Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats.

The kappa-opioid receptor (KOR) is the primary target for the endogenous opioid peptide dynorphin (DYN), and KORs reside within brain circuitry underlying the complex integration of information related to different behavioral domains such as motivation, negative affect, and decision-making. Alterations in extended amygdala DYNs and KOR function following chronic alcohol exposure have been shown to mediate escalated alcohol self-administration during acute withdrawal. In addition to excessive alcohol consumption and increased negative affect, other symptoms of alcohol dependence include compromised impulse control. Given that DYN and KOR expressions are dysregulated within prefrontal brain circuitry associated with decision-making and impulse control in alcohol-dependent humans and rodents, and have been shown to modify multiple neurotransmitter systems associated with impulse-control disorders, we hypothesized that KOR activation could contribute to impulsive phenotypes. To test this hypothesis, separate cohorts of male Wistar rats were trained in one of the two animal models of impulsivity: delay-discounting (DD) or stop-signal reaction time (SSRT) tasks, and once stable responding was observed, received intracerebroventricular (ICV) infusions of the KOR agonist U50,488 (0-50 µg) according to a within-subject dosing regimen. The results demonstrated a dissociable effect of U50,488 on impulsive phenotypes related to intolerance to delay or response inhibition, with selective effects in the SSRT. Furthermore, the pro-impulsive effects of KOR activation were rescued by pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI). Therefore, KOR activation was shown to induce an impulsive phenotype that was nor-BNI-sensitive. Dysregulation of impulsive behavior by increased DYN/KOR activity could serve to increase vulnerability for the initiation, or perpetuate existing patterns of excessive alcohol abuse and can enhance the probability of relapse in dependent individuals. Furthermore, KOR-mediated impulsivity has implications for numerous neuropsychiatric disorders.

Randomized, double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of MAP0004 (orally-inhaled DHE) in adult asthmatics.

BACKGROUND: MAP0004 (a proprietary formulation of dihydroergotamine mesylate [DHE]) for inhaled delivery is being developed for acute migraine treatment. Because asthma and migraine often occur as co-morbid conditions, it is considered important to study the safety of MAP0004 in a population of asthmatic adults and to confirm that the pharmacokinetics of DHE, when inhaled by asthmatic subjects, were comparable to a population of healthy volunteers. The safety, tolerability, and pharmacokinetics of orally-inhaled MAP0004 administered by the Tempo inhaler were studied in adult asthmatics. SCOPE: This was a randomized, double-blind, placebo-controlled study of two doses of inhaled MAP0004. Eligible subjects were randomized in a 2 : 1 ratio to MAP0004 or placebo and observed for 4 h after each dose. Pharmacokinetic parameters were determined pre-dose and up to 36 h post-dose. FINDINGS: Among 19 subjects, geometric mean AUC(0-36) was 6754 pg.h/mL and geometric mean AUC(0-inf) was 7483 pg.h/mL. Geometric mean t(max) was 9.6 min, geometric mean C(max) was 3174 pg/mL, and geometric mean t((1/2)) was 9.5 h. Overall, 13 of 19 (68%) subjects reported at least one adverse event, most commonly nausea, vomiting, dysgeusia, and headache. CONCLUSION: MAP0004 results in rapid and efficient systemic absorption in asthmatic subjects. Systemic DHE concentrations were similar to those previously reported in healthy subjects, and no clinically relevant safety issues were observed. While this small study was suitable for pharmacokinetic analysis and conclusions, MAP0004 use in migraineurs with concomitant stable asthma should be supported by larger studies of longer duration to confirm that it does not present additional safety risks compared to non-asthmatic migraineurs.

Lifetime nonnarcotic analgesic use and decline in renal function in women.

BACKGROUND: Analgesics are commonly used and may impair kidney function. However, limited prospective information is available on the long-term effects of aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen on renal function. METHODS: A total of 1697 women participating in the Nurses' Health Study provided information on a mailed questionnaire in 1999 about lifetime use of acetaminophen, aspirin, and NSAIDs and provided blood samples in 1989 and 2000. The main outcome was change in estimated glomerular filtration rate (GFR) in 11 years. Multivariate logistic regression was used to determine the odds of developing the outcome according to lifetime analgesic intake. RESULTS: The mean +/- SD estimated GFR decreased from 88 +/- 17 to 79 +/- 17 mL/min per 1.73 m(2). There were no substantial differences in the unadjusted or estimated GFR levels among the categories of lifetime intake for the 3 analgesic groups at baseline or after 11 years. Acetaminophen use was associated with an increased risk of a GFR decline of at least 30 mL/min per 1.73 m(2) (P trend =.01) and a GFR decline of 30% or greater (P trend<.001), but aspirin and NSAID use were not. Compared with women consuming less than 100 g of acetaminophen, multivariate-adjusted odds ratio (95% confidence intervals) for a decline in GFR of at least 30 mL/min per 1.73 m(2) for women consuming more than 3000 g was 2.04 (1.28-3.24). CONCLUSIONS: Higher lifetime use of aspirin and NSAIDs is not associated with renal function decline, but high acetaminophen use may increase the risk of loss of renal function. The absolute risk of renal function decline due to even high lifetime analgesic intake seems to be modest.

beta-Endorphin-like peptide SLTCLVKGFY is a selective agonist of nonopioid beta-endorphin receptor.

It has been found that beta-endorphin (beta-END) and a synthetic beta-END-like decapeptide Ser-Leu-Thr-Cys-Leu-Val-Lys-Gly-Phe-Tyr (termed immunorphin, IMN) corresponding to the sequence 364-373 of human IgG heavy chain stimulate Con A-induced proliferation of T lymphocytes from the blood of healthy donors. [Met(5)]enkephalin ([Met(5)]ENK) and an antagonist of opioid receptors naloxone (NAL) tested in parallel were not active. The stimulating effect of beta-END and IMN on T lymphocyte proliferation was not inhibited by NAL. Studies on receptor binding of (125)I-labeled IMN to T lymphocytes revealed that it binds with high affinity to NAL-insensitive binding sites (K(d) = 7.0 +/- 0.3 nM). Unlabeled beta-END completely inhibited the specific binding of (125)I-labeled IMN to NAL-insensitive binding sites on T lymphocytes (K(i) = 1.1 +/- 0.2 nM). Thus, beta-END and IMN bind to common NAL-insensitive binding sites on T lymphocytes and enhance Con A-induced proliferation of these cells.