In conclusion, as RHO was effective for reducing craving and vulnerability to relapse, it might be a very effective natural remedy for the treatment of opioid addiction.

This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(−)-2 and (S)-(+)-2, displaying α 2C -adrenoreceptor (AR) agonism/α 2A -AR antagonism, similarly to allyphenyline (1) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT 1A receptor (5-HT 1A -R) activation. Indeed, 1 or the single (S)-(+)-1, 2, or both its enantiomers, all behaving as α 2C -AR agonists/α 2A -AR antagonists/5-HT 1A -R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction. KEYWORDS: α 2 -adrenergic ligands, 5-HT 1A -R agonists, morphine withdrawal symptoms reduction, antidepressant-like effect M orphine use is the classical approach in the treatment of chronic or cancer-related pain. Nevertheless, even when legally allowed and closely monitored, long-term opioid administration alters central pain-related systems, inducing tolerance and dependence. Opioid addiction, termed a "chronic relapsing disease", is associated with a myriad of health and social problems; hence, its management is an extremely important area of research. 1 α 2 -Adrenoreceptors (α 2 -ARs), which have been demonstrated to be extremely sensitive to opioid exposure and to play a key role in opiate withdrawal symptoms, 2 belong to the superfamily of G-protein-coupled receptors. The three α 2A -, α 2B -, and α 2C -AR subtypes are widely distributed in the central nervous system (CNS) and peripheral tissues. 3 Studies with genetically engineered mice have demonstrated that the α 2A subtype mediates hypotension, sedation, and analgesia, as well as inhibition of monoamine release and metabolism in the brain. The α 2B subtype mediates vasoconstriction, while the α 2C subtype appears to be involved in many CNS processes, such as the startle reflex, stress responses, and control of locomotion as well as feedback inhibition of adrenal cathecolamine release. Moreover, in the brain, α 2A -and α 2C -ARs, as "heteroreceptors", inhibit dopamine and serotonin release. Finally, the α 2C subtype can contribute to adrenergic-opioid synergy and spinal α 2 -agonist-mediated analgesia. 3−5 In detoxification, α 2 -AR agonists such as clonidine and lofexidine are often clinically used alone or in combination with traditional treatments to reduce the intensity of withdrawal symptoms, thus increasing treatment duration. However, the α 2A -AR activation triggered by these compounds is responsible for side effects such as sedation and hypotension.

The present study showed the positive effects of R. rosea L. in reducing rewarding properties and preventing relapse to nicotine and evidenced the important role of salidroside in the effects of the extract.

Opioid addiction is often characterized as a chronic relapsing condition due to the severe somatic and behavioral signs, associated with depressive disorders, triggered by opiate withdrawal. Since prolonged abstinence remains a major challenge, our interest has been addressed to such objective. Exploring multitarget interactions, the present investigation suggests that 3 or its (S)-enantiomer and 4, endowed with effective α 2C -AR agonism/α 2A -AR antagonism/5-HT 1A -R agonism, or 7 and 9−11 producing efficacious α 2C -AR agonism/α 2A -AR antagonism/I 2 −IBS interaction might represent novel multifunctional tools potentially useful for reducing withdrawal syndrome and associated depression. Such agents, lacking in sedative side effects due to their α 2A -AR antagonism, might afford an improvement over current therapies with clonidine-like drugs.KEYWORDS: α 2 -Adrenergic ligands, 5-HT 1A agonists, I 2 −IBS ligands, morphine withdrawal symptoms reduction, antidepressant-like effect O pioid exposure is known to induce potent analgesic effect as well as relaxation and euphoria. The repeated use of opiate drugs, both for the relief of chronic or cancer-related pain and for recreational drug-taking behavior, can lead to the development of dependence. Addiction to opioids is a complex syndrome involving tolerance, drug-seeking, and physical dependence with withdrawal avoidance behaviors. It is often characterized as a chronic relapsing condition and is a major health and social issue in most societies. 1 Detoxification, a necessary step for many forms of long-term abstinence-based treatments, makes use of two approaches: tapering using methadone or buprenorphine, or abrupt termination of opioid use, potentially precipitated by an opioid antagonist (i.e., naltrexone) with administration of α 2 -adrenoreceptor (α 2 -AR) agonists to reduce withdrawal symptoms. 1 α 2 -ARs have been demonstrated to be extremely sensitive to opioid exposure. 2 Subdivided into α 2A -, α 2B -, and α 2C -subtypes, α 2 -ARs belong to the superfamily of G-protein-coupled receptors and are widely distributed in the central nervous system (CNS) and in peripheral tissues. 3 The α 2A subtype mediates hypotension, sedation and analgesia, as well as inhibition of monoamine release and metabolism in the brain. The α 2B -subtype mediates vasoconstriction. The α 2C -subtype appears to be involved in feedback inhibition of adrenal cathecolamine release and can contribute to adrenergic-opioid synergy. In the brain, α 2A -and α 2C -ARs, as "heteroreceptors", inhibit dopamine and serotonin release. 3−5 The nonsubtype selective α 2 -AR agonist clonidine has been clinically used alone or in combination with traditional treatments for relief of withdrawal symptoms during detoxification, thus increasing treatment duration. Nevertheless, clonidine, due to its α 2A -AR subtype activation, is responsible for side effects of sedation and hypotension, 1 that limit the use of high doses. Strong association between protracted abstinence and depressive disorder...

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