The role of endogenous dynorphin in ethanol-induced state-dependent CPP

The aim of this study was to determine the role of the endogenous dynorphin/kappa opioid receptor (DYN/KOP) system in ethanol-induced state-dependent conditioned place preference (CPP). To this end, mice lacking the pro-DYN gene and their wild-type littermates/controls were tested for baseline place preference on day 1, received 15-min morning and afternoon conditionings with saline or ethanol (2 g/kg) each day for three consecutive days and were then tested for CPP under a drug-free state on day 5 and following a saline or ethanol (1 or 2 g/kg) challenge on day 8. Given that compensatory developmental changes may occur in knockout mice, the effect of nor-binaltorphimine (nor-BNI), a KOP antagonist, on state-dependent CPP induced by ethanol was also studied in wild-type mice. On day 1, mice were tested for baseline place preference and, 4 h later, treated with saline or nor-BNI (10 mg/kg). On days 2-4, mice received 15-min morning and afternoon conditionings and were tested for CPP under a drug-free state on day 5 and following an ethanol (1 g/kg) challenge on day 8. A comparable CPP was observed in mice lacking the pro-DYN gene and their wild-type littermates/controls as well as in wild-type mice treated with nor-BNI and their saline-treated controls. However, these mice compared to their respective controls exhibited a greater CPP response following an ethanol (1 g/kg) challenge, suggesting that the endogenous DYN/KOP system may negatively regulate ethanol-induced state-dependent CPP.     

Liver X receptor agonist T0901317 inhibition of glucocorticoid receptor expression in hepatocytes may contribute to the amelioration of diabetic syndrome in db/db mice

The glucocorticoid receptor (GR) is a crucial target gene for glucocorticoid-induced insulin resistance and hepatic gluconeogenesis linked to the development of type 2 diabetes. The liver X receptors (LXRs) are nuclear receptors that play an important role in the regulation of the metabolic gene linked to carbohydrate homeostasis. To assess the tissue-specific interaction of LXR with GR in the development of type 2 diabetes, we examined the possible effect of LXR agonist T0901317 on GR gene expression in vivo and in vitro in hepatocytes from db/db mice (a model of type 2 diabetes). Chronic ligand activation of LXR by a synthetic LXR T0901317 markedly decreased the expression of both GR mRNA and its protein in liver and improved the phenotype of type 2 diabetes in obese db/db mice. Suppression of hepatic GR expression was correlated with reduced levels of glucose and corresponded to the inhibition of phosphoenolpyruvate carboxykinase mRNA and 11beta-hydroxysteroid dehydrogenase type 1-mediated synthesis of active corticosterone from inactive 11-dehydrocorticosterone in liver. Treatment of db/db mouse primary hepatocytes with T0901317 resulted in dramatic suppression of GR mRNA and required ongoing protein synthesis. Addition of T0901317 to primary hepatocytes also suppressed the expression of both 11beta-hydroxysteroid dehydrogenase type 1 and phosphoenolpyruvate carboxykinase. These findings suggest that some of antidiabetic actions of LXR agonist T0901317 may be mediated, at least in part, through the suppression of hepatic GR gene expression.     

Effect of nicotine on body composition in mice

Nicotine induces weight loss in both humans and rodents consuming a regular diet; however, the effect of nicotine on body weight and fat composition in rodents consuming a high-fat diet (HFD) has not been well studied. Thus, this study examined the effect of nicotine vs saline on body weight and fat composition in mice fed with either an HFD (62% of kcal from fat) or a standard normal chow diet (NCD) for 7 weeks. Nicotine dose dependently reduced body weight gain in mice that consumed both diets, but this effect was significantly greater in mice on the HFD. Caloric intake was decreased in nicotine-treated mice. Estimates of energy intake suggested that decreased caloric intake accounted for all the reduced weight gain in mice on an NCD and 66% of the reduced weight gain on an HFD. Computed tomography analysis for fat distribution demonstrated that nicotine was effective in reducing abdominal fat in mice that consumed the HFD, with nicotine treatment leading to lower visceral fat. The effect of nicotine on weight loss in mice on an HFD was completely blocked by mecamylamine, a nonselective nicotinic acetylcholine receptor (nAChR) antagonist, but only partially blocked by the α4β2 nAChR partial agonist/antagonist, varenicline. We conclude that nicotine is effective in preventing HFD-induced weight gain and abdominal fat accumulation.     

Subcutaneous Fat Necrosis of the Neonate with a Delayed Second Eruption

Subcutaneous fat necrosis (SCFN) of the neonate is a rare panniculitis of early life that occurs in association with gestational diabetes and preeclampsia, as well as perinatal asphyxia, hypothermia, and trauma. A characteristic feature of this condition is its self‐limiting and monophasic nature. We report a highly unusual case of delayed SCFN in a male neonate involving an anatomically discrete eruption, reminiscent of erythema nodosum, occurring many weeks after his original eruption had resolved.     

Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist

BACKGROUND AND PURPOSE

The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception.

EXPERIMENTAL APPROACH

We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception.

KEY RESULTS

Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg⁻¹), unmasked etorphine (3 mg·kg⁻¹) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg⁻¹) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg⁻¹) and diazepam (1 mg·kg⁻¹).

CONCLUSIONS AND IMPLICATIONS

Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

The gradient index lens of the eye: an opto-biological synchrony

The refractive power of a lens is determined largely by its surface curvatures and the refractive index of its medium. These properties can also be used to control the sharpness of focus and hence the image quality. One of the most effective ways of doing this is with a gradient index. Eye lenses of all species, thus far, measured, are gradient index (GRIN) structures. The index gradation is one that increases from the periphery of the lens to its centre but the steepness of the gradient and the magnitudes of the refractive index vary so that the optics of the lens accords with visual demands. The structural proteins, the crystallins, which create the index gradient, also vary from species to species, in type and relative distribution across the tissue. The crystallin classes do not contribute equally to the refractive index, and this may be related to their structure and amino acid content. This article compares GRIN forms in eye lenses of varying species, the relevance of these forms to visual requirements, and the relationship between refractive index and the structural proteins. Consideration is given to the dynamics of a living lens, potential variations in the GRIN form with physiological changes and the possible link between discontinuities in the gradient and growth. Finally, the property of birefringence and the characteristic polarisation patterns seen in highly ordered crystals that have also been observed in specially prepared eye lenses are described and discussed.     

Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats

1. Recent evidence from studies in mice lacking the opioid receptor-like (ORL-1) receptor and from experiments using antibodies raised against orphanin FQ/nociceptin (OFQ/N) suggest that this peptide may be involved in morphine tolerance. In the present study we sought to investigate if administration of exogenous OFQ/N would modulate the development of tolerance to the antinociceptive effect of morphine. 2. Rats were treated for 3 days with either saline or morphine (10 mg kg(-1), s.c.) followed, 15 and 75 min later, by two intracerebroventricular injections of either artificial cerebrospinal fluid (aCSF) or OFQ/N. The dose of OFQ/N was doubled each day (7.5, 15, 30 nmol). On day 4, rats were tested on a hot plate apparatus before and 30, 60 and 90 min after morphine administration. 3. Repeated OFQ/N treatment did not affect basal nociceptive responses or morphine-induced antinociception. However, the same treatment significantly attenuated the development of morphine tolerance. 4. Since learning and memory could contribute to the development of morphine tolerance, in subsequent studies, we examined the effect of OFQ/N administered in the CA3 region of the hippocampus, where OFQ/N has been shown to block LTP and impair spatial memory. A greater attenuation of morphine tolerance with no alteration of baseline hot plate latency or morphine-induced antinociception was observed when OFQ/N was administered in this area of the rat brain. 5. Taken together, our results demonstrate that OFQ/N may act in the hippocampus to attenuate morphine tolerance.     

Orphanin FQ/nociceptin attenuates motor stimulation and changes in nucleus accumbens extracellular dopamine induced by cocaine in rats

RATIONALE: Orphanin FQ (OFQ; also known as nociceptin), the endogenous ligand of the opioid receptor-like receptor, injected intracerebroventricularly (i.c.v.) decreases basal motor activity and basal extracellular levels of dopamine (DA) in the nucleus accumbens (Nuc Acc) in rats. OBJECTIVE: The present study was designed to determine if OFQ similarly attenuates cocaine-induced motor stimulation and to determine if this effect is dependent on attenuation of the increase in extracellular DA. METHODS: After a 1-h adaptation period, rats were injected with either artificial cerebrospinal fluid or OFQ (3-30 nmol, i.c.v.) 5 min prior to cocaine (10 mg/kg, i.p.) or apomorphine (3 mg/kg, i.p.) administration and the total distance traveled was measured for a further 1 h. In a separate experiment, changes in extracellular DA were monitored by microdialysis following cocaine and OFQ treatment in anesthetized rats. RESULTS: OFQ dose-dependently attenuated both basal and cocaine-induced motor stimulation. OFQ (30 nmol, i.c.v.) also attenuated both the basal and the cocaine-induced increase in extracellular DA in the Nuc Acc. OFQ, at the highest dose, also decreased the motor stimulation induced by apomorphine. CONCLUSIONS: Our results suggest that the modulatory effect of OFQ on locomotor activity is not solely due to its inhibitory action on extracellular DA in the Nuc Acc.