Accepted Article
Received Date : 26-Sep-2013 Revised Date : 19-Feb-2014 Accepted Date : 21-Feb-2014 Article type
: Original Article
GABAA receptors are involved in the analgesic effects of morphine microinjected into the central nucleus of the amygdala
Rashvand Ma, Khajavi Aa, Parviz Ma, Hasanein Pb, Keshavarz Ma
a
Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
b
Department of Biology, School of Basic Sciences, Bu-Ali Sina University, Hamedan, Iran
*Corresponding author: Keshavarz Ave, Poursina St, Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran (Parviz M.). Tel /fax: 98 2166419484. E-mail addresses: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1440-1681.12223 This article is protected by copyright. All rights reserved.
Accepted Article
Summary The central nucleus of the amygdala (CeA) has an important role in pain perception and analgesia. Opioid and GABAA receptors, which are both involved in pain modulation, are found in high concentration in the CeA. The present study was designed to examine interaction of opioidergic and GABAergic systems in the CeA during modulation of acute thermal pain. In this study different doses of morphine (25, 50 and 100 µg/rat), either alone or with 5 min pretreatment of a selective GABAA receptor agonist, muscimol, (60 ng/ rat) or a selective GABAA receptor antagonist, bicuculline, (50 ng/rat) were injected bilaterally into the CeA of each rat. Tail-flick latencies (TFLs) were measured every 5 min for 60 min. the results revealed that microinjection of morphine into the CeA significantly increased TFL in a dose-dependent fashion. Microinjection of bicuculline or muscimol in combination with morphine into the CeA respectively increased and decreased TFL in a dose-dependent fashion. It seems that morphine in the CeA, facilitates the function of descending inhibitory systems by interaction with the activity of local GABAA receptors.
Key words: amygdala, antinociception, bicuculline, muscimol, opioid
INTRODUCTION The amygdala is a forebrain structure that is well positioned to influence pain-modulating circuits in the brainstem and spinal cord. The central nucleus of the amygdala, CeA, has direct and reciprocal connections with the PAG. 1 The CeA is also known as "Nociceptive Amygdala"
This article is protected by copyright. All rights reserved.
Accepted Article
and has an important role in pain control system. Neurons originating from the CeA contribute to the antinociceptive effect of systemically administered morphine, 2, 3 and injection of mu-opioid agonists or other compounds into several different amygdaloid nuclei results in antinociception411
that is mediated, in part, by neurons in the PAG. 12, 13 The role of the amygdala in
antinociception is consistent with its role in the generation of emotions14, 15 and defense reactions, 16 and amygdaloid circuitry contributing to morphine antinociception probably overlaps with circuitry mediating the “defensive” antinociception that accompanies fear. 2, 3, 9 It has been shown that bilateral microinjections of morphine into the CeA elicit powerful suppression of nociceptive behaviors in both phases of the formalin test 17 which was reversed by naloxone administration. Furthermore, naloxone microinjection into the CeA reduced the analgesic effects of systemic morphine. Consistent with this, lesions of the CeA largely eliminate the antinociceptive actions of systemic morphine in both tail-flick (TF) and formalin tests in rats.2, 3
GABAA receptors are the main mediators of inhibitory neurotransmission in the central nervous system3 which involves pain modulation at the supraspinallevel. 19 GABAA receptors are found at high concentration in the CeA. 20, 21 Opioid receptors in the CeA locate presynaptically on axon terminals of GABAergic interneurons and GABA acts as an important inhibitory neurotransmitter in controlling nociception. 22,23 At the supraspinal level, both pronociceptive and antinociceptive roles have been attributed to GABAergic mechanisms in pain modulation.24,25 Furthermore, in parallel with cannabinoids, GABA may be also a part of mechanisms involved in antinociception induced by opioids.26 For example, the ability of morphine to presynaptically
This article is protected by copyright. All rights reserved.
Accepted Article
suppress GABAergic transmission been proposed as a possible mechanism in mediating antinociception induced by administration of morphine in the ventrolateral orbital cortex(VLO) and rostral ventromedial medulla (RVM). 27, 28 However, the role of GABA in mediating antinociception induced by microinjection of opioids into the CeA has not yet been studied. The present study was designed to examine the effects of bilateral intra-CeA microinjection of the GABAA receptor agents on antinociception induced by administration of morphine into the CeA using the TF test.
RESULTS In all experimental groups, baseline tail-flick latencies did not significantly differ.
Effects of bilateral morphine microinjection into the CeA in TF test Microinjection of morphine (25, 50, 100 µg/side) into the CeA induced antinociception in a dose-dependent fashion [F (3, 24) = 332.4, P
Received Date : 26-Sep-2013 Revised Date : 19-Feb-2014 Accepted Date : 21-Feb-2014 Article type
: Original Article
GABAA receptors are involved in the analgesic effects of morphine microinjected into the central nucleus of the amygdala
Rashvand Ma, Khajavi Aa, Parviz Ma, Hasanein Pb, Keshavarz Ma
a
Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
b
Department of Biology, School of Basic Sciences, Bu-Ali Sina University, Hamedan, Iran
*Corresponding author: Keshavarz Ave, Poursina St, Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran (Parviz M.). Tel /fax: 98 2166419484. E-mail addresses: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1440-1681.12223 This article is protected by copyright. All rights reserved.
Accepted Article
Summary The central nucleus of the amygdala (CeA) has an important role in pain perception and analgesia. Opioid and GABAA receptors, which are both involved in pain modulation, are found in high concentration in the CeA. The present study was designed to examine interaction of opioidergic and GABAergic systems in the CeA during modulation of acute thermal pain. In this study different doses of morphine (25, 50 and 100 µg/rat), either alone or with 5 min pretreatment of a selective GABAA receptor agonist, muscimol, (60 ng/ rat) or a selective GABAA receptor antagonist, bicuculline, (50 ng/rat) were injected bilaterally into the CeA of each rat. Tail-flick latencies (TFLs) were measured every 5 min for 60 min. the results revealed that microinjection of morphine into the CeA significantly increased TFL in a dose-dependent fashion. Microinjection of bicuculline or muscimol in combination with morphine into the CeA respectively increased and decreased TFL in a dose-dependent fashion. It seems that morphine in the CeA, facilitates the function of descending inhibitory systems by interaction with the activity of local GABAA receptors.
Key words: amygdala, antinociception, bicuculline, muscimol, opioid
INTRODUCTION The amygdala is a forebrain structure that is well positioned to influence pain-modulating circuits in the brainstem and spinal cord. The central nucleus of the amygdala, CeA, has direct and reciprocal connections with the PAG. 1 The CeA is also known as "Nociceptive Amygdala"
This article is protected by copyright. All rights reserved.
Accepted Article
and has an important role in pain control system. Neurons originating from the CeA contribute to the antinociceptive effect of systemically administered morphine, 2, 3 and injection of mu-opioid agonists or other compounds into several different amygdaloid nuclei results in antinociception411
that is mediated, in part, by neurons in the PAG. 12, 13 The role of the amygdala in
antinociception is consistent with its role in the generation of emotions14, 15 and defense reactions, 16 and amygdaloid circuitry contributing to morphine antinociception probably overlaps with circuitry mediating the “defensive” antinociception that accompanies fear. 2, 3, 9 It has been shown that bilateral microinjections of morphine into the CeA elicit powerful suppression of nociceptive behaviors in both phases of the formalin test 17 which was reversed by naloxone administration. Furthermore, naloxone microinjection into the CeA reduced the analgesic effects of systemic morphine. Consistent with this, lesions of the CeA largely eliminate the antinociceptive actions of systemic morphine in both tail-flick (TF) and formalin tests in rats.2, 3
GABAA receptors are the main mediators of inhibitory neurotransmission in the central nervous system3 which involves pain modulation at the supraspinallevel. 19 GABAA receptors are found at high concentration in the CeA. 20, 21 Opioid receptors in the CeA locate presynaptically on axon terminals of GABAergic interneurons and GABA acts as an important inhibitory neurotransmitter in controlling nociception. 22,23 At the supraspinal level, both pronociceptive and antinociceptive roles have been attributed to GABAergic mechanisms in pain modulation.24,25 Furthermore, in parallel with cannabinoids, GABA may be also a part of mechanisms involved in antinociception induced by opioids.26 For example, the ability of morphine to presynaptically
This article is protected by copyright. All rights reserved.
Accepted Article
suppress GABAergic transmission been proposed as a possible mechanism in mediating antinociception induced by administration of morphine in the ventrolateral orbital cortex(VLO) and rostral ventromedial medulla (RVM). 27, 28 However, the role of GABA in mediating antinociception induced by microinjection of opioids into the CeA has not yet been studied. The present study was designed to examine the effects of bilateral intra-CeA microinjection of the GABAA receptor agents on antinociception induced by administration of morphine into the CeA using the TF test.
RESULTS In all experimental groups, baseline tail-flick latencies did not significantly differ.
Effects of bilateral morphine microinjection into the CeA in TF test Microinjection of morphine (25, 50, 100 µg/side) into the CeA induced antinociception in a dose-dependent fashion [F (3, 24) = 332.4, P
