Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB 1 receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB 1 receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB 1 receptor agonist, completely prevents the analgesic ac- 250CNS Drug Reviews Vol. 12, No. 3-4, pp. 250-275 © 2006 tivity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB 1 agonists are being introduced for pain treatment, it comes out that an indirect cannabinomimetic had been extensively used (and sometimes overused) for more than a century.

No abstract

The present data show, for the first time, that the melanocortin ACTH-(1-24) suppresses the NF-kappaB-dependent systemic inflammatory response triggered by hemorrhage, and reverses shock condition, by brain activation (in real-time) of the "cholinergic anti-inflammatory pathway", this pathway seeming to be melanocortin-dependent.

Besides its role as an energy storage organ, adipose tissue can be viewed as a dynamic and complex endocrine organ, which produces and secretes several adipokines, including hormones, cytokines, extracellular matrix (ECM) proteins, and growth and vasoactive factors. A wide body of evidence showed that adipokines play a critical role in various biological and physiological functions, among which feeding modulation, inflammatory and immune function, glucose and lipid metabolism, and blood pressure control. The aim of this review is to summarize the effects of several adipokines, including leptin, diponectin, resistin, chemerin, lipocalin-2 (LCN2), vaspin, omentin, follistatin-like 1 (FSTL1), secreted protein acidic and rich in cysteine (SPARC), secreted frizzled-related protein 5 (SFRP5), C1q/TNF-related proteins (CTRPs), family with sequence similarity to 19 member A5 (FAM19A5), wingless-type inducible signaling pathway protein-1 (WISP1), progranulin (PGRN), nesfatin-1 (nesfatin), visfatin/PBEF/NAMPT, apelin, retinol binding protein 4 (RPB4), and plasminogen activator inhibitor-1 (PAI-1) in the regulation of insulin resistance and vascular function, as well as many aspects of inflammation and immunity and their potential role in managing obesity-associated diseases, including metabolic, osteoarticular, and cardiovascular diseases.

Ischemic stroke is one of the main causes of death and disability. We investigated whether melanocortin peptides, which have protective effects in severe hypoxic conditions, also produce neuroprotection in a gerbil model of ischemic stroke. A 10-min period of global cerebral ischemia, induced by occluding both common carotid arteries, caused impairment in spatial learning and memory that was associated with activation of inflammatory and apoptotic pathways, including severe DNA damage and delayed neuronal death, in the hippocampus. Treatment with nanomolar doses of the melanocortin analog [Nle4, D-Phe7] alpha-MSH [which activates the melanocortin receptor subtypes (MC) mainly expressed in central nervous system, namely MC3 and MC4] modulated the inflammatory and apoptotic cascades and reduced hippocampus injuries even when delayed up to 9 h after ischemia, with consequent dose-dependent improvement in subsequent functional recovery. The selective MC3 receptor agonist gamma2-MSH had no protective effects. Pharmacological blockade of MC4 receptors prevented the neuroprotective effects of [Nle4, D-Phe7] alpha-MSH and worsened some ischemia outcomes. Together, our findings suggest that MC4 receptor-stimulating melanocortins might provide potential to develop a class of drugs with a broad treatment window for a novel approach to neuroprotection in ischemic stroke.

The present results give evidence for the identification of a protective, melanocortin-activated, efferent vagal cholinergic pathway, operative in conditions of myocardial ischemia/reperfusion. These data suggest that melanocortins and pertinent compounds able to activate such a pathway could provide the potential for development of a new class of drugs for a novel approach to management of ischemic heart disease.

No abstract

Objective.-To quantify and characterize the similarities and the differences between chronic migraine (CM) patients with medication overuse and episodic migraine (EM) patients with only occasional analgesic use. Background.-Population-level epidemiology, characteristics, mechanisms of chronic daily headache, and medication-overuse headache have been widely studied but patient characteristics have received less attention.Methods.-We compared sociodemographic data, family history, physiological and medical history, health services utilized, drugs taken/prescribed, and outcome of 2 groups of subjects: 150 patients, suffering from CM, complicated by probable medication-overuse headache (CM group), consecutively admitted during 2005 to the inpatients' ward of the Headache Centre of the University Hospital of Modena and Reggio Emilia, Italy, to undergo withdrawal from their overused medications; 100 patients suffering from EM, uncomplicated by medication overuse (EM group), consecutively referred to the outpatients' ward of the Headache Centre during November and December 2005.Results.-All sociodemographic characteristics were significantly different between the 2 groups. As a whole, the CM group began to suffer from migraine earlier than the EM group. Drug and/or alcohol abuse was significantly higher among first-degree relatives of CM (19%) than of EM (6%) patients. The most frequent comorbid disorders were psychiatric (67%) and gastrointestinal diseases (43%) in the CM group, and allergies in the EM group (31%). Seventy percent of CM patients and 42% of EM patients were taking daily at least another drug, besides those for headache treatment. Most overused medications in the CM group were triptans (43%); the EM group used above all single NSAIDs (56%). At 3-month follow-up, prophylactic treatments reduced, by at least 50%, the frequency of headache in about three-fourths of patients of both the groups; however, headache remained significantly more frequent in the CM than in EM group: only a minority (15%) of CM patients reverted to a headache frequency comparable to that of the EM group.Conclusions.-CM patients present more multiple comorbid disorders, polypharmacy, and social impediments than EM patients. These associated conditions complicate CM clinical management. Even after withdrawal from medication overuse, CM could not be completely reverted by current prophylactic treatments.