A comparison of muscarinic cholinergic involvement in the antinociceptive effects of morphine and clonidine in the mouse

Lipman, Jonathan J.; Spencer, P.S.

doi:10.1016/0014-2999(80)90232-0

Cited by 22 publications

(3 citation statements)

References 23 publications

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“…The fact that naloxone was without any effect on respiratory failure induced by oxotremorine suggests that it is not the activation of muscarinic receptors that induces the opioidergic influence of respiratory centre in the pontomedullar region of the rat brain. Similar lack of interaction between oxotremorine and naloxone was described in the tail-immersion nociceptive test in mice [38].…”

Section: Oxotremorinesupporting

confidence: 77%

Naloxone Antagonizes Soman‐induced Central Respiratory Depression in Rats

Škrbić

Stojiljković

Ćetković

et al. 2017

Basic Clin Pharma Tox

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The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve-diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose-dependently antagonized the soman-induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman-induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors.

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Section: Oxotremorinesupporting

confidence: 77%

Naloxone Antagonizes Soman‐induced Central Respiratory Depression in Rats

Škrbić

Stojiljković

Ćetković

et al. 2017

Basic Clin Pharma Tox

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“…Muscarinic cholinergic agonists are known from the literature to produce antinociception in a variety of species in several different antinociceptive tests. [1][2][3][4] The antinociceptive effect of muscarinic agonists were antagonized by centrally acting muscarinic antagonists, e.g., atropine, but not by peripherally acting antagonists such as methylatropine nor by opioid antagonists, 5,6 demonstrating that muscarinic antinociception was mediated by direct stimulation of centrally acting muscarinic receptors. Clinically, none of the currently available cholinergic agonists have been evaluated as analgesics, probably because of their prominent cholinergic side effects.…”

Section: Introductionmentioning

confidence: 99%

Conformationally Constrained Analogues of the Muscarinic Agonist 3-(4-(Methylthio)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine. Synthesis, Receptor Affinity, and Antinociceptive Activity

et al. 1998

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Conformationally constrained analogues of the potent muscarinic agonist 3-(4-methylthio)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methy lpyridine (methylthio-TZTP, 17) were designed and synthesized with the aim of (a) improving the antinociceptive selectivity over salivation and tremor and (b) predicting the active conformation of 17 with respect to the dihedral angle C4-C3-C3'-N2'. Using MOPAC 6.0 tricyclic analogues (7, 15, 16) with C4-C3-C3'-N2' dihedral angles close to 180 degrees and a rotation hindered analogue (9) with a C4-C3-C3'-N2' dihedral angle close to 274 degrees were designed, as these conformations had previously been suggested as being the active conformations. The analogues were tested for central muscarinic receptor binding affinity, for their antinociceptive activity in the mouse grid shock test, and, in the same assay, for their ability to induce tremor and salivation. The data showed that the tricyclic analogues (7, 15, 16) were equipotent with 17 as analgesics, but with no improved side effect profiles. The rotation-hindered analogue 9 had neither muscarinic receptor binding affinity nor antinociceptive activity. These results suggest that the active conformation of 17 has a C3-C4-C3'-N2' dihedral angle close to 180 degrees.

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“…Manipulation that alter the activity of acetylcholine in the central nervous system (CNS) frequently modify the effects of morphine and other opioid drugs [18][19][20][21].…”

Section: U50-488hmentioning

confidence: 99%

The Role of Muscarinic Receptors in the Control of Acute Opioid Withdrawal

Capasso¹

2007

LDDD

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This study was undertaken to determine which muscarinic receptors mediate parasympathetic responses in the ovine submandibular gland. The effects of selective muscarinic blocking agents on secretory and vascular responses to electrical stimulation of the chorda-lingual nerve were determined and morphological correlates were assessed by Western blotting. Anaesthesia was induced and maintained with sodium pentobarbitone (Sagatal; 15-30 mg kg _1 I.V., then 0.1_0.3 mg min _1 kg _1 I.V.). The ipsilateral ascending cervical sympathetic nerve was cut to eliminate effects of sympathetic activity and the animals were eventually killed with a lethal dose of barbiturate. Stimulation of the cut end of the parasympathetic chorda-lingual nerve continuously at 2 Hz, or in bursts of 1 s at 20 Hz every 10 s, for 10 min induced similar fluid responses (19 ± 5 vs. 21 ± 5 ml min _1 g gland _1 ; n = 10) although the protein output was about 50 % greater (P = 0.015; Student's t test) during stimulation in bursts. The vasodilator response was also significantly greater at 20 Hz 1:10 than at 2 Hz continuously as reflected by the fall in submandibular vascular resistance _53 ± 5 vs. _45 ± 4 %; P = 0.016; n = 10). Stimulation at 8 Hz induced a fluid response approximately three times as large (74 ± 11 ml/min g gland; n = 10) and a protein output 5 times greater than at 2 Hz; the reduction in vascular resistance was _75 ± 3 % (n = 10). Pirenzepine (40 mg/kg I.V.) significantly reduced the fluid response at all frequencies tested (P < 0.05-0.01), most conspicuously at 2 Hz where it was reduced by 85 %, but did not cause any significant change in the protein output or the vascular response. p-Fluoro-hexahydro-sila-diphenidol (4 mg/kg I.V.) in the presence of pirenzepine tended to further reduce the salivary secretion (reduced by 20 % at 8 Hz; n.s.), without causing any further change in the vascular or protein responses. Methoctramine (100 mg/kg IV), had no effect on either the fluid or the vascular response but significantly increased the protein output during the initial few min (2-4) of stimulation at 2 (+170 %; P < 0.007) and 20 Hz 1:10 (+125 %; P = 0.014), but not at 8 Hz. Western blot studies employing muscarinic receptor subtype-specific antibodies, revealed distinct bands corresponding to muscarinic M1, M3 and M5 receptors, with a faint band corresponding to the M4 type. Thus, M1 receptors occur in the ovine submandibular gland and contribute to the secretory response to parasympathetic stimulation but have little effect on the vasodilatation. Inhibitory muscarinic receptors seem to be of the M4 subtype, and blockade by methoctramine of neuronal inhibitory receptors causing increases in transmitter release would explain the increase in protein output. All procedures accord with current UK legislation C20 ATP is an important neurotransmitter and modulator that can act at two classes of receptors within the CNS. As many of the functions of ATP are incompletely understood, the ability to measure ATP release from the CNS in real time is...

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A comparison of muscarinic cholinergic involvement in the antinociceptive effects of morphine and clonidine in the mouse

Cited by 22 publications

References 23 publications

Naloxone Antagonizes Soman‐induced Central Respiratory Depression in Rats

Naloxone Antagonizes Soman‐induced Central Respiratory Depression in Rats

Conformationally Constrained Analogues of the Muscarinic Agonist 3-(4-(Methylthio)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine. Synthesis, Receptor Affinity, and Antinociceptive Activity

The Role of Muscarinic Receptors in the Control of Acute Opioid Withdrawal

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