After chronic opioid exposure sensory neurons become supersensitive to the excitatory effects of opioid agonists and antagonists as occurs after acute elevation of GM1 ganglioside

doi:10.1016/0006-8993(92)90417-8

Brain Research

Volume 575, Issue 1, 13 March 1992, Pages 13-24

https://doi.org/10.1016/0006-8993(92)90417-8 Get rights and content

Abstract

Mouse sensory dorsal-root ganglion (DRG) neurons chronically exposed to 1 μM D-Ala²-D-Leu⁵-enkephalin (DADLE) for >1 week in culture become tolerant to opioid inhibitory effects, i.e. shortening of the duration of the calcium-dependent component of the action potential (APD). Acute application of higher concentrations of DADLE (ca. 10 μM) to these treated neurons not only fails to shorten the APD but, instead, generally elicits excitatory effects, i.e. prolongation of the APD. The present study shows that chronic DADLE- or morphine-treated DRG neurons also become supersensitive to the excitatory effects of opioids. Whereas nM concentrations of dynorphin(1–13) are generally required to prolong the APD of naive DRG neurons, fM levels become effective after chronic opioid treatment. Whereas 1–30 nM naloxone or diprenorphine do not alter the APD of naive DRG neurons, both opioid antagonists unexpectedly prolong the APD of most of the treated cells. Similar supersensitivity to the excitatory effects of opioid agonists and antagonists was previously observed after acute treatment of naive DRG neurons with GM1 ganglioside. Our results suggest that both chronic opioid and acute GM1 treatments of DRG neurons greatly enhance the efficacy of opioid excitatory receptor functions so that even the extremely weak agonist properties of naloxone and diprenorphine become effective in prolonging the APD of these treated cells when tested at low concentrations, whereas their antagonist properties at inhibitory opioid receptors do not appear to be altered. Furthermore, whereas cholera toxin-B subunit (CTX-B; 1–10 nM) blocks opioid-induced APD prolongation in naive DRG neurons (presumably by interfering with endogenous GM1 modulation of excitatory opioid receptors functions), even much higher concentrations of CTX-B were ineffective in chronic opioid-treated as well as acute GM1-elevated neurons. These and related data suggest that opioid excitatory supersensitivity in chronic opioid-treated DRG neurons may be due to a cyclic AMP-dependent increase in GM1 ganglioside levels. Our results may clarify mechanisms of opioid dependence and the paradoxical supersensitivity to naloxone which triggers withdrawal symptoms after opiate addiction.

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After chronic opioid exposure sensory neurons become supersensitive to the excitatory effects of opioid agonists and antagonists as occurs after acute elevation of GM1 ganglioside

Abstract

Neuron

Neuroscience

Brain Research

Trends Pharmacol. Sci.

Life Sci.

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Brain Res.

J. Biol. Chem.

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Neuropharmacology

Neurosci. Lett.

Brain Research

Neuropharmacology

Life Sci.

Eur. J. Pharmacol.

Neurosci. Lett.

Peptides

Brain Research

Neuropharmacology

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

κ-Opiate agonists inhibit adenylate cyclase and produce heterologous desensitization in rat spinal cord

J. Neurochem.

Regulation of adenylyl cyclase-coupled beta-adrenergic receptors

Annu. Rev. Cell Biol.

Evidence for [d-Ala2,d-Leu5]enkephalin-induced supersensitivity to 5-hydroxytryptamine in a neurotumor X brain hybrid cell line (NCB-20)

J. Neurochem.

Possible role of gangliosides in regulating an adenylate cyclase-linked 5-hydroxytryptamine (5-HT1)_receptor

J. Neurochem.

Interaction of opiates with opioid binding sites in the bovine adrenal medulla II. Interaction with kappa sites

J. Neurochem.

Inhibition of adenosine 3′:5′-monophosphate-dependent protein kinase blocks presynaptic facilitation in Aplysia

J. Neurosci.

Sufentanil, morphine, Met-enkephalin and κ-agonist (U-50, 488H) inhibit substance P release from primary sensory neurons: a model for presynaptic spinal opioid actions

Anesthesiology

Desensitization of hormonal stimuli coupled to regulation of cyclic AMP levels

Development and loss of tolerance to morphine in the rat after single and multiple injections

J. Pharmacol. Exp. Ther.

Molecular and cellular mechanisms in opioid tolerance

Spinal cord tissue culture models for analyses of opioid analgesia, tolerance and plasticity

Regulation of excitatory opioid responsivity of dorsal root ganglion neurons

After GM1 ganglioside treatment of sensory neurons naloxone paradoxically prolongs the action potential but still antagonizes opioid inhibition

J. Pharmacol. Exp. Ther.

Chronic opioid-treated sensory neurons become supersensitive to the excitatory effects of opioids as occurs after acute elevation of GM1 ganglioside level

Soc. Neurosci. Abstr.

Opioids can evoke direct receptor-mediated excitatory as well as inhibitory effects on sensory neuron action potentials

The mechanism of action of opiates and other neuroactive agents

Electrophysiology of opioids

Pharmacol. Rev.

Evidence for [d-Ala²,d-Leu⁵]enkephalin-induced supersensitivity to 5-hydroxytryptamine in a neurotumor X brain hybrid cell line (NCB-20)

Possible role of gangliosides in regulating an adenylate cyclase-linked 5-hydroxytryptamine (5-HT₁)_receptor