GABA Transporter Currents Activated by Protein Kinase A Excite Midbrain Neurons during Opioid Withdrawal

Bagley, Elena E.; Gerke, Michelle B.; Vaughan, Christopher W.; Hack, Stephen P.; Christie, MacDonald J.

doi:10.1016/j.neuron.2004.12.049

Cited by 71 publications

(93 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…mice were treated with hypertonic sucrose (50 mM) before and during ME desensitization. We have reported previously that treatment of slices with hypertonic sucrose (50 mM) impairs vesicle recycling and presumably endocytosis (Bagley et al, 2005b). Similar to blocking dynamin-dependent endocytosis with DYNi peptide, hypertonic sucrose did not affect MOR activation of GIRK currents or acute desensitization but significantly enhanced the rate of MOR resensitization (Fig.…”

Section: Disruption Of ␤Arrestin-2-dependent Receptor Trafficking Accmentioning

confidence: 57%

Cellular Morphine Tolerance Produced by βArrestin-2-Dependent Impairment of μ-Opioid Receptor Resensitization

Dang

Chieng²,

Azriel³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

Chronic morphine treatment produces behavioral and cellular opioid tolerance that has been proposed to be caused by attenuated -opioid receptor (MOR) recovery from desensitization (resensitization). The process of MOR resensitization is thought to require ␤arrestin-2 (␤arr-2)-dependent trafficking of desensitized receptors to endosomal compartments, followed by recycling of resensitized receptors back to the plasma membrane. However, there is little direct evidence for this, particularly in native neurons. This study used whole-cell patch-clamp recording in locus ceruleus (LC) neurons from wild-type (w.t.) and ␤arr-2 knock-out (k.o.) mice to examine whether ␤arr-2/dynamin-dependent trafficking is required for MOR resensitization in neurons from opioid-naive and morphine-treated mice. Surprisingly, recovery of MOR from acute desensitization in LC neurons does not require ␤arr-2-or dynamin-dependent trafficking. To the contrary, MOR resensitization was accelerated by disruption of either ␤arr-2 or dynamin function. Chronic morphine treatment caused cellular MOR tolerance and concurrently impaired MOR resensitization in neurons from w.t. mice, as expected from previous studies, but neither occurred in neurons from ␤arr-2 k.o. mice. Moreover, the impairment of MOR resensitization caused by chronic morphine was reversed in w.t. neurons when G-protein-coupled receptor kinase-2 (GRK2) or dynamin function was disrupted. Together, these results establish that ␤arr-2/dynamin-dependent receptor regulation is not required for MOR resensitization in LC neurons. Furthermore, chronic morphine treatment modifies GRK2-␤arr-2-dynamin-dependent MOR trafficking to impair receptor resensitization, thereby contributing to opioid tolerance in LC neurons by reducing the number of functional receptors on the surface membrane.

show abstract

Section: Disruption Of ␤Arrestin-2-dependent Receptor Trafficking Accmentioning

confidence: 57%

Cellular Morphine Tolerance Produced by βArrestin-2-Dependent Impairment of μ-Opioid Receptor Resensitization

Dang

Chieng²,

Azriel³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…ME-induced currents reversed near the equilibrium potential for potassium (À88±5 mV; n ¼ 5) in the presence of the GAT inhibitor, NO-711 (10 mM) indicating that the more negative reversal potentials in morphine pretreated rats were caused by opioid inhibition of inward current mediated by GAT. However, intermittent morphine does not appear to induce GAT currents as large as those observed by Bagley et al (2005b) because ME-induced currents reversed at À111±3 mV, whereas the reversal potentials for MEinduced currents were generally more negative than À120 mV in rats pretreated with continuous morphine administration. In order to determine the amplitude of GAT currents in rats pretreated with morphine injections, the GAT inhibitor NO-711 (10 mM) was superfused in the presence of the GABA B antagonist CGP-55845 (10 mM).…”

Section: Morphine Pretreatment Increases Opioid-mediated Girk Currentsmentioning

confidence: 72%

“…Previous studies have shown that continuous administration of morphine induces an additional opioid-sensitive current in the PAG that is associated with the GABA transporter (GAT) (Bagley et al, 2005b). This cation current is inhibited by opioids and contributes to ME-induced responses by augmenting the outward current elicited by ME and shifting the reversal potential to more hyperpolarized potentials than the expected value for a potassium current (ie GIRK).…”

Section: Morphine Pretreatment Increases Opioid-mediated Girk Currentsmentioning

confidence: 99%

Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists

Ingram

Macey

Fossum

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

Tolerance to the pain-relieving effects of opiates limits their clinical use. Although morphine tolerance is associated with desensitization of m-opioid receptors, the underlying cellular mechanisms are not understood. One problem with the desensitization hypothesis is that acute morphine does not readily desensitize m-opioid receptors in many cell types. Given that neurons in the periaqueductal gray (PAG) contribute to morphine antinociception and tolerance, an understanding of desensitization in PAG neurons is particularly relevant. Opioid activity in the PAG can be monitored with activation of G-protein-mediated inwardly rectifying potassium (GIRK) currents. The present data show that opioids have a biphasic effect on GIRK currents in morphine tolerant rats. Opioid activation of GIRK currents is initially potentiated in morphine (EC 50 ¼ 281 nM) compared to saline (EC 50 ¼ 8.8 mM) pretreated rats as indicated by a leftward shift in the concentration-response curve for met-enkephalin (ME)-induced currents. These currents were inhibited by superfusion of the m-opioid receptor antagonist b-funaltrexamine (b-FNA) suggesting that repeated morphine administration enhances agonist stimulation of m-opioid receptor coupling to G-proteins. Although supersensitivity of m-opioid receptors in the PAG is counterintuitive to the development of tolerance, peak GIRK currents from tolerant rats desensitized more than currents from saline pretreated rats (56% of peak current after 10 min compared to 15%, respectively). These data indicate that antinociceptive tolerance may be triggered by enhanced agonist potency resulting in increased desensitization of m-opioid receptors.

show abstract

“…However, the amplitudes of our ME-induced GIRK currents at À40 mV, a potential where the nonselective cation current is minimal , were also not different between tolerant and control rats. One reason for this discrepancy in m-opioid receptor coupling to GIRK channels may be that studies where decreased m-opioid receptor coupling to GIRK channels are observed use slow release preparations that release morphine constantly over 3-5 days (Christie et al, 1987;Chieng and Christie, 1996;Chieng and Williams, 1998;Ingram et al, 1998;Hack et al, 2003;Bagley et al, 2005). This would lead to a different pattern of opioid exposure compared to our repeated intermittent injection procedure, and longer opioid exposure may result in additional cellular changes that promote opioid receptor desensitization.…”

Section: Discussionmentioning

confidence: 99%

“…These in vivo studies are supported by in vitro data showing that chronic morphine administration induces profound changes in ventrolateral PAG neurons, including decreased opioid activation of GIRK channels (Chieng and Christie, 1996;Ingram et al, 1998;Hack et al, 2003;Bagley et al, 2005) and increased opioid inhibition of presynaptic GABA release (Chieng and Christie, 1996;Ingram et al, 1998;Hack et al, 2003;Bagley et al, 2005). Studies with GIRK knockout mice have demonstrated that postsynaptic m-opioid receptor coupling to the GIRK channel is important for the antinociceptive effects of morphine (Ikeda et al, 2002;Blednov et al, 2003;Mitrovic et al, 2003;Marker et al, 2005) and suggest that postsynaptic m-opioid receptor coupling to GIRK channels in PAG neurons may contribute to opioid tolerance.…”

Section: Introductionmentioning

confidence: 87%

Behavioral and Electrophysiological Evidence for Opioid Tolerance in Adolescent Rats

Ingram

Fossum

Morgan

2006

Neuropsychopharmacol

View full text Add to dashboard Cite

Morphine and other opiates are successful treatments for pain, but their usefulness is limited by the development of tolerance. Given that recent studies have observed differential sensitivity to drugs of abuse in adolescents, the aim of this study was to assess antinociceptive tolerance to morphine in adolescent rats using both behavioral and cellular measures. Early (28-35 days postnatal) and late (50-59 days) adolescent and adult (73-75 days) male rats were injected with morphine (5 mg/kg, s.c.) or saline twice a day for two consecutive days. On Day 3, tolerance to morphine was evident in morphine-pretreated rats when tested on the hot plate test. Although baseline latencies for the early compared to late adolescent rats were faster, the magnitude of the shift in ED 50 for morphine was similar for the two adolescent groups. However, the shift in ED 50 tended to be greater in adolescent compared to adult rats. Subsequent to behavioral testing, whole cell patch-clamp recordings were made from ventrolateral PAG neurons. The opioid agonist, met-enkephalin (ME), activated similar outward currents in PAG neurons of early and late adolescent rats. However, reversal potentials of ME-induced currents were shifted to more hyperpolarized potentials in cells from morphine-pretreated rats. In addition, ME induced larger currents in morphine-pretreated rats with faster hot plate latencies compared to the mean (more tolerant) than in rats with slower latencies. These results indicate that repeated intermittent administration of morphine produces tolerance in adolescent rats that is associated with novel changes in opioid-sensitive ventrolateral PAG neurons.

show abstract

GABA Transporter Currents Activated by Protein Kinase A Excite Midbrain Neurons during Opioid Withdrawal

Cited by 71 publications

References 51 publications

Cellular Morphine Tolerance Produced by βArrestin-2-Dependent Impairment of μ-Opioid Receptor Resensitization

Cellular Morphine Tolerance Produced by βArrestin-2-Dependent Impairment of μ-Opioid Receptor Resensitization

Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists

Behavioral and Electrophysiological Evidence for Opioid Tolerance in Adolescent Rats

Contact Info

Product

Resources

About