Mendelian randomization case-control PheWAS in UK Biobank shows evidence of causality for smoking intensity in 28 distinct clinical conditions.

Background: Smoking is one of the greatest threats to public health worldwide. We integrated phenome-wide association study (PheWAS) and Mendelian randomization (MR) approaches to explore causal effects of genetically predicted smoking intensity across the human disease spectrum.

Methods: We conducted PheWAS case-control analyses in 152,483 ever smokers of White-British ancestry, aged 39-73 years.

Cognitive dynamics of intertemporal choice in gambling disorder.

Gambling Disorder (GD) is a behavioral addiction characterized by the persistence of recurrent gambling behaviors despite serious adverse consequences. One of the key features of GD is a marked inability to delay gratification and an overall impairment of decision-making mechanisms. Indeed, in intertemporal choice (ITC) tasks, GD patients usually display a marked tendency to prefer smaller-sooner over larger-later rewards (temporal discounting, TD).

The generation of knock-in mice expressing fluorescently tagged galanin receptors 1 and 2.

The neuropeptide galanin has diverse roles in the central and peripheral nervous systems, by activating the G protein-coupled receptors Gal1, Gal2 and the less studied Gal3 (GalR1-3 gene products). There is a wealth of data on expression of Gal1-3 at the mRNA level, but not at the protein level due to the lack of specificity of currently available antibodies. Here we report the generation of knock-in mice expressing Gal1 or Gal2 receptor fluorescently tagged at the C-terminus with, respectively, mCherry or hrGFP (humanized Renilla green fluorescent protein).

The role of physical activity and psychological coping strategies in the management of painful diabetic neuropathy--A systematic review of the literature.

Background: Diabetes is rising in prevalence; painful diabetic neuropathy (PDN) is one complication of diabetes. PDN is primarily managed with medication but analgesic failure is common and people remain in pain and distress. It is unclear whether pain management strategies are appropriate for PDN.

Physiology, signaling, and pharmacology of galanin peptides and receptors: three decades of emerging diversity.

Galanin was first identified 30 years ago as a "classic neuropeptide," with actions primarily as a modulator of neurotransmission in the brain and peripheral nervous system. Other structurally-related peptides-galanin-like peptide and alarin-with diverse biologic actions in brain and other tissues have since been identified, although, unlike galanin, their cognate receptors are currently unknown. Over the last two decades, in addition to many neuronal actions, a number of nonneuronal actions of galanin and other galanin family peptides have been described.

Galanin stimulates neurite outgrowth from sensory neurons by inhibition of Cdc42 and Rho GTPases and activation of cofilin.

We and others have previously shown that the neuropeptide galanin modulates neurite outgrowth from adult sensory neurons via activation of the second galanin receptor; however, the intracellular signalling pathways that mediate this neuritogenic effect have yet to be elucidated. Here, we demonstrate that galanin decreases the activation state in adult sensory neurons and PC12 cells of Rho and Cdc42 GTPases, both known regulators of filopodial and growth cone motility. Consistent with this, activated levels of Rho and Cdc42 levels are increased in the dorsal root ganglion of adult galanin knockout animals compared with wildtype controls.

Galanin-expression and galanin-dependent sensory neurons are not required for itch.

Background: Galanin is a key modulator of nociception, and it is also required for the developmental survival of a subset of C-fibre sensory neurons which are critical to the mediation of neuropathic and inflammatory pain. However, the potential modulatory roles played by galanin, or the galanin-dependent neurons, in pruritoceptive mechanisms underlying the sensation of itch have not been investigated.

Findings: Here we report that mice carrying a loss-of-function mutation in the galanin gene (Gal-KO) show no differences in spontaneous behavioural itch responses compared to wild-type (WT) controls.

Galanin negatively modulates opiate withdrawal via galanin receptor 1.

Rationale: The neuropeptide galanin has been shown to modulate opiate dependence and withdrawal. These effects could be mediated via activation of one or more of the three distinct G protein-coupled receptors, namely galanin receptors 1 (GalR1), 2 (GalR2), and 3 (GalR3).

Objectives: In this study, we used several transgenic mouse lines to further define the mechanisms underlying the role played by galanin and its receptors in the modulation of morphine dependence.

Endogenous galanin protects mouse hippocampal neurons against amyloid toxicity in vitro via activation of galanin receptor-2.

Expression of the neuropeptide galanin is known to be upregulated in the brain of patients with Alzheimer's disease (AD). We and others have shown that galanin plays a neuroprotective role in a number of excitotoxic injury paradigms, mediated by activation of the second galanin receptor subtype (GAL2). In the present study, we investigated whether galanin/GAL2 plays a similar protective role against amyloid-β(Aβ) toxicity.

Characterisation of the nociceptive phenotype of suppressible galanin overexpressing transgenic mice.

The neuropeptide galanin is widely expressed in both the central and peripheral nervous systems and is involved in many diverse biological functions. There is a substantial data set that demonstrates galanin is upregulated after injury in the DRG, spinal cord and in many brain regions where it plays a predominantly antinociceptive role in addition to being neuroprotective and pro-regenerative. To further characterise the role of galanin following nerve injury, a novel transgenic line was created using the binary transgenic tet-off system, to overexpress galanin in galaninergic tissue in a suppressible manner.

Intra-neural administration of fractalkine attenuates neuropathic pain-related behaviour.

There is increasing evidence that a number of cytokines and their receptors are involved in the processes that lead to the development and maintenance of neuropathic pain states. Here we demonstrate that levels of CX3CR1 (the receptor for the chemokine fractalkine) mRNA in lumbar dorsal root ganglia (DRG) increase 5.8-fold 7 days after sciatic nerve axotomy, and 1.

Activation of the galanin receptor 2 (GalR2) protects the hippocampus from neuronal damage.

Expression of the neuropeptide galanin is up-regulated in many brain regions following nerve injury and in the basal forebrain of patients with Alzheimer's disease. We have previously demonstrated that galanin modulates hippocampal neuronal survival, although it was unclear which receptor subtype(s) mediates this effect. Here we report that the protective role played by galanin in hippocampal cultures is abolished in animals carrying a loss-of-function mutation in the second galanin receptor subtype (GalR2-MUT).