsp70) to drug-induced adaptations. Focusing on the NAc core and shell, the present study aims to provide further findings for our understanding of the relation between behavioural sensitization to morphine and Hsp70 at transcriptional and functional levels in rats. Firstly, we delineated the characteristics of behavioural sensitization induced by a single morphine exposure (1-10 mg/kg, s.c.). Secondly, Hsp70 protein expression in the NAc core was time- and dose-relatedly induced during the development of behavioural sensitization to a single morphine exposure in rats, and Pearson analysis indicated a positive correlation between behavioural sensitization and Hsp70 expression in NAc core. Thirdly, at the transcriptional level, intra-NAc core injection of the specific heat shock factor-I (HSF-I) inhibitor N-Formyl-3,4-methylenedioxy-benzylidine-γ-butyrolactam (KNK437) suppressed Hsp70 expression and the development of behavioural sensitization, while the HSF-I specific inducer geranylgeranylacetone (GGA) promoted both of them. Interestingly, intra-NAc shell injection of KNK437 or GGA did not affect the development of behavioural sensitization. Finally, both the functional inhibition of Hsp70 ATPase activity by methylene blue (MB), and the antagonism of Hsp70 substrate binding site (SBD) activity by pifithrin-µ (PES) impaired the development of behavioural sensitization when they were microinjected into the NAc core. Taken together, the critical involvement of chaperone Hsp70 in behavioural sensitization to morphine identifies a biological target for long-lasting adaptations with relevance to addiction.

Molecular chaperone heat shock protein 70 participates in the labile phase of the development of behavioural sensitization induced by a single morphine exposure in mice.

De-novo protein synthesis is required in the development of behavioural sensitization. A prior screening test from our laboratory has implicated heat shock protein 70 (Hsp70) as one of the proteins required in this behavioural plasticity. Thus, this study was designed to extend our understanding of the role of Hsp70 in the development of behavioural sensitization induced by a single morphine exposure in mice. First, by employing transcription inhibitor actinomycin D (AD) and protein synthesis inhibitor cycloheximide (CHX), we identified a protein synthesis-dependent labile phase (within 4 h after the first morphine injection) in the development of behavioural sensitization to a single morphine exposure. Second, Hsp70 protein expression in the nucleus accumbens correlated positively with locomotor responses of sensitized mice and, more importantly, the expression of Hsp70 increased within 1 h after the first morphine injection. Third, AD and CHX both prevented expression of Hsp70 and disrupted the development of the single morphine induced behavioural sensitization, which further implied Hsp70 was highly associated with behavioural sensitization. Finally, the selective Hsp70 inhibitor pifithrin-µ (PES) i.c.v. injected in mice prevented the development of behavioural sensitization and, critically, this inhibitory effect occurred only when PES was given within 1 h after the first morphine injection, which was within the labile phase of the development period. Taken together, we draw the conclusion that Hsp70 is crucially involved in the labile phase of the development of behavioural sensitization induced by a single morphine exposure, probably functioning as a molecular chaperone.

The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring Fawn-Hooded rats.

BACKGROUND: Alcohol dependence is a complex psychiatric disorder demanding development of novel pharmacotherapies. Because the cyclic adenosine monophosphate (cAMP) signaling cascade has been implicated in mediating behavioral responses to alcohol, key components in this cascade may serve as potential treatment targets. Phosphodiesterase-4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cAMP, represents a key point in regulating intracellular cAMP levels. Thus, it was of interest to determine whether PDE4 was involved in the regulation of alcohol use and abuse. METHODS: Male Fawn-Hooded (FH/Wjd) rats were tested for 5% (v/v) ethanol (EtOH) and 10% (w/v) sucrose operant oral self-administration following treatment with the selective PDE4 inhibitor rolipram (0.0125, 0.025, or 0.05 mg/kg, subcutaneous [s.c.]); rolipram at higher doses (0.05, 0.1, and 0.2 mg/kg, s.c.) was tested to determine its impact on the intake of EtOH, sucrose, or water using the 2-bottle choice drinking paradigm. Subsequent open-field testing was performed to evaluate the influence of higher doses of rolipram on locomotor activity. RESULTS: Acute administration of rolipram dose-dependently reduced operant self-administration of 5% EtOH, but had no effect on 10% sucrose responding. Time-course assessment revealed significant decreases in EtOH consumption after rolipram (0.1, 0.2 mg/kg) treatment in continuous- and intermittent access to EtOH at 5% or 10%, respectively. Moreover, chronic rolipram treatment time-dependently decreased 5% EtOH consumption and preference during treatment days and after the termination of rolipram administration. Rolipram at the highest doses (0.1 and 0.2 mg/kg) did decrease locomotor activity, but the effect lasted only 10 and 20 minutes, respectively, which did not likely alter long-term EtOH drinking. CONCLUSIONS: These results suggest that PDE4 plays a role in alcohol seeking and consumption behavior. Drugs interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.

Septal nuclei critically mediate the development of behavioral sensitization to a single morphine injection in rats.

Behavioral sensitization to a single morphine injection is a unique model to study the neuroanatomical substrates of long-lasting behavioral plasticity associated with opioid reward and abuse. Earlier observations have demonstrated that septal nuclei are critically involved in the processes of reward, learning and memory. In the present study, we investigated the effects of septal nuclei lesions on behavioral sensitization to a single morphine injection, morphine induced conditioned place preference and antinociception in rats. Behavioral sensitization was established by a single injection of 3-30 mg/kg morphine in rats. Bilateral electrical lesions of septal nuclei were carried out 7 days before morphine pretreatment. Acute morphine injection induced hyperactivity in the non-surgery control, sham surgery and septal nuclei-lesioned rats. Seven days later, the challenge injection with 3mg/kg morphine induced significant behavioral sensitization in rats with no surgery and sham surgery, but failed to induce behavioral sensitization in septal nuclei-lesioned rats. When the septal nuclei ablation was carried out after acute morphine pretreatment, the expression of behavioral sensitization was unaffected and not different among rats. In addition, septal nuclei lesions did not impact the rewarding and antinociceptive effects of 10 mg/kg morphine when the rats were tested in a conditioned place preference test and tail-flick test, respectively. Collectively, these results suggest that septal nuclei may be selectively involved in the initiation of behavioral sensitization to morphine, which is separable from the effects of morphine for exerting its rewarding and antinociceptive effects.