Enhanced Opioid Efficacy in Opioid Dependence Is Caused by an Altered Signal Transduction Pathway

Ingram, Susan; Vaughan, Christopher W.; Bagley, Elena E.; Connor, Mark; Christie, MacDonald J.

doi:10.1523/jneurosci.18-24-10269.1998

Cited by 150 publications

(144 citation statements)

References 39 publications

(68 reference statements)

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“…ME-induced GIRK currents are larger and the concentration-response relationship is shifted to the left in rats pretreated with morphine compared to saline. Although supersensitivity of m-opioid receptor coupling to adenylyl cyclase in the PAG has been reported previously (Ingram et al, 1998), it is the first time that supersensitivity has been observed for m-opioid receptor coupling to membrane delimited potassium channels (ie GIRK channels). The increase in GIRK activation is probably evident because morphine is not present.…”

Section: Discussionmentioning

confidence: 84%

“…GIRK channels are directly activated by bg subunits (Huang et al, 1995), so an increase in bg release after increased excitatory G as signaling mediated by m-opioid receptors could also increase activation of GIRK channels. Interestingly, m-opioid receptor inhibition of GABA release is potentiated via a G ai -adenylyl cyclase-PKA signaling pathway in rats pretreated with continuous morphine (Ingram et al, 1998) indicating that this m-opioid receptor coupling is not diminished by desensitization. Therefore, it is likely that m-opioid receptors become uncoupled from some effectors (ie membrane delimited potassium channels) more readily than other effectors, (ie adenylyl cyclase) after chronic morphine administration.…”

Section: Discussionmentioning

confidence: 99%

“…Uncoupling of the m-opioid receptors from these effectors is consistent with decreased antinociception, or tolerance to opiates. In contrast, m-opioid receptor inhibition of GABA release is enhanced via a cAMP-dependent mechanism (Ingram et al, 1998;Hack et al, 2003) suggesting that continuous morphine administration also induces supersensitivity of m-opioid receptor coupling to adenylyl cyclase. Figure 4 Repeated administration of morphine induces a current associated with the GABA transporter (GAT).…”

Section: Discussionmentioning

confidence: 99%

“…Continuous morphine pretreatment induces profound changes in ventrolateral PAG neurons, including decreased opioid activation of G-protein-mediated inwardly rectifying potassium (GIRK) and K v channels (Chieng and Christie, 1996;Ingram et al, 1998;Hack et al, 2003;Bagley et al, 2005a, b). Given that opioid inhibition of GABA neurons and disinhibition of PAG output neurons is necessary for antinociception (Moreau and Fields, 1986;Depaulis et al, 1987;Osborne et al, 1996), decreasing opioid activation of potassium channels is consistent with antinociceptive tolerance.…”

Section: Introductionmentioning

confidence: 99%

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

Ingram

Macey

Fossum

et al. 2007

Neuropsychopharmacol

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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.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Ingram

Macey

Fossum

et al. 2007

Neuropsychopharmacol

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“…In fact, a cAMP-dependent component of presynaptic inhibition that directly modulates vesicle priming has recently been described (33). Moreover, when cAMP levels increase during withdrawal after chronic exposure to morphine, the p r of GABAergic synapses increases, leading to stronger presynaptic inhibition by morphine (34,35). A similar mechanism appears to operate in ␤-arrestin2 KO mice, which may explain the enhanced efficacy to opioids and its reversal by PKA inhibitors.…”

Section: Pre-and Postsynaptic Inhibition Of Lc Neurons By Morphinementioning

confidence: 95%

β-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids

Bradaı̈a

Berton

Ferrari

et al. 2005

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

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Most -opioid receptor agonists recruit ␤-arrestin2, with some exceptions such as morphine. Surprisingly, however, the acute analgesic effect of morphine is enhanced in the absence of ␤-arrestin2. To resolve this paradox, we examined the effects of morphine and fentanyl in acute brain slices of the locus coeruleus and the periaqueductal gray from ␤-arrestin2 knockout mice. We report that, in these mice, presynaptic inhibition of evoked inhibitory postsynaptic currents was enhanced, whereas postsynaptic G protein-coupled K ؉ (Kir3͞GIRK) currents were unaffected. The frequency, but not amplitude, of miniature inhibitory postsynaptic currents was increased in ␤-arrestin2 knockout mice, indicating a higher release probability compared to WT mice. The increased release probability resulted from increased cAMP levels because of impaired phosphodiesterase 4 function and conferred an enhanced efficacy of morphine to inhibit GABA release. Thus, ␤-arrestin2 attenuates presynaptic inhibition by opioids independent ofopioid receptor-driven recruitment, which may make ␤-arrestin2 a promising target for regulating analgesia.synaptic transmission ͉ -opioid receptors ͉ locus coeruleus ͉ periaqueductal gray ͉ analgesia A rrestin interaction with phosphorylated -opioid receptors (MORs) prompts desensitization of signaling by receptor uncoupling from G proteins followed by endocytosis (1). In addition, it has been found recently that during adrenergic signaling, ␤-arrestin2 forms a complex with phosphodiesterase 4 (PDE4). PDE4 is the cAMP-specific phosphodiesterase (2, 3); its interaction with ␤-arrestin2 thereby delivers the rate-limiting enzyme for cAMP degradation to the receptor site and thus quenches protein kinase A (PKA)-dependent processes (4-6).In contrast to most other MOR agonists, morphine does not lead to ␤-arrestin recruitment and subsequent MOR internalization (7, 8). Nevertheless, opioid-mediated analgesia is strongly enhanced in ␤-arrestin2 knockout (KO) animals (9), but not in ␤-arrestin1 KO animals (8). The effects of morphine are mediated by two cellular functions localized in distinct compartments. Whereas activation of MORs expressed on the soma and dendrites leads to strong hyperpolarization of the neuron, MORs on synaptic terminals regulate transmitter release, in particular at GABAergic synapses (10). The molecular effectors have been shown to differ in the two cellular compartments. Postsynaptic inhibition is mediated by the activation of Kir3͞GIRK channels (11,12). Presynaptic inhibition, on the other hand, is caused by an inhibition of calcium channels (13), direct effects on the release machinery downstream of calcium entry (14), or activation of voltage-gated potassium channels (15).Here, we have characterized the effects of the two MOR agonists, morphine and fentanyl, in acute slices of the locus coeruleus (LC) and the periaqueductal gray (PAG) of ␤-arrestin2 KO animals. The LC was chosen because it consists of a homogeneous population of adrenergic neurons that are ideal for studying pre-and postsyna...

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How to design an opioid drug that causes reduced tolerance and dependence

Berger

Whistler

2010

Annals of Neurology

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Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.Opioids have been used to treat pain for well over 5,000 years. 1 Before the 19th century, the drug of choice was opium, the resin released from the seed pods of the opium poppy. The potency of opium varied greatly from batch to batch, making it impossible to standardize dosage and greatly increasing the risk of overdose. The purification of morphine from opium in 1803 finally solved this problem and greatly improved the safety of using opioids; however, once drug doses were easily quantifiable, the problem of tolerance, defined as the need for higher doses of drug to achieve the same effect, became increasingly apparent. Tolerance was frequently accompanied by physical dependence, the need for continued drug use to prevent somatic and affective withdrawal symptoms, and in some cases by addiction.Scientists have assumed, or at least hoped, that the biological mechanisms mediating opioid analgesia are distinct from, and can be divorced from, those mediating tolerance, dependence, and addiction, and from the time of morphine's discovery, they have tried to develop opioids with a reduced propensity to cause these negative sequelae of prolonged opioid use. Two hundred years later, however, morphine is still a mainstay of modern pain management, and Many attempts to develop a better opioid have been based on flawed or incomplete hypotheses of tolerance development. As a case in point, both heroin and sustained release oxycodone (trade name OxyContin), today 2 of the most highly sought after opioid drugs of ...

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Enhanced Opioid Efficacy in Opioid Dependence Is Caused by an Altered Signal Transduction Pathway

Cited by 150 publications

References 39 publications

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

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

β-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids

How to design an opioid drug that causes reduced tolerance and dependence

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