Contribution of brainstem GABA(A) synaptic transmission to morphine analgesic tolerance.

Pain
Junyi Ma, Zhizhong Z Pan

Abstract

Chronic opioid-induced analgesic tolerance remains a major obstacle to improving clinical management of moderate to severe chronic pain. Our understanding of the underlying mechanisms for opioid tolerance is only partially understood at present. In this study, we investigated the effects of chronic morphine on GABA(A) receptor-mediated synaptic transmission, a major opioid target for pain inhibition, and the behavioral role of GABA synaptic transmission in the development of morphine tolerance. In the nucleus raphe magnus (NRM), a critical brainstem site for opioid analgesia, the GABA(A) receptor-mediated inhibitory postsynaptic current (IPSC) was significantly increased in NRM neurons kept in a morphine-tolerant state from chronic morphine-treated rats. The potency of cAMP analogs for enhancing the GABA IPSC was also enhanced. The protein kinase A (PKA) inhibitor H89 reversed the chronic morphine-induced synaptic adaptation in GABA IPSCs. Behaviorally, a low dose of GABA(A) receptor antagonist bicuculline microinjected into the NRM, ineffective alone, blocked morphine antinociception in control rats, but failed to do so in morphine-tolerant rats. With chronic treatment through daily NRM microinjections, bicuculline augmented t...Continue Reading

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Citations

Oct 11, 2011·Nature Medicine·Zhi ZhangZhizhong Z Pan
Apr 23, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Bihua BieZhizhong Z Pan
Apr 2, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Zhi Zhang, Zhizhong Z Pan
Jul 23, 2009·Clinical Drug Investigation·Pierangelo Geppetti, Silvia Benemei
Jun 26, 2014·Medical Science Monitor : International Medical Journal of Experimental and Clinical Research·Fuzhou WangRichard M Kream
Mar 14, 2014·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Erin N BobeckSusan L Ingram
Sep 16, 2014·European Journal of Pharmacology·Parisa Hasanein, Saeed Shakeri
Aug 18, 2009·Pain Medicine : the Official Journal of the American Academy of Pain Medicine·Colin S GoodchildRay Nadeson
Apr 9, 2013·Pharmacological Reports : PR·Hugo F MirandaJuan C Prieto
Jul 9, 2010·Pain Medicine : the Official Journal of the American Academy of Pain Medicine·R Norman HardenErrol M Gould
Dec 7, 2007·Anesthesiology Clinics·Gary McCleane, Howard S Smith
Feb 8, 2008·Behavioural Brain Research·Heberto Suarez-RocaLuis Quintero
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May 4, 2010·Annals of Neurology·Amy Chang Berger, Jennifer L Whistler
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Oct 29, 2014·Behavioural Pharmacology·Xiaqing MaWei Jiang
Feb 22, 2012·Chemistry : a European Journal·Hitoshi MiyasakaRodolphe Clérac

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