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. Author manuscript; available in PMC: 2021 Oct 19.
Published in final edited form as: Handb Behav Neurosci. 2020 Mar 31;26:161–212. doi: 10.1016/B978-0-12-815134-1.00008-8

TABLE 7.

Amygdala opioid regulation of opiate (morphine) dependence and withdrawal.

Subregion Manipulation or injection OR Behavioral test or response measured Subjects Summary of findings Overall opiate effect Authors
Amygdala
AMY Chronic morphine administration MOR DAMGO stimulated GTPγS binding Rats (male) Neither chronic nor acute morphine administration changed amygdala MOR-stimulated GTPγS binding Morphine administration did not change amygdala MOR-stimulated GTPγS binding Sim, Selley, Dworkin, and Childers (1996)
AMY Heroin self-administration MOR, DOR DOR or MOR stimulated GTPγS binding, 3H-naltrexone binding Rats (male) Heroin self-administration decreased MOR, but not DOR, stimulated GTPγS binding in amygdala, but did not alter receptor number (3H-naloxone binding) Heroin self-administration decreased MOR stimulated GTPγS binding in amygdala Sim-Selley et al. (2000)
CEA, BNST Naloxone, control and morphine-dependent rats ENK cFos in CRFir and ENKir neurons Rats (male) Naloxone-precipitated withdrawal in morphine-dependent rats induced cFos in ENKir neurons, but not CRFir neurons, in the CEA and BNSTL. Naloxone in controls induced less cFos in these areas but activated both CRFir and ENKir neurons Naloxone-precipitated withdrawal activated ENKir neurons in the CEA and BNSTL Veinante, Stoeckel, Lasbennes, and Freund-Mercier (2003)
AMY Morphine tolerance and withdrawal DYN DYN(1–13) levels (radioimmunoassay) Rats (male) Increased levels of DYN in amygdala during morphine treatment and during withdrawal (18 h) Morphine treatment and withdrawal increased DYN levels Rattan, Koo, Tejwani, and Bhargava (1992)
Central amygdala
CEA Morphine microinjections MOR morphine CPP Rats (male) CEA injections of morphine did not produce CPP although the numbers of subjects was very low in this early study CEA injections of morphine did not produce CPP van der Kooy, Mucha, O’Shaughnessy, and Bucenieks (1982)
CEA, MEA, BLA Naloxone injections in morphine tolerant rats; CEA lesions OR Naloxone injections in CEA, withdrawal signs Rats (male) Naloxone injections (unilateral) in the CEA, MEA, BLA, or lateral anterior nucleus induced withdrawal symptoms in morphine tolerant rats (jumps, wet dog shakes, paw tremor, chewing, teeth chattering, diarrhea). Jumps were only seen with injections in CEA, and were reduced during withdrawal with CEA lesions Opioid antagonist in amygdala precipitated withdrawal in morphine-dependent rats Lagowska, Calvino, and Ben-Ari (1978), Calvino, Lagowska, and Ben-Ari (1979)
CEA Methyl-naloxonium in morphine-dependent rats (morphine pellets) OR Methylnaloxonium-induced conditioned place aversion (CPA) and somatic withdrawal signs Rats (male) Microinjections of methylnaloxonium in CEA-induced conditioned place aversion (CPA) in morphine-dependent rats, but did not induce physical abstinence signs. Injections in PAG induced both CPA and physical withdrawal (including escapes) Microinjections of methylnaloxonium in the CEA induced CPA in morphine-dependent rats Stinus, Le Moal, and Koob (1990)
CEA Naltrexone precipitated withdrawal from morphine MOR Acoustic startle Rats DAMGO injections (unilateral) in CEA blocked the enhanced acoustic startle responses seen during naltrexone-precipitated withdrawal from acute morphine tolerance DAMGO in CEA blocked enhanced startle during morphine withdrawal Cabral, Ruggiero, Nobre, Brandao, and Castilho (2009)
CEA Morphine, DADL, naloxone, ICI 174864, clonidine, NE, control, morphine-dependent rats MOR, DOR Glutamate-driven firing rate in anesthetized rats, micro-iontophoresis of drugs Rats (male) Iontophoretic application of morphine or DADL decreased glutamate-driven firing rate in CEA and MEA, but not BLA. All cells responding to morphine were inhibited by the α2 agonist clonidine. In morphine-dependent rats, but not controls, both naloxone and the DOR antagonist ICI174864 increased firing rates, and these effects could be blocked with clonidine Naloxone and a DOR antagonist increased CEA firing rates morphine-dependent rats Freedman and Aghajanian (1985)
CEA (CM) Deltorphin II, DAMGO, brain slices (control, morphine-dependent rats) MOR, DOR Postsynaptic inhibition, morphine CPP Rats (male) Morphine-treated rats showed increased glutamate synaptic strength (eEPSCs) in CM. This was associated with enhanced DOR effects in morphine-treated slices, with the DOR agonist DPDPE inducing decreases in evoked EPSCs in 70% of CEA neurons (compared to no effect in controls) through inhibition of presynaptic glutamate release. Consistent with this, DOR expression was enhanced in a synaptosomal preparation Slices from morphine-dependent rats showed increased DOR-mediated presynaptic inhibition of evoked glutamate release in CM Bie et al. (2009b)
CEA (CM) Deltorphin II, DAMGO, brain slices, control, morphine-dependent rats MOR, DOR Postsynaptic inhibition (GIRK-mediated) Rats (male) Chronic morphine increased the number of cells responding to deltorphin II (GIRK current) from ~35% (controls) to 69% (morphine dependent). In control slices DOR responsive neurons also responded to DAMGO, but chronic morphine increased the number of neurons responding to the DOR agonist alone (31%) and decreased the number of neurons responding to DAMGO alone (62% to 15%). In neurons projecting from CM to PAG, the number of DOR responsive neurons increased from 29% (controls) to 86% (morphine dependent), with a decrease in MOR responsive neurons Morphine-dependent animals showed increased DOR responsive neurons in CM, especially in CM neurons projecting to the PAG Chieng and Christie (2009)
CEA Morphine, DAMGO, CTOP, brains slices from control, morphine-dependent rats MOR GABA neurotransmission (mIPSCs, epics) in the presence of morphine-independent rats Rats (male) Morphine and DAMGO decreased eIPSCs in ~50% of neurons (no effect in ~30%). MOR agonists decreased mIPSCs, while CTOP increased mIPSC frequency, suggesting tonic tone at MOR. Many responses were unaltered in slices from morphine-dependent rats, although the inhibitory effects of MOR agonists were blunted suggesting the development of tolerance Slight tolerance to the inhibitory effects of MOR agonists on GABA neurotransmission in CEA Bajo et al. (2011)
CEA Morphine, brain slices after naloxone-precipitated withdrawal MOR GABA neurotransmission (mIPSCs) in the presence of naloxone (controls), morphine/naloxone (dependent rats) Rats (male) Increased mIPSCs were observed in CEA slices following naloxone-precipitated withdrawal. Morphine, in the presence of continuous naloxone perfusion, either increased (64%) or decreased (32%) mIPSCs in control rats, but this ratio shifted in naloxone-withdrawn slices Naloxone-precipitated withdrawal in morphine-dependent rats increased GABA inhibition (mIPSCs) in CEA Bajo et al. (2014)
Basolateral amygdala
LA Morphine microinjections, lesions MOR Morphine CPP Rats (male) Lateral amygdala injections of morphine did not produce CPP and lesions did not block CPP induced by systemic morphine administration. Injections in VTA or PAG produced CPP and naloxone in these sites blocked CPP from systemic morphine Lateral amygdala injections of morphine did not produce CPP and lesions did not block CPP induced by systemic morphine administration Olmstead and Franklin (1997a, 1997b)