Development and use of a high-throughput screen to identify novel modulators of the corticotropin releasing factor binding protein.

Background: Stress responses are believed to involve corticotropin releasing factor (CRF), its two cognate receptors (CRF and CRF), and the CRF-binding protein (CRFBP). Whereas decades of research has focused on CRF, the role of CRF in the central nervous system (CNS) has not been thoroughly investigated. We have previously reported that CRF, interacting with a C terminal fragment of CRFBP, CRFBP(10kD), may have a role in the modulation of neuronal activity.

Intermittent access ethanol consumption dysregulates CRF function in the hypothalamus and is attenuated by the CRF-R1 antagonist, CP-376395.

Corticotrophin-releasing factor (CRF) is a mediator of stress responses and a key modulator of ethanol-mediated behaviors. We report here that the CRF receptor 1 (CRF-R1) antagonist, CP-376395 reduces 20% ethanol consumption in animals trained to consume ethanol on an intermittent, but not a continuous, schedule. Furthermore, using [(35) S]GTPγS binding assays, we demonstrate that CRF-mediated G-protein signaling in the hypothalamus of the intermittent drinkers is decreased when compared to controls suggesting that the effects of CP-376395 are mediated by extrahypothalamic mechanisms.

The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration.

Recent studies have implicated the hypocretin/orexinergic system in reward-seeking behavior. Almorexant, a dual orexin/hypocretin R(1) and R(2) receptor antagonist, has proven effective in preclinical studies in promoting sleep in animal models and was in Phase III clinical trials for sleep disorders. The present study combines behavioral assays with in vitro biochemical and electrophysiological techniques to elucidate the role of almorexant in ethanol and sucrose intake.

The delta opioid receptor antagonist, SoRI-9409, decreases yohimbine stress-induced reinstatement of ethanol-seeking.

A major problem in treating alcohol use disorders (AUDs) is the high rate of relapse due to stress and re-exposure to cues or an environment previously associated with alcohol use. Stressors can induce relapse to alcohol-seeking in humans or reinstatement in rodents. Delta opioid peptide receptors (DOP-Rs) play a role in cue-induced reinstatement of ethanol-seeking; however, their role in stress-induced reinstatement of ethanol-seeking is not known.

Observation of soliton molecules with independently evolving phase in a mode-locked fiber laser.

We report the experimental generation of two-soliton molecules in an all-polarization-maintaining ytterbium-doped fiber laser operating in the normal dispersion regime. These molecules exhibit an independently evolving phase and are characterized by a regular spectral modulation pattern with a modulation depth of 80% measured as an averaged value. Moreover, the numerical modeling confirms that the limited modulation depth of the spectrum is caused by the evolution of the phase difference between the pulses.

chi-Conopeptide pharmacophore development: toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain.

Norepinephrine (NE) amplifies the strength of descending pain inhibition, giving inhibitors of spinal NET clinical utility in the management of pain. chi-MrIA isolated from the venom of a predatory marine snail noncompetitively inhibits NET and reverses allodynia in rat models of neuropathic pain. An analogue of chi-MrIA has been found to be a suitable drug candidate.

Cabergoline decreases alcohol drinking and seeking behaviors via glial cell line-derived neurotrophic factor.

Background: Cabergoline is an ergotamine derivative that increases the expression of glial cell line-derived neurotrophic factor (GDNF) in vitro. We recently showed that GDNF in the ventral tegmental area (VTA) reduces the motivation to consume alcohol. We therefore set out to determine whether cabergoline administration decreases alcohol-drinking and -seeking behaviors via GDNF.

A novel delta opioid receptor antagonist, SoRI-9409, produces a selective and long-lasting decrease in ethanol consumption in heavy-drinking rats.

Background: Naltrexone, a compound with high affinity for the mu opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at delta opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption to determine the consequences of altering the naltrexone compound to a form with increased efficacy at DOP-Rs.

Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence.

Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids.

All-fiber mode-locked fiber laser.

An environmentally stable mode-locked fiber laser based on nonlinear polarization rotation is experimentally demonstrated. The laser is based on a novel laser configuration that has negligible low-power steady-state reflectivity from one side and, consequently, no CW gain. The laser is self starting and the configuration is implementable as an all-fiber laser with standard polarization-maintaining fiber-pigtailed components.

Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain.

Previously, we reported that oxycodone is a putative kappa-opioid agonist based on studies where intracerebroventricular (i.c.v.

Fiber laser-based light source for coherent anti-Stokes Raman scattering microspectroscopy.

We demonstrate an alternative light source for CARS microspectroscopy based on a fiber laser and a photonic-crystal fiber. The light source simultaneously delivers a near-transform-limited picosecond pump pulse at 1033.5 nm and a frequency-shifted, near-transform-limited femtosecond Stokes pulse, tunable from 1033.

Microjoule-level all-polarization-maintaining femtosecond fiber source.

We report on a high-power, high-energy femtosecond fiber source based on direct amplification of parabolic pulses from an environmentally stable passively mode-locked fiber oscillator in an Yb-doped single-polarization photonic crystal fiber. The special pulse shape allows for the generation of high-quality femtosecond pulses beyond nonlinearity limits. The system delivers a pulse energy of 1.

Anti-allodynic efficacy of the chi-conopeptide, Xen2174, in rats with neuropathic pain.

Xen2174 is a structural analogue of Mr1A, a chi-conopeptide recently isolated from the venom of the marine cone snail, Conus marmoreus. Although both chi-conopeptides are highly selective inhibitors of the norepinephrine transporter (NET), Xen2174 has superior chemical stability relative to Mr1A. It is well-known that tricyclic antidepressants (TCAs) are also potent NET inhibitors, but their poor selectivity relative to other monoamine transporters and various G-protein-coupled receptors, results in dose-limiting side-effects in vivo.