Papers by Alessandro Bartolini
British Journal of Pharmacology, 2000
The eect on cholinergic analgesia of inactivation of the M 1 gene by an antisense oligodeoxyribon... more The eect on cholinergic analgesia of inactivation of the M 1 gene by an antisense oligodeoxyribonucleotide (aODN) was investigated in the mouse hot plate test. Mice received a single intracerebroventricular (i.c.v.) injection of anti-M 1 aODN (0.3, 1.0 or 2.0 nmol per injection), degenerate ODN (dODN) or vehicle on days 1, 4 and 7. 2 A dose-dependent inhibition of the antinociception induced by the muscarinic agonists oxotremorine (0.1 mg kg 71 s.c.) and McN-A-343 (30 mg per mouse i.c.v.) and the cholinesterase inhibitor physostigmine (0.2 mg kg 71 s.c.) was observed 24 h after the last i.c.v. injection of aODN. Time-course experiments revealed that, after the end of the aODN treatment, sensitivity to analgesic drugs progressively appeared reaching the normal range at 96 h. 3 The anti-M 1 aODN was selective against muscarinic antinociception since the enhancement of pain threshold produced by morphine and baclofen were not aected by the above-mentioned treatment. dODN, used as control, did not aect muscarinic antinociception. 4 Binding studies evidenced a selective reduction of M 1 receptor levels in the hippocampus of aODN-treated mice. 5 Neither aODN, dODN nor vehicle produced any behavioural impairment of mice as revealed by the rota-rod and Animex experiments. 6 These results indicate that activation of M 1 muscarinic receptor subtype is fundamental to induce central cholinergic analgesia in mice.
Recent Patents on CNS Drug Discovery, 2011
The role of muscarinic and nicotinic cholinergic receptors in analgesia and neuropathic pain reli... more The role of muscarinic and nicotinic cholinergic receptors in analgesia and neuropathic pain relief is relatively unknown. This review describes how such drugs induce analgesia or alleviate neuropathic pain by acting on the central cholinergic system. Several pharmacological strategies are discussed which increase synthesis and release of acetylcholine (ACh) from cholinergic neurons. The effects of their acute and chronic administration are described. The pharmacological strategies which facilitate the physiological functions of the cholinergic system without altering the normal modulation of cholinergic signals are highlighted. It is proposed that full agonists of muscarinic or nicotinic receptors should be avoided. Their activation is too intense and un-physiological because neuronal signals are distorted when these receptors are constantly activated. Good results can be achieved by using agents that are able to a) increase ACh synthesis, b) partially inhibit cholinesterase activity c) selectively block the autoreceptor or heteroreceptor feedback mechanisms. Activation of M 1 subtype muscarinic receptors induces analgesia. Chronic stimulation of nicotinic (N 1) receptors has neuronal protective effects. Recent experimental results indicate a relationship between repeated cholinergic stimulation and neurotrophic activation of the glial derived neurotrophic factor (GDNF) family. At least 9 patents covering novel chemicals for cholinergic system modulation and pain control are discussed.
Neuropharmacology, 2002
The analgesic activity of acetyl-L-carnitine (ALCAR) in neuropathic pain is well established. By ... more The analgesic activity of acetyl-L-carnitine (ALCAR) in neuropathic pain is well established. By contrast, its potential efficacy in the relief of acute pain has not been reported. The antinociceptive effect of ALCAR was, therefore, examined in the mouse hotplate and abdominal constriction tests, and in the rat paw-pressure test. ALCAR (100 mg kg Ϫ1 s.c. twice daily for seven days) produced an increase of the pain threshold in both mice and rats. ALCAR was also able to reverse hyperalgesia induced by kainic acid and NMDA administration in the mouse hot-plate test. The antinociception produced by ALCAR was prevented by the unselective muscarinic antagonist atropine, the M 1 selective antagonists pirenzepine and S-(-)-ET126, and by the choline uptake inhibitor hemicholinium-3 (HC-3). By contrast the analgesic effect of ALCAR was not prevented by the opioid antagonist naloxone, the GABA B antagonist CGP 35348, the monoamine synthesis inhibitor (a)-methyl-p-tyrosine, and the Gi-protein inactivator pertussis toxin. Moreover, ALCAR antinociception was abolished by pretreament with an antisense oligonucleotide (aODN) against the M 1 receptor subtype, administered at the dose of 2 nmol per single i.c.v injection. On the basis of the above data, it can be postulated that ALCAR exerted an antinociceptive effect mediated by a central indirect cholinergic mechanism. In the antinociceptive doserange, ALCAR did not impair mouse performance evaluated by the rota-rod and hole-board tests.
Clinical Neuropharmacology, 2008
This study was designed to determine the short-term effect of acetyl-l-carnitine (ALC) on symptom... more This study was designed to determine the short-term effect of acetyl-l-carnitine (ALC) on symptoms of withdrawal in opiate-dependent subjects and animals and, in particular, on pain, given the efficacy of ALC in other typologies of pain. The study consists of 2 branches: a clinical study and a preclinical one, both with a randomized placebo-controlled design. Thirty subjects meeting clinical criteria for methadone dependence were consecutively recruited and treated with ALC 2 g/d or placebo for a 3-week detoxification period. Withdrawal symptoms and pain were evaluated through the Short Opiate Withdrawal Syndrome scale, and the Huskisson's analogue scale for pain. In the preclinical study, mice previously received a pretreatment (saline solution or morphine), and subsequently, each group was randomly divided in 4 subgroups that received a treatment of saline, methadone, ALC, or amitriptyline, respectively. Hot plate test and Writhing test were used to evaluate pain intensity. Average Short Opiate Withdrawal Syndrome total scores during the first 5 days of treatment resulted significantly higher in controls than in the ALC group (P < 0.05). Pain scores in the Huskisson's analogue scale were considerably lower in the group of patients taking ALC than in the control group after 1 week of ALC treatment until the end of the study. Results of the preclinical study show that the administration of methadone for 7 days in morphine-tolerant mice did not produce any modification of the pain threshold. By contrast, the 7-day coadministration of methadone and ALC in morphine-tolerant mice induced an analgesic effect evaluated 3 hours after the last injection. Acetyl-L-carnitine acted as an effective antihyperalgesic agent for relieving opiate-withdrawal hyperalgesia in animals and displayed clinical efficacy on other withdrawal symptoms such as muscular tension, muscular cramps, and insomnia. Considering its tolerability, the excellent side effect profile, the absence of significant interactions, and the lack of abuse potential, ALC can be considered as a useful pharmacological adjunct in the treatment of opiate withdrawal.
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Papers by Alessandro Bartolini