Role of muscarinic receptor subtypes in central antinociception

Bartolini, Alessandro; Ghelardini, Carla; Fantetti, Lia; Malcangio, Marzia; Malmberg-Aiello, P.; Giotti, A

doi:10.1111/j.1476-5381.1992.tb14213.x

Cited by 103 publications

(50 citation statements)

References 27 publications

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“…Several reports have also provided evidence for the receptorial mechanism involved in the muscarinic antinociception. Literature data indicates that supraspinal cholinergic antinociception induced both directly, through muscarinic agonists, and indirectly, by enhancing ACh extracellular levels through cholinesterase inhibitors, is mediated by M 1 receptor stimulation, evidencing that M 1 muscarinic receptor subtype plays an essential role in the modulation of pain perception [2,11,12,20,23]. The involvement of the M 2 muscarinic receptor subtype in the induction of analgesia has also been postulated by using pharmacological antagonists [13] and by generating M 2 muscarinic receptor knockout mice [14].…”

Section: Introductionmentioning

confidence: 99%

Ryanodine receptors are involved in muscarinic antinociception in mice

Galeotti

Bartolini

Ghelardini

2005

Behavioural Brain Research

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The role of ryanodine receptors (RyRs) in the induction of muscarinic antinociception was investigated in a condition of acute thermal pain by means of the mouse hot-plate test. I.c.v. administration of non-hyperalgesic doses of ryanodine (0.001-0.06 nmol per mouse i.c.v.), an antagonist of ryanodine receptors (RyRs), dose-dependently prevented the antinociception induced by both physostigmine (100-150 g kg −1 s.c.) and oxotremorine (40-70 g kg −1 s.c.). A shift to the right of the dose-response curve of both cholinomimetic compounds was observed. Pretreatment with non-analgesic doses of 4-chloro-m-cresol (4-Cmc; 0.003-0.3 nmol per mouse i.c.v.), an agonist of RyRs, reversed in a dosedependent manner the antagonistic effect produced by ryanodine of muscarinic antinociception. The pharmacological treatments employed neither modified the animals' gross behavior nor produced any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate that a variation of intracellular calcium contents at the central nervous system level is involved in muscarinic antinociception. In particular, the stimulation of RyRs appears to play an important role in the increase of the pain threshold produced by physostigmine and oxotremorine in mice.

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Section: Introductionmentioning

confidence: 99%

Ryanodine receptors are involved in muscarinic antinociception in mice

Galeotti

Bartolini

Ghelardini

2005

Behavioural Brain Research

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“…Several literature reports indicate that cholinergic antinociception induced both directly, through muscarinic agonists, and indirectly, by enhancing ACh extracellular levels through cholinesterase inhibitors, is mediated by M 1 receptor stimulation, evidencing that M 1 muscarinic receptor subtype plays an essential role in the modulation of pain perception (Bartolini et al, 1992;Iwamoto and Marion, 1993;Ghelardini et al, 1996;Naguib and Yaksh, 1997;Ghelardini et al, 2000). The involvement of the M 2 muscarinic receptor subtype in the induction of analgesia has also been postulated by using pharmacological antagonists (Gillbert et al, 1989) and by generating M 2 muscarinic receptor knockout mice (Gomeza et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

Galeotti¹,

Bartolini²,

Ghelardini³

2002

Neuropsychopharmacol

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The cellular events involved in muscarinic analgesia were investigated in the mouse hot-plate test. Intracerebroventricular (i.c.v.) pretreatment with antisense oligonucleotides (aODNs) against the a subunit of G q and G 11 proteins prevented the analgesia induced by physostigmine and oxotremorine. Furthermore, administration of the phospholipase C (PLC) inhibitor U-73122, as well as the injection of an aODN complementary to the sequence of PLCb 1 , antagonized the increase of the pain threshold induced by both cholinomimetic drugs. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, or treatment with heparin, an IP 3 receptor antagonist, the antinociception induced by physostigmine and oxotremorine was dose-dependently antagonized. I.c.v. pretreatment with TMB-8, a blocker of Ca 2+ release from intracellular stores, prevented the increase of pain threshold induced by the investigated cholinomimetic drugs. Coadministration of Ca 2+ restored the muscarinic analgesia in LiCl, heparin, and TMB-8-preatreated mice. On the other hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitor calphostin C, resulted in a dose-dependent enhancement of physostigmine-and oxotremorine-induced antinociception. The administration of PKC activators, such as PMA and PDBu, dose dependently prevented the cholinomimetic drug-induced increase of pain threshold. Neither aODNs nor pharmacological treatments employed produced any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate a role for the PLC-IP 3 pathway in central muscarinic analgesia in mice. Furthermore, activation of PKC by cholinomimetic drugs may represent a pathway of negative modulation of muscarinic antinociception.

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“…It has long been known that the direct and indirect activation of the cholinergic system produces analgesia in both animals (1,2,9,(16)(17)(18)21,23,24) and humans (20). Because sumatriptan is endowed with cholinergic antinociceptive properties and 8-OH-DPAT enhances ACh release, the goals of the present study were to explore whether other 5-HT 1A agonists, such as gepirone and 8-OH-DPAT, were able to increase the pain threshold in mice and then investigate whether a cholinergic mechanism underlies 5-HT 1A antinociception.…”

mentioning

confidence: 99%

5-HT1A Agonists Induce Central Cholinergic Antinociception

Galeotti

Ghelardini

Bartolini

1997

Pharmacology Biochemistry and Behavior

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GALEOTTI, N., C. GHELARDINI AND A. BARTOLINI. 5-HT 1A agonists induce central cholinergic antinociception. PHARMACOL BIOCHEM BEHAV 57 (4) 835-841, 1997.-The antinociceptive effects of the 5-HT 1A agonists buspirone [3 mg/kg intraperitoneally (IP)], gepirone (3-6 mg/kg IP), and 8-OH-DPAT [3-5 mg/kg IP; 1-3 g per mouse intracerebroventricularly (ICV)] were examined in mice by using the hot-plate (thermal stimulus) and abdominal constriction (chemical stimulus) tests. Buspirone, gepirone, and 8-OH-DPAT produced significant antinociception, which was prevented by atropine (5 mg/kg IP), the ACh depletor hemicholinium-3 (1 g per mouse ICV), and the 5-HT 1A antagonist NAN 190 (0.5 g per mouse ICV), but not by naloxone (1 mg/kg IP), the GABA B antagonist CGP 35348 (100 mg/kg IP), and pertussis toxin (0.25 g per mouse ICV). NAN 190, which totally antagonized buspirone, gepirone, and 8-OH-DPAT antinociception, did not modify the analgesic effect of morphine (5 mg/kg subcutaneously). In the antinociceptive dose range, none of the 5HT 1A agonists impaired mouse performance evaluated by rota-rod and hole board tests. On the basis of these data, it can be postulated that buspirone, gepirone, and 8-OH-DPAT exert an antinociceptive effect mediated by a central amplification of cholinergic transmission. © 1997 Elsevier Science Inc. 8-OH-DPATBuspirone Gepirone 5-HT 1A receptors ACh Cholinergic neurotransmission Antinociception Analgesia THE nonbenzodiazepine anxiolytic drugs buspirone, gepirone, and 8-OH-DPAT are agonists of the serotoninergic 5-HT 1A receptors in the central nervous system. Serotonin 5-HT 1A sites are localized predominantly on the axon terminals of serotoninergic neurons. They function as autoreceptors (14), and their stimulation leads to the disinhibition of the cholinergic system that is tonically inhibited by tryptaminergic control (11). Bianchi et al. (4) demonstrated that the full 5-HT 1A agonist 8-OH-DPAT was able to increase ACh release from the cerebral cortex of freely moving guinea pigs. Recent studies have shown that buspirone, given systemically, produces antinociception in several pain tests in rats (12). Giordano and Rogers (13) reported that buspirone-induced analgesia may be a nonopioid, adrenally mediated co-and/or epi-phenomenon to core hypothermia evoked by 5-HT 1A receptor agonism. Recently, it was reported that sumatriptan, another 5-HT 1A agonist, was able to induce antinociception in mice and rats through a cholinergic mechanism (3).It has long been known that the direct and indirect activation of the cholinergic system produces analgesia in both animals (1,2,9,16-18,21,23,24) and humans (20). Because sumatriptan is endowed with cholinergic antinociceptive properties and 8-OH-DPAT enhances ACh release, the goals of the present study were to explore whether other 5-HT 1A agonists, such as gepirone and 8-OH-DPAT, were able to increase the pain threshold in mice and then investigate whether a cholinergic mechanism underlies 5-HT 1A antinociception. Moreover, we examined whether such antinoci...

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Role of muscarinic receptor subtypes in central antinociception

Abstract: 1 The ability to modify the pain threshold by the two M,-muscarinic agonists: AF-102B and by the specific M2-agonist arecaidine was examined in mice and rats by using three different noxious stimuli: chemical (writhing test), thermic (hot-plate test) and mechanical (paw pressure test).

Cited by 103 publications

References 27 publications

Ryanodine receptors are involved in muscarinic antinociception in mice

Ryanodine receptors are involved in muscarinic antinociception in mice

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

5-HT1A Agonists Induce Central Cholinergic Antinociception

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