Lack of Effect of the Adenosine A1 Receptor Agonist, GR79236, on Capsaicin-Induced CGRP Release in Anaesthetized Pigs

Cephalalgia ◽  
2005 ◽  
Vol 25 (11) ◽  
pp. 1082-1090 ◽  
Author(s):  
U Arulmani ◽  
JPC Heiligers ◽  
D Centurión ◽  
IM Garrelds ◽  
CM Villalón ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Sensory Nerves ◽  
Cgrp Release ◽  
Calcitonin Gene ◽  
Adenosine A1 ◽  
Potent Vasodilator ◽  
Haemodynamic Changes ◽  
A1 Receptor ◽  
The Difference ◽  
Prejunctional Inhibition

Migraine is a common neurological disorder that is associated with an increase in plasma calcitonin gene-related peptide (CGRP) levels. CGRP, a potent vasodilator released from the activated trigeminal sensory nerves, dilates intracranial blood vessels and transmits vascular nociception. Hence, inhibition of trigeminal CGRP release may prevent neurotransmission and, thereby, ameliorate migraine headache. Therefore, the present study in anaesthetized pigs investigates the effects of a selective adenosine A1 receptor agonist, GR79236 (3, 10 and 30 μg/kg, i.v.) on capsaicin-induced carotid haemodynamic changes and on plasma CGRP release. Intracarotid (i.c.) infusion of capsaicin (10 μg/kg/min, i.c.) increased the total carotid blood flow and conductance as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently attenuated by GR79236. However, the increases in the plasma CGRP concentrations by capsaicin remained essentially unmodified after GR79236 treatment. The above results suggest that GR79236 may have an antimigraine potential due to its postjunctional effects (carotid vasoconstriction) rather than to prejunctional inhibition of trigeminal CGRP release.

Effects of Sumatriptan on Capsaicin-Induced Carotid Haemodynamic Changes and CGRP Release in Anaesthetized Pigs

Cephalalgia ◽  
2004 ◽  
Vol 24 (9) ◽  
pp. 717-727 ◽  
Author(s):  
U Arulmani ◽  
JPC Heiligers ◽  
IM Garrelds ◽  
A Sánchez-López ◽  
EW Willems ◽  
...  
Keyword(s):  
Migraine Headache ◽  
Plasma Concentrations ◽  
Sensory Nerves ◽  
Induced Responses ◽  
Therapeutic Action ◽  
Cgrp Release ◽  
Calcitonin Gene ◽  
Haemodynamic Changes ◽  
The Difference ◽  
Venous Plasma

It is suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Hence, inhibition of trigeminal CGRP release may prevent the above vasodilatation and, accordingly, abort migraine headache. Therefore, this study investigated the effects of sumatriptan (100 and 300 μg/kg, i.v.) on capsaicin-induced carotid haemodynamic changes and on CGRP release. Intracarotid (i.c.) infusions of capsaicin (10 μg/kg/min, i.c.) increased total carotid, arteriovenous anastomotic and capillary conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. Except for some attenuation of arteriovenous anastomotic changes, the capsaicin-induced responses were not affected by sumatriptan. Moreover, i.c. infusions of capsaicin (0.3, 1, 3 and 10 μg/kg/min, i.c.) dose-dependently increased the jugular venous plasma concentrations of CGRP, which also remained unaffected by sumatriptan. The above results support the contention that the therapeutic action of sumatriptan is mainly due to cranial vasoconstriction rather than trigeminal (CGRP release) inhibition.

Adenosine and 5-HT inhibit substance P release from nerve endings in myenteric ganglia by distinct mechanisms

1993 ◽  
Vol 264 (3) ◽  
pp. G454-G461 ◽  
Author(s):  
R. M. Broad ◽  
T. J. McDonald ◽  
M. A. Cook
Keyword(s):  
Substance P ◽  
Nerve Endings ◽  
Enteric Ganglia ◽  
Adenosine A1 ◽  
Inhibit Substance ◽  
A1 Receptor ◽  
K Concentration ◽  
Prejunctional Inhibition ◽  
Substance P Release ◽  
Myenteric Ganglia

Release of substance P-like immunoreactivity (SP-LI) from dissociated enteric ganglia and the receptor-mediated prejunctional inhibition of this release were investigated with the use of a perifusion technique. SP-LI release was evoked by elevated extracellular K+ concentration and was inhibited, in a graded manner, by N6-cyclopentyl adenosine (CPA), an adenosine analogue with selectivity for adenosine A1 receptors. Similar inhibition of SP-LI release was obtained with 5-hydroxytryptamine (5-HT); incrementing concentrations, however, yielded a biphasic concentration-response relationship. The selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentyl-xanthine abolished the inhibition due to CPA, whereas the inhibitory action of 5-HT was sensitive to the 5-HT1A-selective antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine hydrobromide. Inhibition due to both agonists was insensitive to blockade by tetrodotoxin, suggesting a prejunctional locus for both adenosine and 5-HT1A receptors on the tachykininergic nerve endings. Pretreatment of ganglia with pertussis toxin had no effect on CPA-mediated inhibition of SP-LI release, whereas 5-HT-mediated inhibition was abolished. The findings demonstrate that adenosine and 5-HT receptors on enteric nerve endings are coupled to inhibition of tachykinin release through distinct mechanisms, putatively distinct G proteins.

Adenosine Modulation of Calcium Currents and Presynaptic Inhibition of GABA Release in Suprachiasmatic and Arcuate Nucleus Neurons

1997 ◽  
Vol 77 (6) ◽  
pp. 3035-3047 ◽  
Author(s):  
Gong Chen ◽  
Anthony N. van den Pol
Keyword(s):  
Presynaptic Inhibition ◽  
Receptor Agonist ◽  
Arcuate Nucleus ◽  
Gaba Release ◽  
Calcium Currents ◽  
Whole Cell ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Arcuate Neurons ◽  
A2 Receptors

Chen, Gong and Anthony N. van den Pol. Adenosine modulation of calcium currents and presynaptic inhibition of GABA release in suprachiasmatic and arcuate nucleus neurons. J. Neurophysiol. 77: 3035–3047, 1997. Adenosine modulation of calcium channel currents and synaptic γ-aminobutyrate (GABA) release was investigated with whole cell voltage-clamp recordings in rat suprachiasmatic nucleus (SCN) and arcuate nucleus cultures ( n = 94). In SCN cultures, ∼70% of the neurons showed a reversible inhibition of whole cell barium currents on the application of adenosine or its analogues. Adenosine at 1 μM reduced the amplitude of the barium currents by ∼27%. In contrast to the significant reduction in the amplitude, the rising and decaying phases of the barium currents, and the inverted bell shape of the current-voltage curve of the barium currents, were not changed by adenosine. The adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA; 100 nM) and the adenosine A2 receptor agonist N6-[2-(3,5-dimethoxyphenyl)-ethyl]adenosine (DPMA; 100 nM) inhibited the barium currents by 21% and 16%, respectively, in SCN neurons, indicating both A1 and A2 receptor actions. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM) significantly reduced the effect of CPA but did not change the effect of DPMA on the barium currents. In the presence of tetrodotoxin to block action potentials, the frequency, but not the amplitude, of miniature inhibitory postsynaptic currents was significantly reduced (46%) by 1 μM adenosine, suggesting a presynaptic mechanism of adenosine action. In support of this suggestion, the postsynaptic GABA receptor responses were not influenced by 1 μM adenosine in the majority of SCN neurons. Most solitary self-innervating SCN neurons in microisland cultures were GABAergic. In these cells, the evoked autaptic GABA release (inhibitory postsynaptic current) was significantly inhibited by adenosine (37%), CPA (27%), and DPMA (28%), indicating that both A1 and A2 receptors were present in presynaptic axons. Similar to the effect in SCN neurons, adenosine inhibited both barium currents and GABA release in arcuate neurons. The reduction of whole cell barium currents by adenosine (1 μM), CPA (100 nM), and DPMA (100 nM) was 24, 17, and 19%, respectively. In solitary self-innervating arcuate neurons, adenosine inhibited the evoked GABA release (inhibitory postsynaptic current) by ∼48%. We conclude that both adenosine A1 and A2 receptors are present in the SCN and arcuate nucleus of the hypothalamus. Adenosine inhibits calcium currents and presynaptically reduces inhibitory GABA neurotransmission.

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