Mechanisms of Tolerance to Opiates in Locus Coeruleus Neurons

Mj, Christie; Jt, Williams; Ra, North

doi:10.1037/e496682006-011

Cited by 21 publications

(22 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The major change identifiable in direct binding experiments with 3H-labeled agonist was a decrease in pu receptor number, without change in the affinity of the receptor for the agonist DAMGO The binding characteristics of the p. sites in membranes from brains of morphine-tolerant guinea pigs and pertussis toxin-treated guinea pig cortical membranes were similar to those from morphine-treated or pertussis toxin-treated 7315c pituitary tumor cells (10 (1989) reserve in guinea pig ileum myenteric plexus (23) and in rat locus coeruleus neurons (24).…”

Section: Discussionmentioning

confidence: 84%

“…If t receptors are associated with a unique pool of G protein(s), it is also possible that chronic morphine exposure causes a change in the properties of this G protein(s) or simply a reduction in the G-protein concentration in the A receptor-associated pool. Christie et al (24) have shown in rat locus coeruleus neurons that ,u receptors and a2-adrenergic receptors are coupled to the same potassium conductance. While morphine tolerance impaired the ability of tt agonists to activate the potassium conductance, a2 agonists were still capable of eliciting this effect.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Selective changes in mu opioid receptor properties induced by chronic morphine exposure.

Werling

McMahon

Cox

1989

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Chronic infusion of morphine to guinea pigs produced selective changes in Im agonist binding properties in cerebrocortical membrane preparations. Employing the pselective opioid agonist MePhe4, in direct binding studies and in competition of labeled antagonist binding, we found that the major changes were a decrease in the number of sites with high affnity for agonist, a small reduction in total receptor number, and a loss in the ability of guanosine 5'-[y-thio]triphosphate to regulate binding. A fraction of high-affinity p receptors appeared to retain their high affinity for agonist and their sensitivity to guanine nucleotide analogue after the induction of morphine tolerance, possibly because the morphine concentrations achieved in brain were insufficient to uncouple all p receptors from associated guanine nucleotide-binding regulatory proteins. Some membrane preparations were treated with pertussis toxin, which has been shown to functionally uncouple IL opioid receptors from their effector systems. In these preparations, a single agonist-affinity state of the receptor was observed. The apparent dissociation constant for this affinity state in pertussis toxin-treated membranes was similar to the lower-affinity state observed in preparations from morphinetolerant animals. In contrast to the changes observed at , opioid binding sites, no significant changes in agonist affinity or binding density were observed for selective 8 or K agonists, consistent with the development of selective tolerance at Ip receptors.The mechanisms by which opiate drugs induce tolerance and dependence are not clearly understood. A number of observations suggest that changes occur in the function of the receptors through which the tolerance-inducing drug acts to evoke its primary pharmacologic effect. A significant fraction of the receptors must be activated for tolerance and dependence to develop (1,2). In tissues where more than one type of opioid receptor is present, the occurrence of receptorselective tolerance (3-5) also suggests that receptor-specific mechanisms are critical in the tolerance process. Studies of the interaction of agonists with 8 opioid receptors in NG108-15 neuroblastoma-glioma hybrid cells in culture after chronic receptor activation have demonstrated that sustained agonist exposure leads initially to a loss of the ability of 8 agonists to regulate their effector system (in this case, to inhibit adenylate cyclase), followed later by a reduction in the number of 8 receptors detected by radiolabeled ligand binding (6). Recently, similar results have been reported in a study of the chronic activation by morphine of 1 opioid receptors in 7315c pituitary tumor cells maintained in primary culture (7). Thus, in these cell systems in which opioid receptors negatively regulate adenylate cyclase, sustained exposure to morphine resulted in an initial desensitization followed by receptor down-regulation.Early studies examining the binding of opioid receptors in brain membranes from small mammals following treatment wi...

show abstract

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Selective changes in mu opioid receptor properties induced by chronic morphine exposure.

Werling

McMahon

Cox

1989

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The molecular basis of tolerance manifests as a reduction in opioid agonist efficacy as demonstrated by a reduction in the rate of G-protein activation by the agonist-bound receptor complex (1)(2)(3). Furthermore, the modest reduction in cell surface receptor does not account for the observed decrease in agonist efficacy that accompanies tolerance measured biochemically (4,5), cytochemically (6), or electrophysiologically (7). One mechanism of opioid receptor desensitization may be a receptor uncoupling from its effector system caused by receptor phosphorylation by a G-protein receptor kinase (GRK) 1 and subsequent binding of an arrestin.…”

mentioning

confidence: 99%

Threonine 180 Is Required for G-protein-coupled Receptor Kinase 3- and β-Arrestin 2-mediated Desensitization of the μ-Opioid Receptor in Xenopus Oocytes

Celver¹,

Lowe²,

Kovoor³

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

, arr2(R169E), that desensitizes G protein-coupled receptors in an agonist-dependent but phosphorylation-independent manner. arr2(R169E) produced robust desensitization of MOR and MOR-(T180A) in the absence of GRK3 coexpression. These results demonstrate that the T180A mutation probably blocks GRK3-and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors.

show abstract

“…Continuous infusion of guinea pigs or rats with morphine results in an uncoupling of opioid receptors from associated G proteins as measured biochemically (10,11). Recordings from single rat brain neurons of the locus coeruleus show a homologous desensitization to opioid-induced increases in potassium conductance after chronic morphine treatment (12). Prolonged morphine administration reduced the ability of DAMGO, 1 a selective opioid agonist, to stimulate […”

mentioning

confidence: 99%

μ and δ Opioid Receptors Are Differentially Desensitized by the Coexpression of β-Adrenergic Receptor Kinase 2 and β-Arrestin 2 in Xenopus Oocytes

Kovoor

Nappey

Kieffer

et al. 1997

Journal of Biological Chemistry

125

136

View full text Add to dashboard Cite

The Xenopus oocyte expression system was used to test the hypothesis that homologous opioid receptor desensitization results from receptor phosphorylation by G protein-coupled receptor kinases. Activation of ␦ (DOR), (MOR) opioid, or ␤ 2 -adrenergic receptors increased K ؉ conductance in oocytes coexpressing the G protein-gated inwardly rectifying K ؉ channel subunits GIRK1 and GIRK4, and the intrinsic rate of desensitization was small. Coexpression of ␤-adrenergic receptor kinase 2 (␤-ARK2) and ␤-arrestin 2 (␤-arr2) synergistically produced a rapid desensitization of both DOR and ␤2-adrenergic receptor signaling with a t1 ⁄2 < 4 min. ␤-ARK2 and ␤-arr2 more slowly desensitized MOR responses; a similar synergistic effect on MOR required 2-3 h of agonist treatment. DOR mutants lacking serine and threonine residues at the end of the cytoplasmic tail coupled effectively to GIRK channels but were insensitive to ␤-ARK2 and ␤-arr2. However, a DOR mutant having serine residues mutated to alanine in the third cytoplasmic loop was indistinguishable in coupling and desensitization from the wild type DOR. These studies establish that opioid receptors can be regulated by ␤-ARK2 and ␤-arr2 and that a portion of the COOH terminus of DOR enhances sensitivity to this modulation.Opioid agonists are the drugs of choice in the management of severe and chronic pain; however, continuous use of opioids can cause undesirable side effects including drug tolerance and addiction. The processes underlying tolerance are complex and involve learning mechanisms, compensatory changes in neuronal circuits, and desensitization of signal transduction mechanisms (1). Three classes of opioid receptors: , ␦, and , have been defined pharmacologically, shown to couple to G proteins of the G i /G o family, and cloned (2, 3). Previous studies have examined the molecular mechanisms underlying opiate tolerance. Chronic treatment of animals with opiates has not revealed a functionally significant change in opioid receptor number (4, 5) or mRNA levels (Ref. 6, but see also Refs. 7 and 8). However, opioid receptor desensitization has been consistently implicated as one of the molecular events accompanying tolerance (9). Continuous infusion of guinea pigs or rats with morphine results in an uncoupling of opioid receptors from associated G proteins as measured biochemically (10, 11). Recordings from single rat brain neurons of the locus coeruleus show a homologous desensitization to opioid-induced increases in potassium conductance after chronic morphine treatment (12). Prolonged morphine administration reduced the ability of DAMGO, 1 a selective opioid agonist, to stimulate [ 35 S]GTP␥S binding in distinct rat brain areas (13). Chronic morphine treatment of rats also led to a homologous (e.g. receptor-specific) desensitization of either ␦ or opioid receptor activity as measured by the ability of specific agonists to inhibit adenylyl cyclase in several brain structures (14).Termination of signaling of other G protein-coupled receptors results from agonist-depe...

show abstract

Mechanisms of Tolerance to Opiates in Locus Coeruleus Neurons

Cited by 21 publications

References 0 publications

Selective changes in mu opioid receptor properties induced by chronic morphine exposure.

Selective changes in mu opioid receptor properties induced by chronic morphine exposure.

Threonine 180 Is Required for G-protein-coupled Receptor Kinase 3- and β-Arrestin 2-mediated Desensitization of the μ-Opioid Receptor in Xenopus Oocytes

μ and δ Opioid Receptors Are Differentially Desensitized by the Coexpression of β-Adrenergic Receptor Kinase 2 and β-Arrestin 2 in Xenopus Oocytes

Contact Info

Product

Resources

About