Behavioral evidence linking opioid-sensitive GABAergic neurons in the ventrolateral periaqueductal gray to morphine tolerance

Morgan, Michael M.; Clayton, Cecilea C.; Lane, Diane

doi:10.1016/s0306-4522(02)00822-9

Cited by 38 publications

(25 citation statements)

References 23 publications

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“…This is consistent with the view that an internal GABA inhibition controls the output of the PAG. In fact, our previous study [17] provided the first in vivo biochemical evidence indicating that putative unilateral peripheral nociception causes a significant reduction in GABA veratridine-stimulated release in the mid-brain PAG; in addition, both pharmacological and electrophysiological evidences indicate a tonic GABAergic inhibitory control of the descending pain modulation system [37,38]. In this study the highest release of GABA was found in the PAG followed by the NRM which supports the hypothesis suggesting that GABAergic neurons in the PAG may be activated during nociception.…”

Section: Discussionmentioning

confidence: 99%

A Comparative Study of Excitatory and Inhibitory Amino Acids in Three Different Brainstem Nuclei

et al. 2007

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This study was designed to shed more light onto the three different brainstem regions which are implicated in the pain pathway for the level of various excitatory and inhibitory neurotransmitters before and following neuronal stimulation. The in vivo microdialysis technique was used in awake, freely moving adult Sprague-Dawley rats. The neurotransmitters studied included aspartate, glutamate, GABA, glycine, and taurine. The three brainstem regions examined included the mid-brain periaqueductal gray (PAG), the medullary nucleus raphe magnus (NRM), and the spinal trigeminal nucleus (STN). Neuronal stimulation was achieved following the administration of the sodium channel activator veratridine. The highest baseline levels of glutamate (P < 0.0001), aspartate (P < 0.0001), GABA (P < 0.01), taurine (P < 0.0001), and glycine (P < 0.001) were seen in the NRM. On the other hand, the lowest baseline levels of glutamate, GABA, glycine, and taurine were found in the PAG, while that of aspartate was found in the STN. Following the administration of veratridine, the highest release of the above neurotransmitters except for the aspartate and glycine was found in the PAG where the level of glutamate increased by 1,310 +/- 293% (P < 0.001), taurine by 1,008 +/- 143% (P < 0.01), and GABA by 10,358 +/- 1,920% (P < 0.0001) when comparison was performed among the three brainstem regions and in relation to the baseline levels. The highest release of aspartate was seen in the STN (2,357 +/- 1,060%, P < 0.001), while no significant difference was associated with glycine. On the other hand, the lowest release of GABA and taurine was found in the STN (696 +/- 91 and 305 +/- 25%, respectively), and glutamate and aspartate in the NRM (558 +/- 200 and 874 +/- 315%, respectively). Our results indicate, and for the first time, that although some differences are seen in the baseline levels of the above neurotransmitters in the three regions studied, there are quite striking variations in the level of release of these neurotransmitters following neuronal stimulation in these regions. In our opinion this is the first study to describe the pain activation/modulation related changes of the excitatory and inhibitory amino acids profile of the three different brainstem areas.

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Section: Discussionmentioning

confidence: 99%

A Comparative Study of Excitatory and Inhibitory Amino Acids in Three Different Brainstem Nuclei

et al. 2007

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“…ERK1/2 also has been found to directly increase synaptic vesicle exocytosis via calcium channels (Subramanian and Morozov, 2011). Given that opioids in the vlPAG produce antinociception by inhibiting GABA release (Depaulis et al, 1987, Morgan et al, 2003, Heinricher et al, 2009), an increase in GABA release via ERK1/2 inhibition would require a higher opioid dose to produce antinociception.…”

Section: Discussionmentioning

confidence: 99%

Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance

Bobeck

Ingram

Hermes

et al. 2016

Behavioural Brain Research

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Opioids produce antinociception by activation of G protein signaling linked to the mu-opioid receptor (MOPr). However, opioid binding to the MOPr also activates β-arrestin signaling. Opioids such as DAMGO and fentanyl differ in their relative efficacy for activation of these signaling cascades, but the behavioral consequences of this differential signaling are not known. The purpose of this study was to evaluate the behavioral significance of G protein and internalization dependent signaling within ventrolateral periaqueductal gray (vlPAG). Antinociception induced by microinjecting DAMGO into the vlPAG was attenuated by blocking Gαi/o protein signaling with administration of pertussis toxin (PTX), preventing internalization with administration of dynamin dominant-negative inhibitory peptide (dyn-DN) or direct inhibition of ERK1/2 with administration of the MEK inhibitor, U0126. In contrast, the antinociceptive effect of microinjecting fentanyl into the vlPAG was not altered by administration of PTX or U0126, and was enhanced by administration of dyn-DN. Microinjection of DAMGO, but not fentanyl, into the vlPAG induced phosphorylation of ERK1/2, which was blocked by inhibiting receptor internalization with administration of dyn-DN, but not by inhibition of Gαi/o proteins. ERK1/2 inhibition also prevented the development and expression of tolerance to repeated DAMGO microinjections, but had no effect on fentanyl tolerance. These data reveal that ERK1/2 activation following MOPr internalization contributes to the antinociceptive effect of some (e.g., DAMGO), but not all opioids (e.g., fentanyl) despite the known similarities for these agonists to induce β-arrestin recruitment and internalization.

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“…Many factors limit the potency of opiates, including tolerance (Christie et al ., 1987; Morgan et al ., 2003; Bagley et al ., 2005; Lane et al ., 2005; Loyd et al ., 2008), negative side effects (Cepeda & Carr, 2003; Cepeda et al ., 2003; Fillingim et al ., 2005; Panchal et al ., 2007) and more recently recognized, ‘gender’ or ‘sex’ (Wang et al, 2006). It is now well known that morphine is more potent in males compared to females; however, the mechanism(s) driving this phenomenon is unknown.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in μ-Opioid Receptor Expression in the Rat Midbrain Periaqueductal Gray Are Essential for Eliciting Sex Differences in Morphine Analgesia

Loyd¹,

Wang²,

Murphy³

2008

J. Neurosci.

163

136

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Opioid-based narcotics are the most widely prescribed therapeutic agent for the alleviation of persistent pain; however, it is becoming increasingly clear that morphine is significantly less potent in women compared with men. Morphine primarily binds to -opioid receptors (MORs), and the periaqueductal gray (PAG) contains a dense population of MOR-expressing neurons. Via its descending projections to the rostral ventromedial medulla and the dorsal horn of the spinal cord, the PAG is considered an essential neural substrate for opioid-based analgesia. We hypothesized that MOR expression in the PAG was sexually dimorphic, and that these sex differences contribute to the observed sex differences in morphine potency. Using immunohistochemistry, we report that males had a significantly higher expression of MOR in the ventrolateral PAG compared with cycling females, whereas the lowest level of expression was observed in proestrus females. CFA-induced inflammatory pain produced thermal hyperalgesia in both males and females that was significantly reversed in males with a microinjection of morphine into the ventrolateral PAG; this effect was significantly greater than that observed in proestrus and estrus females. Selective lesions of MOR-expressing neurons in the ventrolateral PAG resulted in a significant reduction in the effects of systemic morphine in males only, and this reduction was positively correlated with the level of MOR expression in the ventrolateral PAG. Together, these results provide a mechanism for sex differences in morphine potency.

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Behavioral evidence linking opioid-sensitive GABAergic neurons in the ventrolateral periaqueductal gray to morphine tolerance

Cited by 38 publications

References 23 publications

A Comparative Study of Excitatory and Inhibitory Amino Acids in Three Different Brainstem Nuclei

A Comparative Study of Excitatory and Inhibitory Amino Acids in Three Different Brainstem Nuclei

Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance

Sex Differences in μ-Opioid Receptor Expression in the Rat Midbrain Periaqueductal Gray Are Essential for Eliciting Sex Differences in Morphine Analgesia

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