Projection-specific dopamine neurons in the ventral tegmental area participated in morphine-induced hyperalgesia and anti-nociceptive tolerance in male mice

Background: Long-term morphine use is associated with serious side effects, such as morphine-induced hyperalgesia and analgesic tolerance. Previous investigations have documented the association between dopamine (DA) neurons in the ventral tegmental area (VTA) and pain. However, whether VTA DA neurons are implicated in morphine-induced hyperalgesia and analgesic tolerance remains elusive. Methods: Initially, we observed behavioural effects of lidocaine administration into VTA or ablation of VTA DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance. Subsequently, c-Fos expression in nucleus accumbens (NAc) shell-projecting and medial prefrontal cortex (mPFC)-projecting VTA DA neurons after chronic morphine treatment was respectively investigated. Afterwards, the effects of chemogenetic manipulation of NAc shell-projecting or mPFC-projecting DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance were observed. Additionally, effects of chemogenetic manipulation of VTA GABA neurons on c-Fos expression in VTA DA neurons were investigated. Results: Lidocaine injection into VTA relieved established hyperalgesia and anti-nociceptive tolerance whereas ablation of VTA DA neurons prevented the development of morphine-induced hyperalgesia and anti-nociceptive tolerance. Chronic morphine treatment increased c-Fos expression in NAc shell-projecting DA neurons, rather than in mPFC-projecting DA neurons. Chemogenetic manipulation of NAc shell-projecting DA neurons had influence on morphine-induced hyperalgesia and tolerance. However, chemogenetic manipulation of mPFC-projecting DA neurons had no significant effects on morphine-induced hyperalgesia and anti-nociceptive tolerance. Chemogenetic manipulation of VTA GABA neurons affected the c-Fos expression in VTA DA neurons. Conclusions: These findings revealed the involvement of NAc shell-projecting VTA DA neurons in morphine-induced hyperalgesia and anti-nociceptive tolerance, and may shed new light on the clinical management of morphine-induced hyperalgesia and analgesic tolerance. Perspective: This study demonstrated that NAc shell-projecting DA neurons rather than mPFC-projecting DA neurons in the VTA were implicated in morphine-induced hyperalgesia and anti-nociceptive tolerance. Our findings may pave the way for the discovery of novel therapies for morphine-induced hyperalgesia and analgesic tolerance.

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Effect of chronic opioid therapy on pain and survival in a humanized mouse model of sickle cell disease

Blood Advances ◽

10.1182/bloodadvances.2018024299 ◽

2019 ◽

Vol 3 (6) ◽

pp. 869-873 ◽

Cited By ~ 3

Author(s):

Huy Tran ◽

Varun Sagi ◽

Waogwende Leonce Song-Naba ◽

Ying Wang ◽

Aditya Mittal ◽

...

Keyword(s):

Opioid Therapy ◽

Cell Disease ◽

Chronic Opioid Therapy ◽

Morphine Treatment ◽

Humanized Mouse ◽

Chronic Morphine ◽

Humanized Mouse Model ◽

Analgesic Tolerance ◽

Key Points ◽

Chronic Morphine Treatment

Key Points Chronic morphine treatment leads to decreased survival in control mice, but not in sickle mice. Chronic morphine treatment leads to hyperalgesia in sickle mice, but does not lead to analgesic tolerance.

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Ventral Tegmental Area GABA, glutamate, and glutamate-GABA neurons are heterogenous in their electrophysiological and pharmacological properties

10.1101/2020.07.22.216093 ◽

2020 ◽

Author(s):

Jorge Miranda-Barrientos ◽

Ian Chambers ◽

Smriti Mongia ◽

Bing Liu ◽

Hui-Ling Wang ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Viral Vectors ◽

Ex Vivo ◽

Glutamate Transporter ◽

Receptor Activation ◽

Firing Frequency ◽

Dopamine Neurons ◽

Gaba Neurons ◽

Double Transgenic Mouse ◽

Ventral Tegmental

AbstractThe ventral tegmental area (VTA) contains dopamine neurons intermixed with GABA-releasing (expressing vesicular GABA transporter, VGaT), glutamate-releasing (expressing vesicular glutamate transporter, VGluT2), and co-releasing (co-expressing VGaT and VGluT2) neurons. By delivering INTRSECT viral vectors into VTA of double vglut2-Cre/vgat-Flp transgenic mice, we targeted specific VTA cell populations for ex vivo recordings. We found that VGluT2+ VGaT− and VGluT2+ VGaT+ neurons on average had relatively hyperpolarized resting membrane voltage, greater rheobase, and lower spontaneous firing frequency compared to VGluT2− VGaT+ neurons, suggesting that VTA glutamate-releasing and glutamate-GABA co-releasing neurons require stronger excitatory drive to fire than GABA-releasing neurons. In addition, we detected expression of Oprm1mRNA (encoding μ opioid receptors, MOR) in VGluT2+ VGaT− and VGluT2− VGaT+ neurons, and their hyperpolarization by the MOR agonist DAMGO. Collectively, we demonstrate the utility of the double transgenic mouse to access VTA glutamate, glutamate-GABA and GABA neurons, and show some electrophysiological heterogeneity among them.Impact StatementSome physiological properties of VTA glutamate-releasing and glutamate-GABA co-releasing neurons are distinct from those of VTA GABA-releasing neurons. μ-opioid receptor activation hyperpolarizes some VTA glutamate-releasing and some GABA-releasing neurons.

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Determination of circuit-specific morphological adaptations in ventral tegmental area dopamine neurons by chronic morphine

Molecular Brain ◽

10.1186/s13041-019-0435-6 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 3

Author(s):

Sarah C. Simmons ◽

Katie Wheeler ◽

Michelle S. Mazei-Robison

Keyword(s):

Ventral Tegmental Area ◽

Dopamine Neurons ◽

Chronic Morphine ◽

Morphological Adaptations ◽

Ventral Tegmental

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Central metabolism as a potential origin of sex differences in morphine analgesia but not in the induction of analgesic tolerance in mice

10.1101/2020.12.07.414185 ◽

2020 ◽

Author(s):

Florian Gabel ◽

Volodya Hovhannisyan ◽

Virginie Andry ◽

Yannick Goumon

Keyword(s):

Sex Differences ◽

Brain Regions ◽

Central Metabolism ◽

Morphine Analgesia ◽

Morphine Treatment ◽

Chronic Morphine ◽

Analgesic Tolerance ◽

Male And Female ◽

Female Mice ◽

Chronic Morphine Treatment

ABSTRACTIn rodents, morphine analgesia is influenced by sex. However, conflicting results exist regarding the interaction between sex and morphine analgesic tolerance. Morphine is metabolized in the liver and brain into morphine-3-glucuronide (M3G). Sex differences in morphine metabolism and differential metabolic adaptations during tolerance development might explain the behavioral discrepancies. The present article investigates the differences in peripheral and central morphine metabolism after acute and chronic morphine treatment in male and female mice.The first experiment aimed to determine whether morphine analgesia and tolerance differ between male and female mice using the tail-immersion test. The second experiment evaluated morphine and M3G metabolic kinetics in the blood using LC-MS/MS. Morphine and M3G were also quantified in several central nervous system (CNS) regions after acute and chronic morphine treatment. Finally, the blood-brain barrier permeability of M3G was assessed in male and female mice.This study demonstrated that female mice showed weaker morphine analgesia. In addition, tolerance appeared earlier in females but the sex discrepancies observed seemed to be due to the initial differences in morphine analgesia rather than to sex-specific mechanisms involving metabolism. Additionally, compared to male mice, female mice showed higher levels of M3G in the blood and in several CNS regions, whereas lower levels of morphine were observed in these brain regions. These differences are attributable mainly to morphine central metabolism, which differed between males and females in pain-related brain regions, consistent with the weaker analgesic effect in females. However, the role of morphine metabolism in analgesic tolerance seems rather limited.

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Ventral tegmental area astrocytes orchestrate avoidance and approach behavior

10.1101/401919 ◽

2018 ◽

Cited By ~ 1

Author(s):

J. A. Gomez ◽

J. M. Perkins ◽

G. M. Beaudoin ◽

N. B. Cook ◽

S. A. Quraishi ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Glutamate Transporter ◽

Dopamine Neurons ◽

Inhibitory Neurons ◽

Approach Behavior ◽

Gaba Neurons ◽

Avoidance Behaviors ◽

Glutamatergic Signaling ◽

Ventral Tegmental

AbstractThe ventral tegmental area (VTA) is a heterogeneous midbrain structure, containing neurons and astrocytes, that coordinates approach and avoidance behaviors by integrating activity from numerous afferents. Within neuron-astrocyte networks, astrocytes control signals from distinct afferents in a circuit-specific manner, but whether this capacity scales up to drive motivated behavior has been undetermined. Using genetic and optical dissection strategies in vitro and during behavior we report that VTA astrocytes tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learned avoidance. In this circuit, VTA astrocytes facilitate excitation of local GABA neurons to increase inhibition of dopamine neurons. The increased inhibition of dopamine neurons elicits real-time and learned avoidance behavior that is sufficient to impede expression of learned preference for reward. Despite the large number of functions performed by astrocytes, loss of one glutamate transporter (GLT-1) from VTA astrocytes selectively blocks these avoidance behaviors and spares preference for reward. Thus, VTA astrocytes selectively regulate excitation of local GABA neurons to drive a distinct learned avoidance circuit that opposes learned approach behavior.

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