Synthesis and resolution of cis-(+/-)-methyl (1R,2S/1S2R)-2-[(4-hydroxy-4-phenylpiperidin-1-il)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [(+/-)-PPCC)]:new sigma receptor ligands with neuroprotective effect.

The enantiomers of cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [1, (+/-)-PPCC], a selective sigma ligand, were synthesized. The (+)- and (-)-enantiomers bind predominantly to sigma(1) receptors and have a reduced sigma(2) affinity. Both individually restore the astroglial oxidative status modified by glutamate, counteracting also transglutaminase-2 overexpression. They exhibited in vivo anti-opioid effects on kappa opioid (KOP) receptor-mediated analgesia. Our findings demonstrate that the enantiomers display mainly sigma(1) agonist activity and that they have neuroprotective effects

NOP-related mechanisms in substance use disorders

Nociceptin/orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995 and has been widely studied since. The role of the N/OFQ system in drug abuse has attracted researchers’ attention since its initial discovery. The first two scientific papers describing the effect of intracranial injection of N/OFQ appeared 20 years ago and reported efficacy of the peptide in attenuating alcohol intake, whereas heroin self-administration was insensitive. Since then more than 100 scientific articles investigating the role of the N/OFQ and N/OFQ receptor (NOP) system in drug abuse have been published. The present article provides an historical overview of the advances in the field with focus on three major elements. First, the most robust data supportive of the efficacy of NOP agonists in treating drug abuse come from studies in the field of alcohol research, followed by psychostimulant and opioid research. In contrast, activation of NOP appears to facilitate nicotine consumption. Second, emerging data challenge the assumption that activation of NOP is the most appropriate strategy to attenuate consumption of substances of abuse. This assumption is based first on the observation that animals carrying an overexpression of NOP system components are more prone to consume substances of abuse, whereas NOP knockout rats are less motivated to self-administer heroin, alcohol, and cocaine. Third, administration of NOP antagonists also reduces alcohol consumption. In addition, NOP blockade reduces nicotine self-administration. Hypothetical mechanisms explaining this apparent paradox are discussed. Finally, we focus on the possibility that co-activation of NOP and mu opioid (MOP) receptors is an alternative strategy, readily testable in the clinic, to reduce the consumption of psychostimulants, opiates, and, possibly, alcohol

Pericytes in Muscular Dystrophies

The muscular dystrophies are an heterogeneous group of inherited myopathies characterised by the progressive wasting of skeletal muscle tissue. Pericytes have been shown to make muscle in vitro and to contribute to skeletal muscle regeneration in several animal models, although recent data has shown this to be controversial. In fact, some pericyte subpopulations have been shown to contribute to fibrosis and adipose deposition in muscle. In this chapter, we explore the identity and the multifaceted role of pericytes in dystrophic muscle, potential therapeutic applications and the current need to overcome the hurdles of characterisation (both to identify pericyte subpopulations and track cell fate), to prevent deleterious differentiation towards myogenic-inhibiting subpopulations, and to improve cell proliferation and engraftment efficacy