Adenosine A1 receptors in mouse pontine reticular formation modulate nociception only in the presence of systemic leptin

Abstract Background: Clinical and preclinical data demonstrate the analgesic actions of adenosine. Central administration of adenosine agonists, however, suppresses arousal and breathing by poorly understood mechanisms. This study tested the two-tailed hypothesis that adenosine A1 receptors in the pontine reticular formation (PRF) of C57BL/6J mice modulate breathing, behavioral arousal, and PRF acetylcholine release. Methods: Three sets of experiments used 51 mice. First, breathing was measured by plethysmography after PRF microinjection of the adenosine A1 receptor agonist N6-sulfophenyl adenosine (SPA) or saline. Second, mice were anesthetized with isoflurane and the time to recovery of righting response (RoRR) was quantified after a PRF microinjection of SPA or saline. Third, acetylcholine release in the PRF was measured before and during microdialysis delivery of SPA, the adenosine A1 receptor antagonist 1, 3-dipropyl-8-cyclopentylxanthine, or SPA and 1, 3-dipropyl-8-cyclopentylxanthine. Results: First, SPA significantly decreased respiratory rate (−18%), tidal volume (−12%), and minute ventilation (−16%). Second, SPA concentration accounted for 76% of the variance in RoRR. Third, SPA concentration accounted for a significant amount of the variance in acetylcholine release (52%), RoRR (98%), and breathing rate (86%). 1, 3-dipropyl-8-cyclopentylxanthine alone caused a concentration-dependent increase in acetylcholine, a decrease in RoRR, and a decrease in breathing rate. Coadministration of SPA and 1, 3-dipropyl-8-cyclopentylxanthine blocked the SPA-induced decrease in acetylcholine and increase in RoRR. Conclusions: Endogenous adenosine acting at adenosine A1 receptors in the PRF modulates breathing, behavioral arousal, and acetylcholine release. The results support the interpretation that an adenosinergic-cholinergic interaction within the PRF comprises one neurochemical mechanism underlying the wakefulness stimulus for breathing.

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Microinjection of the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA) into the pontine reticular formation (PRF) of C57BL/6J mouse increases antinociception in a concentration-dependent manner

Journal of Pain ◽

10.1016/j.jpain.2012.01.189 ◽

2012 ◽

Vol 13 (4) ◽

pp. S45

Author(s):

S. Watson ◽

M. Frank ◽

C. Watson ◽

H. Baghdoyan ◽

R. Lydic

Keyword(s):

Reticular Formation ◽

Receptor Agonist ◽

Adenosine A1 Receptor ◽

Dependent Manner ◽

Pontine Reticular Formation ◽

Concentration Dependent Manner ◽

Adenosine A1 ◽

A1 Receptor

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Thermal Nociception is Decreased by Hypocretin-1 and an Adenosine A1 Receptor Agonist Microinjected into the Pontine Reticular Formation of Sprague Dawley Rat

Journal of Pain ◽

10.1016/j.jpain.2009.09.010 ◽

2010 ◽

Vol 11 (6) ◽

pp. 535-544 ◽

Cited By ~ 16

Author(s):

Sarah L. Watson ◽

Christopher J. Watson ◽

Helen A. Baghdoyan ◽

Ralph Lydic

Keyword(s):

Reticular Formation ◽

Receptor Agonist ◽

Adenosine A1 Receptor ◽

Pontine Reticular Formation ◽

Sprague Dawley ◽

Thermal Nociception ◽

Sprague Dawley Rat ◽

Adenosine A1 ◽

A1 Receptor ◽

Hypocretin 1

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ATP-sensitive and voltage-dependent potassium channel involved in the antinociceptive effects produced by an adenosine A1 agonist into the brainstem medial pontine reticular formation in rats

European Journal of Anaesthesiology ◽

10.1097/00003643-200505001-00325 ◽

2005 ◽

Vol 22 (Supplement 34) ◽

pp. 91-92

Author(s):

C. S. Feng ◽

Y. Yue ◽

H. C. Ma

Keyword(s):

Potassium Channel ◽

Reticular Formation ◽

Pontine Reticular Formation ◽

Antinociceptive Effects ◽

Adenosine A1 ◽

Voltage Dependent

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Microinjection of an Adenosine A1Agonist into the Medial Pontine Reticular Formation Increases Tail Flick Latency to Thermal Stimulation

Anesthesiology ◽

10.1097/00000542-200212000-00036 ◽

2002 ◽

Vol 97 (6) ◽

pp. 1597-1601 ◽

Cited By ~ 12

Author(s):

Diana Tanase ◽

Helen A. Baghdoyan ◽

Ralph Lydic

Keyword(s):

Reticular Formation ◽

Adenosine A1 Receptor ◽

Saline Control ◽

Tail Flick ◽

Thermal Stimulus ◽

Pontine Reticular Formation ◽

Adenosine Agonist ◽

Tail Flick Latency ◽

Adenosine A1 ◽

A1 Receptor

Background Both pain and the pharmacologic management of pain can cause the undesirable effect of sleep disruption. One goal of basic and clinical neuroscience is to facilitate rational drug development by identifying the brain regions and neurochemical modulators of sleep and pain. Adenosine is thought to be an endogenous sleep promoting substance and adenosinergic compounds can contribute to pain management. In the pontine brain stem adenosine promotes sleep but the effects of pontine adenosine on pain have not been studied. This study tested the hypothesis that an adenosine agonist would cause antinociception when microinjected into pontine reticular formation regions that regulate sleep. Methods The tail flick latency (TFL) test quantified the time in seconds for an animal to move its tail away from a thermal stimulus created by a beam of light. TFL measures were used to evaluate the antinociceptive effects of the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA). Pontine microinjection of SPA (0.1 microg/0.25 microl, 0.88 mm) was followed by TFL measures as a function of time after drug delivery and across the sleep-wake cycle. Results Compared with saline (control), pontine administration of the adenosine agonist significantly increased latency to tail withdrawal (P < 0.0001). The increase in antinociceptive behavior evoked by the adenosine agonist SPA was blocked by pretreatment with the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 0.75 ng/0.25 microl, 10 microm). Conclusions These preclinical data encourage additional research on the cellular mechanisms by which adenosine in the pontine reticular formation contributes to the supraspinal modulation of pain.

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