Highlights
- •Activation of γ-aminobutyric acid type A (GABAA) receptors in the central nucleus of the amygdala (CeA) produce an antinociceptive effect.
- •Activation of GABAA receptors in the CeA inhibits an itch-related response.
- •Inactivation of GABAA receptors in the CeA enhances the itch-related response.
Abstract
Itch and pain are unpleasant sensations that distress many patients with disease.
However, most studies have focused on the neural mechanisms of pain, and much less
effort has been devoted to itch. It has been reported that itch and pain might share
a common pathway, and γ-aminobutyric acid type A (GABAA) receptors in the central nucleus of the amygdala (CeA) are involved in pain modulation.
However, the contribution of GABAA receptors in the CeA to the modulation of itch remains poorly understood. Herein,
we report that bilateral intra-CeA microinjection of a selective GABAA receptor agonist muscimol hydrochloride (Mus; 50 ng per side), but not a selective
GABAA receptor antagonist bicuculline (Bic; 20 ng per side) or vehicle, showed significant
analgesic effects, reflected by an increase in tail-flick latency and a decrease in
allyl isothiocyanate (mustard oil)–evoked ipsilateral forelimb wipes. More importantly,
rats subjected to intra-CeA infusion of Bic showed a significantly greater number
of scratching bouts and time in acute and chronic pruritus animal models than control
rats. Conversely, intra-CeA infusion of Mus in animal models dramatically decreased
the number of scratching bouts and time compared with control rats. In addition, intra-CeA
infusion of Bic or Mus at the current dose had no obvious effects on other behaviors
including locomotor activity and spontaneous facial grooming in rats subjected to
cheek microinjection of 5-hydroxytryptamine. Taken together, these results indicate
that the GABAA receptor–mediated inhibitory system in the CeA is involved in itch modulation as
well as is known in pain control.
Perspective
Itch, especially chronic itch, remains a challenge in clinic. Results of this study
showed that the GABAA receptors in the CeA play an important role in itch modulation, which might help
us to better understand the mechanisms of itch and subsequently develop novel mechanisms-based
strategies to treat chronic itch in clinic.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Neural processing of itch.Neuroscience. 2013; 250: 697-714
- Differential itch- and pain-related behavioral responses and micro-opioid modulation in mice.Acta Derm Venereol. 2010; 90: 575-581
- Spontaneous itch in the absence of hyperalgesia in a mouse hindpaw dry skin model.Neurosci Lett. 2010; 484: 62-65
- Amygdala and extended amygdala.in: Paxinos G. The Rat Nervous System. 2nd ed. Academic Press, San Diego, CA1995: 495-578
- Involvement of the spino-parabrachio-amygdaloid and -hypothalamic pathways in the autonomic and affective emotional aspects of pain.Prog Brain Res. 1996; 107: 243-255
- Pathway-specific targeting of GABA(A) receptor subtypes to somatic and dendritic synapses in the central amygdala.J Neurophysiol. 2001; 86: 717-723
- Morphine withdrawal modifies antinociceptive effects of acute morphine in rats.Biochem Biophys Res Commun. 2006; 346: 578-582
- Pain pathways and parabrachial circuits in the rat.Exp Physiol. 2002; 87: 251-258
- Itch mechanisms and circuits.Annu Rev Biophys. 2014; 43: 331-355
- GABAA receptors in the central nucleus of amygdala (CeA) affect on pain modulation.Brain Res. 2008; 1241: 36-41
- Sensitization of neurons in the central nucleus of the amygdala via the decreased GABAergic inhibition contributes to the development of neuropathic pain-related anxiety-like behaviors in rats.Mol Brain. 2014; 7: 72
- Facial injections of pruritogens or algogens elicit distinct behavior responses in rats and excite overlapping populations of primary sensory and trigeminal subnucleus caudalis neurons.J Neurophysiol. 2011; 106: 1078-1088
- Preclinical research on pain comorbidity with affective disorders and cognitive deficits: Challenges and perspectives.Prog Neurobiol. 2014; 116: 13-32
- The central nucleus of the amygdala contributes to the production of morphine antinociception in the formalin test.Pain. 1995; 63: 141-152
- The central nucleus of the amygdala contributes to the production of morphine antinociception in the rat tail-flick test.J Neurosci. 1995; 15: 8199-8213
- Functional mapping of GABA A receptor subtypes in the amygdala.Eur J Neurosci. 2004; 20: 1281-1289
- Cortical afferents to the extended amygdala.Ann N Y Acad Sci. 1999; 877: 309-338
- Lesions of the periaqueductal gray disrupt input to the rostral ventromedial medulla following microinjections of morphine into the medial or basolateral nuclei of the amygdala.Brain Res. 2004; 1009: 223-227
- Impact of sedative and non-sedative antihistamines on the impaired productivity and quality of life in patients with pruritic skin diseases.Allergol Int. 2010; 59: 345-354
- Forebrain pain mechanisms.Brain Res Rev. 2009; 60: 226-242
- The amygdala and persistent pain.Neuroscientist. 2004; 10: 221-234
- Noradrenergic agonist administration into the central nucleus of the amygdala increases the tail-flick latency in lightly anesthetized rats.Neuroscience. 2007; 148: 737-743
- Opioid supraspinal analgesic synergy between the amygdala and periaqueductal gray in rats.Brain Res. 1998; 779: 158-169
- The rat brain, in: Stereotaxic Coordinates.5th ed. Academic Press, San Diego2004
- Amygdala GABA-A receptor involvement in mediating sensory-discriminative and affective-motivational pain responses in a rat model of peripheral nerve injury.Pain. 2007; 127: 17-26
- GABAA receptors are involved in the analgesic effects of morphine microinjected into the central nucleus of the amygdala.Clin Exp Pharmacol Physiol. 2014; 41: 338-344
- Opioid receptors of the central amygdala and morphine-induced antinociception.Iran Biomed J. 2007; 11: 75-80
- The amygdaloid complex: Anatomy and physiology.Physiol Rev. 2003; 83: 803-834
- Differential changes in the peptidergic and the non-peptidergic skin innervation in rat models for inflammation, dry skin itch, and dermatitis.J Invest Dermatol. 2015; 135: 2049-2057
- Pruritus: Management algorithms and experimental therapies.Semin Cutan Med Surg. 2011; 30: 127-137
- Central amygdala nicotinic and 5-HT1A receptors mediate the reversal effect of nicotine and MDMA on morphine-induced amnesia.Neuroscience. 2014; 277: 392-402
- The amygdala between sensation and affect: A role in pain.J Mol Psychiatry. 2013; 1: 9
- Itch severity and quality of life in patients with pruritus: Preliminary validity of a Danish adaptation of the itch severity scale.Acta Derm Venereol. 2012; 92: 508-514
Article info
Publication history
Published online: October 28, 2015
Accepted:
October 17,
2015
Received in revised form:
October 9,
2015
Received:
May 13,
2015
Footnotes
This work was supported by the 973 Program of the Ministry of Science and Technology of the People's Republic of China (2014CB548100 and 2012CB517903 to Z.D.), the National Natural Science Foundation of China (81271221 and 81571042 to Z.D., 81400874 to T.T., and 81501143 to H.H.), the Natural Science Foundation of Chongqing (cstc2015jcyjA00037 to H.H.), the China Postdoctoral Science Foundation (2014M562505XB to T.T.), and the Chongqing Postdoctoral Foundation (xm2014051 to T.T.).
The authors have no conflicts of interest to declare.
Identification
Copyright
© 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.
