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Elena Lucarini,1 Laura Micheli,1 Alma Martelli,2 Lara Testai,2 Vincenzo Calderone,2 Carla Ghelardini,1 Lorenzo Di Cesare Mannelli1 1Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research, and Child Health (Neurofarba), University of Florence, Florence, Italy; 2Department of Pharmacy, University of Pisa, Pisa, Italy Purpose: Current pharmacotherapy for persistent pain related to neuropathy or articular diseases is unsatisfactory, due to the large number of unresponsive patients and side effects. Isothiocyanates (ITCs) are a class of natural or synthetic compounds characterized by the general formula R–NCS. ITCs show antihyperalgesic effects in models of central and peripheral nervous tissue injury and anti-inflammatory properties. The pharmacodynamics are strictly related to the release of the gasotransmitter hydrogen sulfide (H2S) from their moiety. In particular, phenyl ITC (PITC) and 3-carboxyphenyl ITC (3C-PITC) exhibit interesting slow H2S-release properties suitable for treating painful pathology. The aim of the present work was to evaluate the efficacy of PITC and 3C-PITC against mechanical hyperalgesia and spontaneous pain induced by nerve injury and osteoarthritis.Methods: Nerve injury and osteoarthritis were induced in rats by ligation of the sciatic nerve (chronic constriction injury) and intra-articular injection of monoiodoacetate, respectively. Behavioral tests were performed 14 days after damage induction.Results: Single subcutaneous administrations of PITC, 3C-PITC (4.43 and 13.31 µmol kg-1, respectively) were able to completely reverse hypersensitivity to noxious stimuli in both models of neuropathic and osteoarticular pain. The effect of ITCs was compared with that of NaHS, the prototypical H2S donor, showing similar efficacy and higher potency. ITCs and NaHS also reduced spontaneous pain.Conclusion: ITCs offer a promising novel approach to counteract persistent, drug-resistant painful pathology. Keywords: neuropathic pain, nerve injury, osteoarthritis, isothiocyanate, H2S

Neuropathic syndromes which are evoked by lesions to the peripheral or central nervous system are extremely difficult to treat, and available drugs rarely joint an antihyperalgesic with a neurorestorative effect. N-Palmitoylethanolamine (PEA) exerts anti-nociceptive effects in several animal models and inhibits peripheral inflammation in rodents. Aimed to evaluate the antineuropathic properties of PEA, a damage of the sciatic nerve was induced in mice by chronic constriction injury (CCI) and a subcutaneous daily treatment with 30 mg kg-1 PEA was performed. On the day 14, PEA prevented pain threshold alterations. Histological studies highlighted that CCI induced oedema and an important infiltrate of CD86 positive cells in the sciatic nerve. Moreover, osmicated preparations revealed a decrease in axon diameter and myelin thickness. Repeated treatments with PEA reduced the presence of oedema and macrophage infiltrate, and a significant higher myelin sheath, axonal diameter, and a number of fibers were observable. In PPAR-α null mice PEA treatment failed to induce pain relief as well as to rescue the peripheral nerve from inflammation and structural derangement. These results strongly suggest that PEA, via a PPAR-α-mediated mechanism, can directly intervene in the nervous tissue alterations responsible for pain, starting to prevent macrophage infiltration. [ABSTRACT FROM AUTHOR]

Abstract: Damages to the nervous system are the primarily cause of neuropathy and chronic pain. Current pharmacological treatments for neuropathic pain are not able to prevent or revert morphological and molecular consequences of tissue injury. On the other hand, many neurotrophins, like nerve growth factor (NGF), paired off restorative effects with hyperalgesia. Interestingly, the glial cell line–derived neurotrophic factors GDNF and Artemin (ARTN) seem to support neuron survival and to normalize abnormal pain behaviour. In the present research protein levels of NGF, GDNF and ARTN were evaluated in a rat model of peripheral neuropathy, the chronic constriction injury (CCI). NGF was increased by CCI in the ipsilateral dorsal root ganglia (DRG), in the spinal cord and in the periaqueductal grey matter (PAG). On the contrary, ARTN was decreased bilaterally in DRG, spinal cord and PAG. GDNF levels decreased in ipsilateral DRG, whereas the constriction did not modify its expression in the central nervous system districts. Repeated treatments with the antihyperalgesic and neuroregenerative compound acetyl-l-carnitine (ALCAR; 100 mgkg−1 i.p. twice daily for 15 days) was able to prevent the increase of NGF levels. In conditions of pain relief ALCAR normalized peripheral and central alterations of GDNF and ARTN levels. Characteristically, sham animals that underwent the same ALCAR treatment, showed increased levels of ARTN both in the DRG and in the spinal cord. These data offer a new point of view on the mechanism of the antihyperalgesic as well as the neuroprotective effect of ALCAR. [Copyright &y& Elsevier]

Abstract: A series of analogs of DM235 and MN19, characterized by rings with different size, have been prepared and evaluated for their nootropic activity in the mouse passive-avoidance test. It was found that the optimal ring size for the analogs of DM235, showing endocyclic both amidic groups, is 6 or 7 atoms. For the compounds structurally related to MN19, carrying an exocyclic amide group, the piperidine ring is the moiety which gives the most interesting compounds. [Copyright &y& Elsevier]

Aim Despite some studies suggested that childhood attention-deficit hyperactivity disorder (ADHD) and inattention symptoms may be related to hoarding, only a small case series study investigated the effectiveness of ADHD medications in hoarding disorder. The aim of the present study was to evaluate the preclinical and clinical effectiveness of atomoxetine, a noradrenaline reuptake inhibitor approved for childhood and adulthood ADHD, in an animal model of compulsive-like behaviors (marble burying test) and in patients with a primary diagnosis of hoarding disorder. Methods We performed a preclinical investigation assessing the effects of atomoxetine on the marble burying behavior test in mice. The number of marbles buried in vehicle and atomoxetine treated groups was measured. Subsequently, we conducted a clinical investigation on five patients fulfilling the DSM-5 criteria for hoarding disorder. These patients were treated with atomoxetine 40–100 mg for 12 weeks. Full response was defined as a more of 35% decrease in UCLA Hoarding Severity Scale (UHSS) and partial response was defined as a more of 25% decrease in UHSS scale. Results Atomoxetine significantly reduced the number of buried marbles in a dose dependent manner in comparison to control mice, without affecting the locomotor activity. Three out of five atomoxetine-treated patients were classified as full responders and two patients as partial responders after 12 weeks of treatment. Conclusions These preclinical and clinical data suggest that atomoxetine may be considered as a potentially effective compound for hoarding disorder and therefore should be considered for future controlled trials in hoarding disorder. [ABSTRACT FROM AUTHOR]

B Introduction: b Opioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and by dependence, particularly in vulnerable individuals. Noradrenergic locus coeruleus (LC) is a pivotal area that contributes to the development of morphine dependence, tolerance and withdrawal. B Conclusions: b Our results show that the NAAA inhibitor AM11095 potentiates morphine-evoked inhibition of LC neurons to nociceptive stimuli, a neural correlate of its analgesic effect, and delays the development of tolerance induced by chronic morphine administration. [Extracted from the article]