The chronic effects of nicotine monomethidide on gastric secretion in pylorus-ligated rats

Thompson, John N.; Angulo, Manuel; Chor, Leslie; Roch, Margaret; Jenden, Donald J.

doi:10.1007/bf01946153

Cited by 4 publications

(4 citation statements)

References 15 publications

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“…Numerous other studies have used methiodides of nicotine as probes to distinguish the central and peripheral actions of nicotine (Domino, ; Geller et al, ; Shechter and Rosecrans, ; Thompson et al, ; Lenoir and Kiyatkin, ; Tang and Kiyatkin, ; Lenoir et al, ). The present study, which used NIC‐PM to differentiate the peripheral and central actions of nicotine, is based on the assumption that NIC‐PM, which is a highly polar molecule, does not cross the blood–brain barrier and that NIC‐PM has nicotine‐like properties.…”

Section: Discussionmentioning

confidence: 99%

Neuroanatomical circuitry mediating the sensory impact of nicotine in the central nervous system

Dehkordi

Rose

Asadi

et al. 2014

J of Neuroscience Research

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Direct actions of nicotine in the CNS appear to be essential for its reinforcing properties. However, activation of nicotinic acetylcholine receptors (nAChRs) on afferent sensory nerve fibers are important components of addiction to, and withdrawal from, cigarette smoking. The present study was to identify the neuroanatomical substrates activated by the peripheral actions of nicotine and to determine whether these sites overlap brain structures stimulated by direct actions of nicotine. Mouse brains were examined by immunohistochemistry for c-Fos protein after intraperitoneal injection of either nicotine (NIC, 30 and 40 µg/kg) and/or nicotine pyrrolidine methiodide (NIC-PM, 20 and 30 µg/kg). NIC-PM induced c-Fos immunoreactivity (IR) at multiple brain sites. In the brainstem, c-Fos IR was detected in locus coeruleus, laterodorsal tegmental nucleus and pedunculotegmental nucleus. In the midbrain, c-Fos IR was observed in areas overlapping the ventral tegmental area (VTA) which includes paranigral nucleus, parainterfascicular nucleus, parabrachial pigmental area and rostral VTA. Other structures of the nicotine brain-reward circuitry activated by NIC-PM included hypothalamus, paraventricular thalamic nucleus, lateral habenular nucleus, hippocampus, amygdala, accumbens nucleus, piriform cortex, angular insular cortex, anterior olfactory nucleus, lateral septal nucleus, bed nucleus of stria terminalis, cingulate and medial prefrontal cortex, olfactory tubercle, medial and lateral orbital cortex. Nicotine, acting through central and peripheral nAChRs, produced c-Fos IR in areas that overlapped NIC-PM induced c-Fos expressing sites. These neuroanatomical data are the first to demonstrate that the CNS structures which are the direct targets of nicotine are also anatomical substrates for the peripheral sensory impact of nicotine.

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Section: Discussionmentioning

confidence: 99%

Neuroanatomical circuitry mediating the sensory impact of nicotine in the central nervous system

Dehkordi

Rose

Asadi

et al. 2014

J of Neuroscience Research

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“…McKennis, Bowman, Hovath & Bederka (1964) have shown that a series of pyridinium methiodides can be Ndemethylated. Also, Thompson et al, (1972) have tried with no success to measure nicotine levels in rat brain after administration of nicotine pyrrolidine methiodide. We found nicotine in mouse brain after administration of the methiodides in levels that constituted approximately one-tenth and one-half of the brain radioactivity of the pyridine and bis methiodides, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The methiodides of nicotine have been used extensively as probes for distinguishing the central and peripheral actions of nicotine (Domino, 1965;Geller, Hartman & Blum, 1971;Schechter & Rosecrans, 1972;Thompson, Angulo, Choi, Roch & Jenden, 1972). The loss of central activity after quatemization of nicotine could be due to a decrease in the penetrability of the blood-brain barrier or to an alteration in the pharmacological activity or a combination of both.…”

Section: Introductionmentioning

confidence: 99%

Antinociceptive action of nicotine and its methiodide derivatives in mice and rats

Aceto

Awaya

Martin

et al. 1983

British J Pharmacology

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1 Three quaternary methiodides of nicotine were prepared and tested for antinociceptive activity in the mouse tail-flick, mouse phenylquinone and rat tail-flick tests. 2 Following peripheral administration, all three methiodides were inactive in the mouse and rat tail-flick procedures, whereas nicotine was active in both tests, which suggested that nicotine was acting centrally. 3 Quatemization of nicotine did not eliminate antinociceptive activity as demonstrated by the intraventricular injection of the methiodides in mice. Nicotine pyrrolidine and bismethiodides were somewhat more potent than nicotine, whereas nicotine pyridine methiodide was considerably less potent than nicotine in the tail-flick procedure. 4 Systemically administered nicotine pyrrolidine methiodine was approximately one-third as active as nicotine in the mouse phenylquinone test; nicotine pyridine methiodide and nicotine bis methiodide were 100 and 300 times less active, respectively. 5 Hexamethonium partially blocked nicotine and nicotine pyrrolidine methiodide, whereas mecamylamine blocked nicotine completely but nicotine pyrrolidine methiodide partially. Nicotine may have both central and peripheral actions in the mouse phenylquinone test, whereas nicotine pyrrolidine methiodide may have both nicotine and non-nicotine like antinociceptive activity. 6 The radiolabelled methiodides were synthesized and their disposition in body tissues studied. The methiodides were found to penetrate brain poorly (plasma-to-brain ratios > 20). 7 The methiodides were metabolized to nicotine to a small extent. This metabolism occurred to a greater extent in mice than in rats.

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“…Pharmacological studies have found that the effects of N-methylnicotines were apparently confined to the peripheral nervous system (8)(9)(10)(11)(12)(13)(14). Many biological studies have suggested, based upon the occurrence of peripheral effects without central effects, that N-methylnicotines did not penetrate the BBB (15)(16)(17)(18)(19). Studies of nicotine metabolites in a number of species have shown the presence of N-methylnicotines (20)(21)(22)(23).…”

mentioning

confidence: 99%

Blood-brain barrier penetration abolished by N-methyl quaternization of nicotine.

Oldendorf¹,

Stoller²,

Harris³

1993

Proc. Natl. Acad. Sci. U.S.A.

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The present study determined the effect of organically quaternizing either ofthe two tertiary nitrogen sites of nicotine to assess the in vivo effects of the permanently ionized states of the synthesized N-[14C]methylnicotines on brain uptake in rat after intracarotid i jection. Male SpragueDawley rats were used to measure the brain uptake index (BUI) by single-pass clearance in brain after rapid in'ection at pH 7.4 into the left common carotid artery (expressed as a percentage) relative to simultaneously injected 3HOH. The BUI 6f ["4CImannitol, a control for the method background, was measured to be 2.6 + 0.6. At physiological pH, in striking contrast to the [pyrroldine-2-14C]nicotine BUI of 120 ±s3, the N-["4C]-methylnicotines had a BUI of 3.0 ± 0.6, which was not significantly different from the method background and which indicated abolition of blood-brain barrier penetration of nicotine with the sensitivity of the BUI method.Many alkaloids contain nitrogen(s) that exist in a positively charged form at physiological pH. Many of these substances are also known to have considerable brain uptake (1). In a study of [pyrrolidine-2-"4C]nicotine at various pH values from 4.7 to 10.4, the brain uptake index (BUI), values varied from 49 ± 10 to 127 ± 5, according to the fraction of neutral (uncharged) nicotine molecules available for blood-brain barrier (BBB) penetration (2). The present study was undertaken to determine iforganic quaternization ofeither nitrogen or nicotine would reduce the fraction of neutral nicotine and its penetration ofthe BBB at physiological pH 7.4 by the BUI method.Prior reports have reviewed theoretical or experimental factors that influence nicotine activity, quaternary nicotine ions, and uncharged molecules at physiological pH values (3)(4)(5)(6)(7). Pharmacological studies have found that the effects of N-methylnicotines were apparently confined to the peripheral nervous system (8-14). Many biological studies have suggested, based upon the occurrence of peripheral effects without central effects, that N-methylnicotines did not penetrate the BBB (15-19). Studies of nicotine metabolites in a number of species have shown the presence of N-methylnicotines (20-23).In the present study nicotine was methylated with [14C]-methyl iodide to synthesize two quaternized and therefore permanently charged cationic derivatives. These quaternized derivatives were nicotine isomethiodide (NIM), in which the pyridine nitrogen was methylated, and nicotine monomethiodide (NMI) in which the pyrrolidine nitrogen was methylated. High-pressure liquid chromatographic (HPLC) procedures were developed to assay these derivatives; product structure was confirmed by nuclear magnetic resonance (NMR) spec- MATERIALS AND METHODS Animals. Studies were performed with 250-to 300-g adult male Sprague-Dawley rats (Harlan-Sprague-Dawley) that were housed in a temperature/humidity/light-controlled (6:00 a.m. to 6:00 p.m.) animal room with free access to food and water until the morning of the experiment. Burdick and Jac...

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The chronic effects of nicotine monomethidide on gastric secretion in pylorus-ligated rats

Cited by 4 publications

References 15 publications

Neuroanatomical circuitry mediating the sensory impact of nicotine in the central nervous system

Neuroanatomical circuitry mediating the sensory impact of nicotine in the central nervous system

Antinociceptive action of nicotine and its methiodide derivatives in mice and rats

Blood-brain barrier penetration abolished by N-methyl quaternization of nicotine.

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