N-Acylethanolamine Acid Amidase Inhibition Potentiates Morphine Analgesia and Delays the Development of Tolerance

Opioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them, N-palmitoylethanolamide (PEA), an endogenous lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of morphine tolerance. A selective augmentation in endogenous PEA levels can be achieved by inhibiting N-acylethanolamine acid amidase (NAAA), one of its primary hydrolyzing enzymes. This study aimed to test the hypothesis that NAAA inhibition, with the novel brain permeable NAAA inhibitor AM11095, modulates morphine’s antinociceptive effects and attenuates the development of morphine tolerance in rats. We tested this hypothesis by measuring the pain threshold to noxious mechanical stimuli and, as a neural correlate, we conducted in vivo electrophysiological recordings from pain-sensitive locus coeruleus (LC) noradrenergic neurons in anesthetized rats. AM11095 dose-dependently (3–30 mg/kg) enhanced the antinociceptive effects of morphine and delayed the development of tolerance to chronic morphine in behaving rats. Consistently, AM11095 enhanced morphine-induced attenuation of the response of LC neurons to foot-shocks and prevented the attenuation of morphine effects following chronic treatment. Behavioral and electrophysiological effects of AM11095 on chronic morphine were paralleled by a decrease in glial activation in the spinal cord, an index of opioid-induced neuroinflammation. NAAA inhibition might represent a potential novel therapeutic approach to increase the analgesic effects of opioids and delay the development of tolerance

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Η λαϊκή βοτανοθεραπευτική στο Ζαγόρι

The popular herbalism was studied in Zagori of Epirus from pharmacological point of view. The influence by quacks (Vicoyatri) is obvious in some villages, even today. The evaluation of the authenticity in the various recipes is handicaped by the fact that herbalism in the area of Zagori has been probably influenced by the exchange of information with other nations. The practice of herbal remedies is nowadays declining, due to the improvement of health care on a nationwide basis. In Zagori, several plants are used in a unique way, while others are already mentioned in the international bibliography. New therapeutic indications are arising by the use of some herbs, which must be studied thoroughly in order to detect the scientific basis of their use.Εξετάζεται, η λαϊκή βοτανοθεραπευτική στο Ζαγόρι, υπό το πρίσμα της σύγχρονης φαρμακογνωσίας και φαρμακολογίας. Η επίδραση των εμπειρικών γιατρών του Ζαγορίου (Βικογιατροί) είναι φανερή σε ορισμένα χωριά, ενώ οι αλληλεπιδράσεις με άλλους λαούς στην πλειονότητα των φυτών κάνουν δύσκολη τη διαπίστωση προέλευσης των συνταγών. Η λαϊκή βοτανοθεραπευτική στο Ζαγόρι σήμερα είναι σε παρακμή, σαν αποτέλεσμα βελτίωσης της υγειονομικής περίθαλψης. Από τα 38 χρησιμοποιούμενα βότανα τα 18 έχουν ένδειξη ή τρόπο χρήσης που δεν απαντούν αλλού, ή είναι σπάνια. Οι ενέργειες των περισσότερων φυτών δικαιολογούνται φαρμακολογικά από τα περιεχόμενα δραστικά συστατικά. Νέες ενδείξεις προκύπτουν για ορισμένα φυτά, που προτρέπουν σε χημική ανάλυση τους και φαρμακολογική μελέτη

N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibition, but Not Fatty Acid Amide Hydrolase Inhibition, Prevents the Development of Experimental Autoimmune Encephalomyelitis in Mice.

N-acylethanolamines (NAEs) are endogenous bioactive lipids reported to exert anti-inflammatory and neuroprotective effects mediated by cannabinoid receptors and peroxisome proliferator-activated receptors (PPARs), among others. Therefore, interfering with NAE signaling could be a promising strategy to decrease inflammation in neurological disorders such as multiple sclerosis (MS). Fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA) are key modulators of NAE levels. This study aims to investigate and compare the effect of NAAA inhibition, FAAH inhibition, and dual inhibition of both enzymes in a mouse model of MS, namely the experimental autoimmune encephalomyelitis (EAE). Our data show that NAAA inhibition strongly decreased the hallmarks of the pathology. Interestingly, FAAH inhibition was less efficient in decreasing inflammatory hallmarks despite the increased NAE levels. Moreover, the inhibition of both NAAA and FAAH, using a dual-inhibitor or the co-administration of NAAA and FAAH inhibitors, did not show an added value compared to NAAA inhibition. Furthermore, our data suggest an important role of decreased activation of astrocytes and microglia in the effects of NAAA inhibition on EAE, while NAAA inhibition did not affect T cell recall. This work highlights the beneficial effects of NAAA inhibition in the context of central nervous system inflammation and suggests that the simultaneous inhibition of NAAA and FAAH has no additional beneficial effect in EAE

Endocannabinoid metabolism and transport as targets to regulate intraocular pressure.

Cannabinoids are part of an endogenous signaling system found throughout the body, including the eye. Hepler and Frank showed in the early 1970s that plant cannabinoids can lower intraocular pressure (IOP), an effect since shown to occur via cannabinoid CB1 and GPR18 receptors. Endocannabinoids are synthesized and metabolized enzymatically. Enzymes implicated in endocannabinoids breakdown include monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), but also ABHD12, NAAA, and COX-2. Inhibition of MAGL activity raises levels of the endocannabinoid 2-arachidonoyl glycerol and substantially lowers IOP. Blocking other cannabinoid metabolizing enzymes or cannabinoid transporters may similarly contribute to lowering IOP and so serve as therapeutic targets for treating glaucoma. We have tested blockers for several cannabinoid-metabolizing enzymes and transporters (FABP5 and membrane reuptake) for their ability to alter ocular pressure in a murine model of IOP. Of FAAH, ABHD12, NAAA, and COX2, only FAAH was seen to play a role in regulation of IOP. Only the FAAH blocker URB597 lowered IOP, but in a temporally, diurnally, and sex-specific manner. We also tested two blockers of cannabinoid transport (SBFI-26 and WOBE437), finding that each lowered IOP in a CB1-dependent manner. Though we see a modest, limited role for FAAH, our results suggest that MAGL is the primary cannabinoid-metabolizing enzyme in regulating ocular pressure, thus pointing towards a role of 2-arachidonoyl glycerol. Interestingly, inhibition of cannabinoid transport mechanisms independent of hydrolysis may prove to be an alternative strategy to lower ocular pressure

Inhibition of N-acylethanolamine acid amidase reduces nicotine-induced dopamine activation and reward

Tobacco smoke is the leading preventable cause of death in the world and treatments aimed to increase success rate in smoking cessation by reducing nicotine dependence are sought. Activation of peroxisome proliferator-activated receptor-alpha (PPARα) by synthetic or endogenous agonists was shown to suppress nicotine-induced activation of mesolimbic dopamine system, one of the major neurobiological substrates of nicotine dependence, and nicotine-seeking behavior in rats and monkeys. An alternative indirect way to activate PPARα is inhibition of N-acylethanolamine acid amidase (NAAA), one of the major hydrolyzing enzyme for its endogenous agonists palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). We synthetized a novel specific brain permeable NAAA inhibitor, AM11095. We administered AM11095 to rats and carried out brain lipid analysis, a functional observational battery (FOB) to assess toxicity, in vivo electrophysiological recording from dopamine cells in the ventral tegmental area, brain microdialysis in the nucleus accumbens shell and behavioral experiments to assess its effect on nicotine -induced conditioned place preference (CPP). AM11095 (5 and 25 mg/kg, i.p.) was devoid of neurotoxic and behavioral effects and did not affect motor behavior and coordination. This NAAA inhibitor (5 mg/kg i.p.) increased OEA and PEA levels in the hippocampus and cortex, prevented nicotine-induced activation of mesolimbic dopamine neurons in the ventral tegmental area, nicotine-induced elevation of dopamine levels in the nucleus accumbens shell and decreased the expression of nicotine CPP. Our results indicate that NAAA inhibitors represent a new class of pharmacological tools to modulate brain PEA/PPARα signalling and show potential in the treatment of nicotine dependence