Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

Zeng, Jianwei; Thomson, Lisa; Aicher, Sue A.; Terman, Gregory W.

doi:10.1523/jneurosci.2530-06.2006

Cited by 63 publications

(83 citation statements)

References 74 publications

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“…We therefore speculate that persistent inflammatory nociception leads to an upregulation of NMDA receptors on the terminals of SPcontaining afferents to RVM neurons, providing a means by which synaptically-released glutamate can cause a concomitant release of SP and activation of postsynaptic NK1 receptors. This idea has support in the literature with the finding that NMDA receptors are upregulated on SP-containing afferents in the dorsal horn under conditions of opioid tolerance (Zeng et al 2006).…”

Section: Mechanisms Of Facilitation In Type 1 and Type 2 Neuronssupporting

confidence: 54%

Substance P Enhances Excitatory Synaptic Transmission on Spinally Projecting Neurons in the Rostral Ventromedial Medulla After Inflammatory Injury

Zhang

Hammond²

2009

Journal of Neurophysiology

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Zhang L, Hammond DL. Substance P enhances excitatory synaptic transmission on spinally projecting neurons in the rostral ventromedial medulla after inflammatory injury. J Neurophysiol 102: 1139 -1151, 2009. First published June 3, 2009 doi:10.1152/jn.91337.2008. It has been proposed, but not directly tested, that persistent inflammatory nociception enhances excitatory glutamatergic inputs to neurons in the rostral ventromedial medulla (RVM), altering the activity and function of these neurons. This study used whole cell patch-clamp methods to record evoked excitatory postsynaptic currents (eEPSCs) in spinally projecting RVM neurons from rats injected with saline or complete Freund's adjuvant (CFA) 3-4 days earlier and to examine the role of substance P (SP) in modulating excitatory synaptic transmission. Input-output relationships demonstrated that CFA treatment facilitated fast excitatory glutamatergic inputs to type 1 and type 2 nonserotonergic spinally projecting RVM neurons, but not to type 3 neurons. The facilitation in type 1 and 2 neurons was dependent on neurokinin-1 (NK1) and N-methyl-D-aspartate (NMDA) receptors and prevented by the PKC inhibitor GF109203X. In a subset of neurons from naïve rats, SP mimicked the effects of CFA and increased the potency and efficacy of glutamatergic synaptic transmission. The facilitation was prevented by 10 M GF109203X, but not by 10 M KN93, a CaMKII inhibitor. SP (0.3-3 M) by itself produced concentration-dependent inward currents in most nonserotonergic, but not serotonergic neurons. The present study is the first demonstration, at the cellular level, that persistent inflammatory nociception leads to a sustained facilitation of fast excitatory glutamatergic inputs to RVM neurons by an NK1 and NMDA receptor-dependent mechanism that involves PKC. Further, it demonstrates that the facilitation is restricted to specific populations of RVM neurons that by inference may be pain facilitatory neurons.

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Section: Mechanisms Of Facilitation In Type 1 and Type 2 Neuronssupporting

confidence: 54%

Substance P Enhances Excitatory Synaptic Transmission on Spinally Projecting Neurons in the Rostral Ventromedial Medulla After Inflammatory Injury

Zhang

Hammond²

2009

Journal of Neurophysiology

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“…Added to this complexity of presynaptic regulation mechanisms is the presynaptic NMDA receptor reported recently by us and others. Endogenous activation of NMDA receptors in the central terminals of primary afferents is critical to the increased glutamate release from primary afferent terminals triggered by peripheral sensory input in neuropathic rats (6) or in rats with morphine tolerance (74). These studies indicate that regulation of presynaptic receptor activities offers a powerful means of dynamically regulating excitatory transmission in the spinal dorsal horn.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

Yan

严

Weng

et al. 2013

Journal of Biological Chemistry

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Background: Excessive activation of glutamate receptors is crucial to the genesis of neuropathic pain. Results: Endogenous IL-1␤ in neuropathic rats enhances glutamate release by increasing presynaptic NMDA receptor activities via sphingomyelinase signaling. Conclusion: Coupling between IL-1␤ receptors and presynaptic NMDA receptors contributes to the genesis of neuropathic pain. Significance: Interruption of such coupling could be an effective approach for the treatment of neuropathic pain.

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“…Repeated or continuous exposure to morphine causes a decrease in the antinociceptive effect of drug in many different paradigms, a phenomenon termed "tolerance." In parallel, responses of individual neurons to MOR agonists in several areas of the central nervous system (CNS) that are of instrumental importance for nociception (Connor et al, 1999;Hack et al, 2003;Zeng et al, 2006;Fyfe et al, 2010) have been shown to be decreased after long-term morphine treatment, a phenomenon described as "desensitization." Thus, there has been a tendency to equate desensitization to the effects of the drug (tolerance) to desensitization/down-regulation of the receptor per se.…”

Section: Introductionmentioning

confidence: 99%

A Novel Knock-In Mouse Reveals Mechanistically Distinct Forms of Morphine Tolerance

Enquist

Kim

Bartlett

et al. 2011

J Pharmacol Exp Ther

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The role of -opioid receptor (MOR) down-regulation in opioid tolerance remains controversial. In this study, we used a novel knock-in mouse to examine how changing the extent of MOR down-regulation alters the development of morphine tolerance. These mice express a mutant MOR, degrading MOR (DMOR), that differs from the wild-type (WT) MOR in two ways: 1) unlike the recycling WT MOR, the mutant DMOR is targeted for degradation after its internalization, thus facilitating down-regulation; and 2) unlike the WT MOR, DMOR is efficiently internalized in response to morphine activation. We found that both WT MOR and DMOR mice develop tolerance to morphine, but DMOR mice exhibit a more rapid onset of tolerance and show receptor down-regulation. WT MOR mice develop morphine tolerance more slowly but even once profoundly tolerant show no receptor down-regulation. Furthermore, WT mice show significantly more morphine dependence than DMOR mice after long-term treatment as indicated by withdrawal. Taken together these data indicate that tolerance mediated by receptor downregulation manifests differently both at the behavioral and biochemical level than does the actual morphine tolerance that occurs in WT mice and that loss of receptor function is not a major contributor to morphine tolerance in WT MOR mice.

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Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

Cited by 63 publications

References 74 publications

Substance P Enhances Excitatory Synaptic Transmission on Spinally Projecting Neurons in the Rostral Ventromedial Medulla After Inflammatory Injury

Substance P Enhances Excitatory Synaptic Transmission on Spinally Projecting Neurons in the Rostral Ventromedial Medulla After Inflammatory Injury

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

A Novel Knock-In Mouse Reveals Mechanistically Distinct Forms of Morphine Tolerance

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