A model for the cellular mechanisms of morphine tolerance and dependence

Carvalho, Luı́s Alfredo Vidal de; Azevedo, Luiz Otávio

doi:10.1016/s0895-7177(00)00180-1

Cited by 6 publications

(13 citation statements)

References 34 publications

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“…A great deal of interest has been devoted to the locus coeruleus (LC) as a prominent model for studying the mechanisms underlying the acute and chronic effects of opioid drugs (Christie, 1991;de Carvalho and de Azevedo, 2000). In this study, we examined the effect of acute injection of morphine on single-unit activity of LC neurons.…”

Section: Discussionmentioning

confidence: 99%

The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective

et al. 2016

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Long-term exposure to opioid agonists results in tolerance to their analgesic effects, so the effectiveness of opioid agonists in the management of pain becomes limited. The locus coeruleus (LC) nucleus has been involved in the development of tolerance to opiates. Orexin type-1 receptors (OX1Rs) are highly expressed in LC nucleus. Orexin plays a noteworthy role in the occurrence of morphine tolerance. The purpose of the present study is to investigate the role of orexin type-1 receptors in the development of morphine tolerance in LC neurons. In this study, adult male Wistar rats weighing 250-300g were utilized. Induction of morphine tolerance was obtained by single injection of morphine per day for 6 successive days. An orexin type-1 receptor antagonist (SB-334867) was injected into the lateral ventricle instantly prior to morphine injection. On day 7, the effect of morphine on the electrical activity of LC neurons was studied using in vivo extracellular single unit recording. The results demonstrate that morphine injection for 6 consecutive days led to the development of morphine-induced tolerance in LC neurons. In other words, there was a significant decrease in LC neuronal responsiveness to morphine injection. Inhibitory responses of LC neurons to intraperitoneally applied morphine can be observed with the treatment of the SB-334867 prior to morphine injection. This study showed that OX1R blockade by SB-334867 prevents the development of morphine tolerance in LC neurons. We hope that further studies will lead to considerable progress in understanding the molecular adaptations that contribute to morphine tolerance.

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Section: Discussionmentioning

confidence: 99%

The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective

et al. 2016

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“…Thus far there have been several mathematical models of locus coeruleus neurons per se, which include a few ionic channels (Putnam et al, 2014;Contreras et al, 2015) or many ionic channels including the usual sodium and potassium, high and low threshold calcium currents, transient potassium I A , persistent sodium, leak and hyperpolarization activated cation current I h (De Carvalho et al, 2000;Alvarez et al 2002;Carter et al, 2012). Noteworthy is the omission of I A in the model of Alvarez et al (2002) and its inclusion in De Carvalho et al (2000) and Carter et al (2012). Also, a persistent sodium current is included in De Carvalho et al (2000) and Alvarez et al (2002) but not in Carter et al (2012).…”

Section: Lc Na Neuronsmentioning

confidence: 99%

“…Noteworthy is the omission of I A in the model of Alvarez et al (2002) and its inclusion in De Carvalho et al (2000) and Carter et al (2012). Also, a persistent sodium current is included in De Carvalho et al (2000) and Alvarez et al (2002) but not in Carter et al (2012).…”

Section: Lc Na Neuronsmentioning

confidence: 99%

“…Despite such uncertainties in the mechanisms involved in pacemaker activity in LC neurons, some of these works have included synaptic input and gap-junction inputs from neighboring LC neurons. The pioneering article of De Carvalho et al (2000) addressed the mechanisms of morphine addiction and included several biochemical reactions involving cAMP, µ-opioid receptors, morphine, G-protein, AC, CREB and Fos. Tuckwell (2017) contains a summary of previous LC modeling as well as a review of LC neuron anatomy and physiology.…”

Section: Lc Na Neuronsmentioning

confidence: 99%

“…Underlying the rhythmic activity are subthreshold oscillations which were demonstrated with a mathematical model to possibly reflect an interplay between an L-type calcium current and a calcium-activated potassium current (Amini et al, 1999) -but see Kuznetsova et al (2010). The mechanisms of pacemaker firing in LC neurons are not fully understood, although there is the possibility that it is sustained by a TTX-insensitive persistent sodium current (De Carvalho et al, 2000;Alvarez et al, 2002). For serotonergic neurons of the DRN, there have been no reports of a persistent sodium current and L-type calcium currents are relatively small or absent (Penington et al, 1991) so the main candidate for depolarization underlying pacemaking is a combination of T-type calcium current and the classical fast TTX-sensitive sodium current which dominates the pre-spike interval (Tuckwell and Penington, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of pacemaker activity in a two-component model of some brainstem neurons

Tuckwell,

Zhou,

Penington

2017

Preprint

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Serotonergic, noradrenergic and dopaminergic brainstem (including midbrain) neurons, often exhibit spontaneous and fairly regular spiking with frequencies of order a few Hz, though dopaminergic and noradrenergic neurons only exhibit such pacemakertype activity in vitro or in vivo under special conditions. A large number of ion channel types contribute to such spiking so that detailed modeling of spike generation leads to the requirement of solving very large systems of differential equations. It is useful to have simplified mathematical models of spiking in such neurons so that, for example, features of inputs and output spike trains can be incorporated including stochastic effects for possible use in network models. In this article we investigate a simple two-component conductance-based model of the Hodgkin-Huxley type. Solutions are computed numerically and with suitably chosen parameters mimic features of pacemaker-type spiking in the above types of neurons. The effects of varying parameters is investigated in detail, it being found that there is extreme sensitivity to eight of them. Transitions from non-spiking to spiking are examined for two of these, the half-activation potential for an activation variable and the added (depolarizing) current and contrasted with the behavior of the classical Hodgkin-Huxley system. The plateaux levels between spikes can be adjusted, by changing a set of voltage parameters, to agree with experimental observations. Experiment has shown that in, in vivo, dopaminergic and noradrenergic neurons' pacemaker activity can be induced by the removal of excitatory inputs or the introduction of inhibitory ones. These properties are confirmed by mimicking opposite such changes in the model, which resulted in a change from pacemaker activity to bursting-type phenomena. The article concludes with a brief review of previous modeling of these types of neurons and a brief discussion of their involvement in some pathological pysychiatric conditions.

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Computational framework for predictive PBPK-PD-Tox simulations of opioids and antidotes

German

Pilvankar

Przekwas

2019

J Pharmacokinet Pharmacodyn

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A model for the cellular mechanisms of morphine tolerance and dependence

Cited by 6 publications

References 34 publications

The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective

The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective

Analysis of pacemaker activity in a two-component model of some brainstem neurons

Computational framework for predictive PBPK-PD-Tox simulations of opioids and antidotes

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