Pertussis toxin inhibits antinociception produced by intrathecal injection of morphine, noradrenaline and baclofen

Hoehn, Katja; Reid, Allison; Sawynok, Jana

doi:10.1016/0014-2999(88)90487-6

Cited by 76 publications

(38 citation statements)

References 22 publications

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“…The lack of antagonism by pretreatment with pertussis toxin further supports the hypothesis of a cholinergic mechanism underlying buspirone-, gepirone-, and 8-OH-DPAT-induced antinociception. In fact, PTX pretreatment was able to prevent opioid (27), catecholaminergic, GABAergic (19), histaminergic (8), and purinergic (29) analgesia but not muscarinic antinociception (8).…”

Section: Discussionmentioning

confidence: 96%

“…In fact, the three compounds examined, in the same range of doses, have been demonstrated to be effective not only in a thermal test (hot plate), in which hypothermia could lead to a misinterpretation of the data, but also in a chemical test (abdominal constriction), indicating that 5-HT 1A -induced hypothermia and antinociception were not related. The adrenergic hypothesis for the antinociception induced by 5-HT 1A agonists can be ruled out, because pertussis toxin, which inactivates G i/o proteins, at doses able to prevent noradrenaline (19) and clonidine (28) antinociception, was not effective in preventing buspirone, gepirone, or 8-OH-DPAT analgesia. Moreover, pretreatment of mice with the monoamine store depletor reserpine did not produce any antagonism of the 5-HT 1A agonists 8-OH-DPAT and sumatriptan (3).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

5-HT1A Agonists Induce Central Cholinergic Antinociception

Galeotti

Ghelardini

Bartolini

1997

Pharmacology Biochemistry and Behavior

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“…Hypofunctionality of PTX-sensitive G-proteins not only induces hyperalgesia (Ohnishi et al, 1990;Galeotti et al, 1996;Womer et al, 1997), but also produces insensitivity to analgesic treatments. Inactivation of Gi-proteins prevents the analgesic activity of inhibitory neurotransmitters such as L-endorphins, GABA, cathecholamines, purines (Chung et al, 1994;Hoehn et al, 1988;Sawynok and Reid, 1988) as well as the induction of analgesia by well-known analgesic drugs such as opioids, tricyclic antidepressants, K 2 -adrenoceptor agonists (Parenti et al, 1986;Sanchez-Blazquez and Garzon, 1991;Galeotti et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Antihistamine antinociception is mediated by Gi-protein activation

Galeotti¹,

Ghelardini²,

Bartolini³

2002

Neuroscience

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AbstractöThe e¡ect of the i.c.v. administration of antisense oligodeoxynucleotides directed against the K subunit of di¡erent Gi-proteins (anti-GiK 1 , anti-GiK 2 , anti-GiK 3 ) on the antinociception induced by the H 1 -antihistamines was evaluated in the mouse hot-plate test. The administration of diphenhydramine (20 mg kg 31 s.c.), pyrilamine (15 mg kg 31 s.c.) and promethazine (6 mg kg 31 s.c.) produced an increase of the pain threshold which peaked 15 min after injection. Pretreatment with anti-GiK 1 (12.5 Wg per mouse i.c.v.), anti-GiK 2 (25 Wg per mouse i.c.v.) and anti-GiK 3 (25 Wg per mouse i.c.v.), administered 24 and 18 h before test, prevented the antihistamine-induced antinociception. At the highest e¡ective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modi¢ed spontaneous motility and inspection activity, as revealed by the hole board test.These results suggest an important role played by the Gi-protein pathway in the transduction mechanism involved in the enhancement of the pain threshold produced by H 1 -antihistamines. ß

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“…Many clinical drugs, such as opioids, GABAergic agonists, and α-2 agonists among others, are ligands and acts via pertussis toxin-sensitive G-protein coupled receptors [24]. Of note, a ligand binding to its receptor activates the coupled G-protein, dissociating the inhibitory subunit αi from the initial trimer formed by the subunits αβγ.…”

Section: Discussionmentioning

confidence: 99%

“…Morphine (2.5 mg/kg, s.c., used as a positive control) was injected by s.c. injection in a volume of 10 ml/kg body weight. All procedures, doses, and administration routes of the various drugs were chosen on the basis of previous studies [22][23][24][25]36] or in preliminary experiments carried out in our laboratory (data not shown).…”

Section: Drug Administration Pertussis Toxin Kmentioning

confidence: 99%

Role of pertussis toxin-sensitive G-protein, K+ channels, and voltage-gated Ca2+ channels in the antinociceptive effect of inosine

Macedo-Júnior

Nascimento

Luiz-Cerutti

et al. 2012

Purinergic Signalling

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Inosine is the first metabolite of adenosine. It exerts an antinociceptive effect by activating the adenosine A 1 and A 2A receptors. We have previously demonstrated that inosine exhibits antinociceptive properties in acute and chronic mice models of nociception. The aim of this study was to investigate the involvement of pertussis toxinsensitive G-protein-coupled receptors, as well as K + and Ca 2+ channels, in the antinociception promoted by inosine in the formalin test. Mice were pretreated with pertussis toxin (2.5 μg/site, i.t., an inactivator of G i/0 protein); after 7 days, they received inosine (10 mg/kg, i.p.) or morphine (2.5 mg/kg, s.c., used as positive control) immediately before the formalin test. Another group of animals received tetraethylammonium (TEA) or 4-aminopyridine (4-AP) (1 μg/site, i.t., a non-specific voltage-gated K + channel blockers), apamin (50 ng/site, i.t., a small conductance Ca 2+ -activated K + channel blocker), charybdotoxin (250 pg/site, i.t., a largeconductance Ca 2+ -activated K + channel blocker), glibenclamide (100 μg/site, i.t., an ATP-sensitive K + channel blocker) or CaCl 2 (200 nmol/site, i.t.). Afterwards, the mice received inosine (10 mg/kg, i.p.), diclofenac (10 mg/kg, i.p., a positive control), or morphine (2.5 mg/kg, s.c., a positive control) immediately before the formalin test. The antinociceptive effect of inosine was reversed by the pre-administration of pertussis toxin (2.5 μg/site, i.t.), TEA, 4-aminopyridine, charybdotoxin, glibenclamide, and CaCl 2 , but not apamin. Further, all K + channel blockers and CaCl 2 reversed the antinociception induced by diclofenac and morphine, respectively. Taken together, these data suggest that the antinociceptive effect of inosine is mediated, in part, by pertussis toxinsensitive G-protein coupled receptors and the subsequent activation of voltage gated K + channel, large conductance Ca 2+ -activated and ATP-sensitive K + channels or inactivation of voltage-gated Ca 2+ channels. Finally, small conductance Ca 2+ -activated K + channels are not involved in the antinociceptive effect of inosine.

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Pertussis toxin inhibits antinociception produced by intrathecal injection of morphine, noradrenaline and baclofen

Cited by 76 publications

References 22 publications

5-HT1A Agonists Induce Central Cholinergic Antinociception

5-HT1A Agonists Induce Central Cholinergic Antinociception

Antihistamine antinociception is mediated by Gi-protein activation

Role of pertussis toxin-sensitive G-protein, K+ channels, and voltage-gated Ca2+ channels in the antinociceptive effect of inosine

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