RESUMO
Cyclo-Gly-Pro (CGP) attenuates nociception, however its effects on salivary glands remain unclear. In this study, we investigated the acute effects of CGP on salivary flow and composition, and on the submandibular gland composition, compared with morphine. Besides, we characterized the effects of naloxone (a non-selective opioid receptor antagonist) on CGP- and morphine-induced salivary and glandular alterations in mice. After that, in silico analyses were performed to predict the interaction between CGP and opioid receptors. Morphine and CGP significantly reduced salivary flow and total protein concentration of saliva and naloxone restored them to the physiological levels. Morphine and CGP also reduced several infrared vibrational modes (Amide I, 1687-1594cm-1; Amide II, 1594-1494cm-1; CH2/CH3, 1488-1433cm-1; C = O, 1432-1365cm-1; PO2 asymmetric, 1290-1185cm-1; PO2 symmetric, 1135-999cm-1) and naloxone reverted these alterations. The in silico docking analysis demonstrated the interaction of polar contacts between the CGP and opioid receptor Cys219 residue. Altogether, we showed that salivary hypofunction and glandular changes elicited by CGP may occur through opioid receptor suggesting that the blockage of opioid receptors in superior cervical and submandibular ganglions may be a possible strategy to restore salivary secretion while maintaining antinociceptive action due its effects on the central nervous system.
Assuntos
Gânglios Parassimpáticos/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Peptídeos Cíclicos/farmacologia , Glândulas Salivares/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Sítios de Ligação , Gânglios Parassimpáticos/metabolismo , Gânglios Parassimpáticos/fisiologia , Masculino , Camundongos , Morfina/farmacologia , Nociceptividade , Ligação Proteica , Receptores Opioides/química , Receptores Opioides/metabolismo , Saliva/metabolismo , Glândulas Salivares/metabolismo , Glândulas Salivares/fisiologiaRESUMO
Acetylcholine and ATP appear to mediate excitatory transmission between receptor (glomus) cells and the petrosal ganglion (PG) neuron terminals in the carotid body. In most species these putative transmitters are excitatory, while inhibitory effects had been reported in the rabbit. We studied the effects of the application of acetylcholine and ATP to the PG on the carotid nerve activity in vitro. Acetylcholine and ATP applied to the PG increased the carotid nerve activity in a dose-dependent manner. Acetylcholine-induced responses were mimicked by nicotine, antagonized by hexamethonium, and enhanced by atropine. Bethanechol had no effect on basal activity, but reduced acetylcholine-induced responses. Suramin antagonized ATP-induced responses, and AMP had little effect on the carotid nerve activity. Our results suggest that rabbit PG neurons projecting through the carotid nerve are endowed with nicotinic acetylcholine and purinergic P2 receptors that increase the carotid nerve activity, while simultaneous activation of muscarinic cholinergic receptors reduce the maximal response evoked by nicotinic cholinergic receptor activation.
Assuntos
Acetilcolina/farmacologia , Trifosfato de Adenosina/farmacologia , Gânglios Parassimpáticos/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Atropina/farmacologia , Betanecol/farmacologia , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/fisiologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Eletrofisiologia , Gânglios Parassimpáticos/citologia , Gânglios Parassimpáticos/efeitos dos fármacos , Hexametônio/farmacologia , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Neurônios Aferentes/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , CoelhosRESUMO
New compounds that target nicotinic receptors (nAChRs) have been sought to correct disorders affecting cholinergic transmission in central and peripheral synapses. A quaternary derivate of l-hyoscyamine, phenthonium (Phen), was shown by our group to enhance the spontaneous acetylcholine (ACh) release without altering the nerve-induced transmitter release at the neuromuscular junction. The effect was unrelated to membrane depolarization, and was not induced by an increase of calcium influx into the nerve terminal. Phen also presented a competitive antimuscarinic activity and blocked noncompetitively the neuromuscular transmission. In this work we re-examined the mechanisms underlying the facilitatory actions of Phen on [(3)H]-ACh release in isolated ganglia of the guinea pig ileal myenteric plexus. Exposure of the preparations to Phen (10-50 microM) increased the release of [(3)H]-ACh by 81 to 68% over the basal. The effect was not affected by the ganglionic nAChR antagonist hexamethonium (1 nM) at a concentration that inhibited the increase of [(3)H]-ACh release induced by the nicotinic agonist dimethylphenylpiperazinium (DMPP, 30 microM). Association of Phen (10 microM) with DMPP potentiated the facilitatory effect of Phen. [(3)H]-ACh release was not altered by the muscarinic antagonists atropine (1 nM) or pirenzepine (1 microM). However, both antagonists inhibited the release of [(3)H]-ACh induced by either the muscarinic M1 agonist McN-343 (10 microM) or Phen (20 microM). The facilitatory effect of Phen was not altered by CdCl(2) (50 mM), but it was potentiated in the presence of tetraethylammonium (40 mM). The results indicate that the facilitatory action of Phen appears to be mediated by an increase of the inwardly rectifying potassium channels conductance probably related to the compound antimuscarinic activity.
Assuntos
Acetilcolina/metabolismo , Derivados da Atropina/farmacologia , Atropina/farmacologia , Gânglios Parassimpáticos/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Plexo Mientérico/efeitos dos fármacos , Alcenos/farmacologia , Animais , Atropina/química , Derivados da Atropina/química , Antagonistas Colinérgicos/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Gânglios Parassimpáticos/metabolismo , Cobaias , Antagonistas Muscarínicos/química , Plexo Mientérico/metabolismo , Agonistas Nicotínicos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Tetraetilamônio/farmacologiaRESUMO
1. The cardiovascular effect of systemic nicotinic and muscarinic cholinergic stimulation were studied in conscious sham operated and sinoaortic denervated (SAD) rats, 7 days after the corresponding operation. 2. The administration of the nicotinic ganglionic agent, 1,1-dimethyl-4-phenylpiperazinium (DMPP, 50-100 micrograms.kg-1, i.v.) induced a fall of heart rate that was significantly higher in SAD rats than in sham rats. DMPP induced in sham rats an increase of arterial pressure but in SAD animals a biphasic response: an initial hypotension followed by an increase of arterial pressure. 3. Under muscarinic blockade, DMPP only showed a pressor and tachycardic action in both groups of rats without differences between them. 4. The muscarinic agonist, carbachol (0.1-10 micrograms.kg-1, i.v.) showed the same hypotensive and bradycardic action in both groups of rats. 5. Our results suggest that after 7 days of SAD, differences in the response to DMPP between sham and denervated animals could be due to the loss of baroreflex mechanisms. The increased bradycardic effect of DMPP in SAD rats could be mediated by a supersensitivity of parasympathetic ganglionic nicotinic receptors, whilst the sympathetic ganglionic nicotinic receptors remained unaltered. On the other side, the cardiovascular muscarinic responses to carbachol remain unaffected in SAD rats.