Fibromyalgia (FM) is an important cause of morbidity and health expenditure. Severe widespread extra-articular chronic pain, along with nonrestorative sleep, dominates the clinical syndrome. The pathogenesis of FM remains unclear. While dysfunction in serotoninergic neurotransmission is believed to play an important role, several neurologic and immuno-endocrine mechanisms may also be relevant. A theory is advanced based on an inherited imbalance in neuro-vegetative systems resulting from increased sympathetic tone because of a metabolic deficiency in the serotoninergic system that, when exposed to a precipitating event, leads to the development of the clinical manifestations of FM. The importance of both nonpharmacological treatments and multimodal medication management is stressed.

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...

Background and Purpose CR4056 is a first‐in‐class imidazoline‐2 (I2) receptor ligand characterized by potent analgesic activity in different experimental animal models of pain. In a recent phase II clinical trial, CR4056 effectively reduced pain in patients with knee osteoarthritis. In the present study, we investigated the effects of CR4056 on PKCε translocation in vitro and on PKCε activation in vivo in dorsal root ganglia (DRG) neurons. Experimental Approach Effects of CR4056 on bradykinin‐induced PKCε translocation were studied in rat sensory neurons by immunocytochemistry. PKCε activation was investigated by immunohistochemistry analysis of DRG from complete Freund's adjuvant‐treated animals developing local hyperalgesia. The analgesic activity of CR4056 was tested on the same animals. Key Results CR4056 inhibited PKCε translocation with very rapid and long‐lasting activity. CR4056 decreased hyperalgesia and phospho‐PKCε immunoreactivity in the DRG neurons innervating the inflamed paw. The effect of CR4056 on PKCε translocation was blocked by pertussis toxin, implying that the intracellular pathways involved Gi proteins. The inhibition of PKCε translocation by CR4056 was independent of the α2‐adrenoeceptor and, surprisingly, was also independent of idazoxan‐sensitive I2 binding sites. The I2 agonist 2BFI had no effect alone but potentiated the activity of low concentrations of CR4056. Conclusions and Implications Our results demonstrate that CR4056 shares the ability to inhibit PKCε translocation with other analgesics. Whether the inhibition of PKCε involves binding to specific subtype(s) of I2 receptors should be further investigated. If so, this would be a new mode of action of a highly specific I2 receptor ligand.

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5-HT receptors are known to form constitutive dimers in membranes. To explore whether multivalency can enhance ligand interactions and/or efficacy in 5-HT receptors, the structure of the partial agonist ML10302 was modified with oligo(ethylene glycol) chains, thus generating, by a gradual approach, short and long tethered bivalent or tetravalent ligands and the corresponding spanner-linked monovalent controls. Both bivalent and tetravalent ligands displayed a 10-20-fold increase in binding affinity compared to appropriate controls, but no multivalent ligand showed greater binding energy than ML10302 itself. Furthermore, the direct assessment of receptor-Gs interaction and studies of cAMP signalling indicated that multivalency does not enhance the efficacy of ML10302.