Ketamine, an N -methyl-d-aspartate Receptor Antagonist, Inhibits the Spinal Neuronal Responses to Distension of the Rat Urinary Bladder

Background The effect of ketamine as a treatment of visceral pain is not known. The current study investigated the effect of ketamine on spinal dorsal horn neurons excited by urinary bladder distension (UBD). The effect of other clinically available N-methyl-D-aspartate receptor antagonists on these responses was also studied. Methods Extracellular recordings of neurons located in the L6-S2 spinal dorsal horn of cervical spinal cord-transected, decerebrate female rats were obtained. Cutaneous receptive fields of neuronal units excited by UBD were characterized for responses to segmental noxious and nonnoxious stimuli. Nonsegmental noxious stimuli were also applied, and neurons were classified as type I (inhibited) and type II (noninhibited) by the stimulus. The effect of intravenous ketamine (1, 3, and 10 mg/kg), dextromethorphan (5 mg/kg), and memantine (16 mg/kg) on neuronal responses of these units was measured. Results Spontaneous and evoked neuronal activity to UBD was reduced in a dose-dependent fashion by ketamine. Responses to nonnoxious cutaneous stimuli were also significantly reduced after treatment. Dextromethorphan inhibited neuronal activity evoked by UBD in type I neurons. A similar selective effect of treatment on type I versus type II neurons was observed after intravenous ketamine and memantine. Conclusions Intravenous ketamine produces dose-dependent inhibition of the spinal cord neuronal responses evoked by UBD. All three N-methyl-D-aspartate receptor antagonists showed selective effects on spinal cord neurons subject to counterirritation. This neurophysiologic evidence supports a spinally mediated analgesic effect of ketamine in this model of urinary bladder nociception, an effect likely caused by N-methyl-D-aspartate receptor antagonism.

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α2δ-1–Bound N-Methyl-d-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents

Anesthesiology ◽

10.1097/aln.0000000000002648 ◽

2019 ◽

Vol 130 (5) ◽

pp. 804-819 ◽

Cited By ~ 5

Author(s):

Meichun Deng ◽

Shao-Rui Chen ◽

Hong Chen ◽

Hui-Lin Pan

Keyword(s):

Spinal Cord ◽

Spinal Dorsal Horn ◽

Receptor Activity ◽

Morphine Treatment ◽

Chronic Morphine ◽

Analgesic Tolerance ◽

Spinal Dorsal ◽

Aspartate Receptor ◽

C Terminus ◽

Opioid Induced Hyperalgesia

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Chronic use of μ-opioid receptor agonists paradoxically causes both hyperalgesia and the loss of analgesic efficacy. Opioid treatment increases presynaptic N-methyl-d-aspartate receptor activity to potentiate nociceptive input to spinal dorsal horn neurons. However, the mechanism responsible for this opioid-induced activation of presynaptic N-methyl-d-aspartate receptors remains unclear. α2δ-1, formerly known as a calcium channel subunit, interacts with N-methyl-d-aspartate receptors and is primarily expressed at presynaptic terminals. This study tested the hypothesis that α2δ-1–bound N-methyl-d-aspartate receptors contribute to presynaptic N-methyl-d-aspartate receptor hyperactivity associated with opioid-induced hyperalgesia and analgesic tolerance. Methods Rats (5 mg/kg) and wild-type and α2δ-1–knockout mice (10 mg/kg) were treated intraperitoneally with morphine twice/day for 8 consecutive days, and nociceptive thresholds were examined. Presynaptic N-methyl-d-aspartate receptor activity was recorded in spinal cord slices. Coimmunoprecipitation was performed to examine protein–protein interactions. Results Chronic morphine treatment in rats increased α2δ-1 protein amounts in the dorsal root ganglion and spinal cord. Chronic morphine exposure also increased the physical interaction between α2δ-1 and N-methyl-d-aspartate receptors by 1.5 ± 0.3 fold (means ± SD, P = 0.009, n = 6) and the prevalence of α2δ-1–bound N-methyl-d-aspartate receptors at spinal cord synapses. Inhibiting α2δ-1 with gabapentin or genetic knockout of α2δ-1 abolished the increase in presynaptic N-methyl-d-aspartate receptor activity in the spinal dorsal horn induced by morphine treatment. Furthermore, uncoupling the α2δ-1–N-methyl-d-aspartate receptor interaction with an α2δ-1 C terminus–interfering peptide fully reversed morphine-induced tonic activation of N-methyl-d-aspartate receptors at the central terminal of primary afferents. Finally, intraperitoneal injection of gabapentin or intrathecal injection of an α2δ-1 C terminus–interfering peptide or α2δ-1 genetic knockout abolished the mechanical and thermal hyperalgesia induced by chronic morphine exposure and largely preserved morphine’s analgesic effect during 8 days of morphine treatment. Conclusions α2δ-1–Bound N-methyl-d-aspartate receptors contribute to opioid-induced hyperalgesia and tolerance by augmenting presynaptic N-methyl-d-aspartate receptor expression and activity at the spinal cord level.

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Effects of ketamine on formalin-induced activity in the spinal dorsal horn of spinal cord-transected cats: differences in response to intravenous ketamine administered before and after formalin

Acta Anaesthesiologica Scandinavica ◽

10.1034/j.1399-6576.2000.440810.x ◽

2000 ◽

Vol 44 (8) ◽

pp. 953-958 ◽

Cited By ~ 6

Author(s):

H. Nagasaka ◽

S. Nakamura ◽

Y. Mizumoto ◽

I. Sato

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Spinal Dorsal ◽

Before And After ◽

Intravenous Ketamine

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Split spinal cord malformations in children

Journal of Neurosurgery ◽

10.3171/jns.1998.88.1.0057 ◽

1998 ◽

Vol 88 (1) ◽

pp. 57-65 ◽

Cited By ~ 72

Author(s):

Yusuf Ersşahin ◽

Saffet Mutluer ◽

Sevgül Kocaman ◽

Eren Demirtasş

Keyword(s):

Spinal Cord ◽

Neurological Deficits ◽

Single Type ◽

Type I ◽

Type Ii ◽

Content Type ◽

Spinal Lesion ◽

The Mean ◽

Fine Print

Object. The authors reviewed and analyzed information on 74 patients with split spinal cord malformations (SSCMs) treated between January 1, 1980 and December 31, 1996 at their institution with the aim of defining and classifying the malformations according to the method of Pang, et al. Methods. Computerized tomography myelography was superior to other radiological tools in defining the type of SSCM. There were 46 girls (62%) and 28 boys (38%) ranging in age from less than 1 day to 12 years (mean 33.08 months). The mean age (43.2 months) of the patients who exhibited neurological deficits and orthopedic deformities was significantly older than those (8.2 months) without deficits (p = 0.003). Fifty-two patients had a single Type I and 18 patients a single Type II SSCM; four patients had composite SSCMs. Sixty-two patients had at least one associated spinal lesion that could lead to spinal cord tethering. After surgery, the majority of the patients remained stable and clinical improvement was observed in 18 patients. Conclusions. The classification of SSCMs proposed by Pang, et al., will eliminate the current chaos in terminology. In all SSCMs, either a rigid or a fibrous septum was found to transfix the spinal cord. There was at least one unrelated lesion that caused tethering of the spinal cord in 85% of the patients. The risk of neurological deficits resulting from SSCMs increases with the age of the patient; therefore, all patients should be surgically treated when diagnosed, especially before the development of orthopedic and neurological manifestations.

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TWIK-Related Spinal Cord K+Channel Expression Is Increased in the Spinal Dorsal Horn after Spinal Nerve Ligation

Yonsei Medical Journal ◽

10.3349/ymj.2015.56.5.1307 ◽

2015 ◽

Vol 56 (5) ◽

pp. 1307 ◽

Cited By ~ 5

Author(s):

Hee Youn Hwang ◽

Enji Zhang ◽

Sangil Park ◽

Woosuk Chung ◽

Sunyeul Lee ◽

...

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Spinal Nerve ◽

Spinal Nerve Ligation ◽

K Channel ◽

Spinal Dorsal ◽

Channel Expression

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Metabotropic glutamate receptor 5 regulates excitability and Kv4.2-containing K+ channels primarily in excitatory neurons of the spinal dorsal horn

Journal of Neurophysiology ◽

10.1152/jn.01050.2010 ◽

2011 ◽

Vol 105 (6) ◽

pp. 3010-3021 ◽

Cited By ~ 29

Author(s):

Hui-Juan Hu ◽

Robert W. Gereau

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Neuronal Excitability ◽

Gabaergic Neurons ◽

Erk Signaling ◽

Metabotropic Glutamate ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Excitatory Neurons

Metabotropic glutamate (mGlu) receptors play important roles in the modulation of nociception. Previous studies demonstrated that mGlu5 modulates nociceptive plasticity via activation of ERK signaling. We have reported recently that the Kv4.2 K+ channel subunit underlies A-type currents in spinal cord dorsal horn neurons and that this channel is modulated by mGlu5-ERK signaling. In the present study, we tested the hypothesis that modulation of Kv4.2 by mGlu5 occurs in excitatory spinal dorsal horn neurons. With the use of a transgenic mouse strain expressing enhanced green fluorescent protein (GFP) under control of the promoter for the γ-amino butyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase 67 (GAD67), we found that these GABAergic neurons express less Kv4.2-mediated A-type current than non-GAD67-GFP neurons. Furthermore, the mGlu1/5 agonist, (R,S)-3,5-dihydroxyphenylglycine, had no modulatory effects on A-type currents or neuronal excitability in this subgroup of GABAergic neurons but robustly modulated A-type currents and neuronal excitability in non-GFP-expressing neurons. Immunofluorescence studies revealed that Kv4.2 was highly colocalized with markers of excitatory neurons, such as vesicular glutamate transporter 1/2, PKCγ, and neurokinin 1, in cultured dorsal horn neurons. These results indicate that mGlu5-Kv4.2 signaling is associated with excitatory dorsal horn neurons and suggest that the pronociceptive effects of mGlu5 activation in the spinal cord likely involve enhanced excitability of excitatory neurons.

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Synergistic Enhancement of Glutamate-Mediated Responses by Serotonin and Forskolin in Adult Mouse Spinal Dorsal Horn Neurons

Journal of Neurophysiology ◽

10.1152/jn.00423.2001 ◽

2002 ◽

Vol 87 (2) ◽

pp. 732-739 ◽

Cited By ~ 24

Author(s):

Guo-Du Wang ◽

Min Zhuo

Keyword(s):

Spinal Cord ◽

Nmda Receptors ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Adult Mouse ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Afferent Fibers ◽

Primary Afferent Fibers ◽

Spinal Dorsal Horn Neurons

Glutamate is the major excitatory amino acid neurotransmitter in the CNS, including the neocortex, hippocampus, and spinal cord. Normal synaptic transmission is mainly mediated by glutamate AMPA and/or kainate receptors. Glutamate N-methyl-d-aspartate (NMDA) receptors are normally inactive and only activated when a sufficient postsynaptic depolarization is induced by the activity. Here we show that in sensory synapses of adult mouse, some synaptic responses (26.3% of a total of 38 experiments) between primary afferent fibers and dorsal horn neurons are almost completely mediated by NMDA receptors. Dorsal root stimulation did not elicit any detectable AMPA/kainate receptor-mediated responses in these synapses. Unlike young spinal cord, serotonin alone did not produce any long-lasting synaptic enhancement in adult spinal dorsal horn neurons. However, co-application of the adenylyl cyclase activator forskolin and serotonin (5-HT) produced long-lasting enhancement, including the recruitment of functional AMPA receptor-mediated responses. Calcium-sensitive, calmodulin-regulated adenylyl cyclases (AC1, AC8) are required for the enhancement. Furthermore the thresholds for generating action potential responses were decreased, and, in many cases, co-application of forskolin and 5-HT led to the generation of action potentials by previously subthreshold stimulation of primary afferent fibers in the presence of the NMDA receptor blocker 2-amino-5-phosphonovaleric acid. Our results suggest that pure NMDA synapses exist on sensory neurons in adult spinal cord and that they may contribute to functional sensory transmission. The synergistic recruitment of functional AMPA responses by 5-HT and forskolin provides a new cellular mechanism for glutamatergic synapses in mammalian spinal cord.

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Xenon Has Greater Inhibitory Effects on Spinal Dorsal Horn Neurons than Nitrous Oxide in Spinal Cord Transected Cats

Anesthesia & Analgesia ◽

10.1213/00000539-199904000-00038 ◽

1999 ◽

Vol 88 (4) ◽

pp. 893-897 ◽

Cited By ~ 22

Author(s):

Yoshiya Miyazaki ◽

Takehiko Adachi ◽

Jun Utsumi ◽

Tsutomu Shichino ◽

Hajime Segawa

Keyword(s):

Spinal Cord ◽

Nitrous Oxide ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Inhibitory Effects ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Spinal Dorsal Horn Neurons

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Decompression Sickness Damaging the Spinal Cord in a Scuba Diver: Case Report

Journal of the World Association for Emergency and Disaster Medicine ◽

10.1017/s1049023x00029046 ◽

1987 ◽

Vol 3 (2) ◽

pp. 41-45

Author(s):

B.G. Mathew

Keyword(s):

Spinal Cord ◽

Decompression Sickness ◽

The United States ◽

Neurological Involvement ◽

Detailed Knowledge ◽

Type I ◽

Type Ii ◽

Pulmonary Barotrauma ◽

Emergency Personnel ◽

Diving Accidents

Scuba diving has become a popular sport resulting in an increased incidence of diving accidents. A survey done by the United States Navy from 1955 to 1960 revealed that decompression sickness (D.C.S.) is the most common serious complication experienced by scuba divers and the third most likely cause of death. The major cause is drowning and the second is arterial gas embolism from pulmonary barotrauma.D.C.S. has been classified into two groups. Type I includes the less severe forms with bubbles in the skin (“itches”), joints and other tissues. Type II includes the serious conditions with neurological involvement “staggers.” A detailed knowledge of D.C.S., commonly known as “the bends,” is essential to both divers and emergency personnel in order to minimize the morbidity and mortality associated with this condition.A case of Type II bends with spinal cord damage is presented and the condition discussed.

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Changes in Properties of Spinal Dorsal Horn Neurons and Their Sensitivity to Morphine after Spinal Cord Injury in the Rat

Anesthesiology ◽

10.1097/00000542-200501000-00024 ◽

2005 ◽

Vol 102 (1) ◽

pp. 152-164 ◽

Cited By ~ 23

Author(s):

Jungang Wang ◽

Mikito Kawamata ◽

Akiyoshi Namiki

Keyword(s):

Spinal Cord ◽

Spontaneous Activity ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

High Threshold ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Cord Injury ◽

Spinal Dorsal Horn Neurons ◽

Wdr Neurons

Background To gain a better understanding of spinal cord injury (SCI)-induced central neuropathic pain, the authors investigated changes in properties of spinal dorsal horn neurons located rostrally and caudally to the lesion and their sensitivity to morphine in rats after SCI. Methods The right spinal cord of Sprague-Dawley rats was hemisected at the level of L2. At 10 to 14 days after the SCI, when mechanical hyperalgesia/allodynia had fully developed, spontaneous activity and evoked responses to mechanical stimuli of wide-dynamic-range (WDR) and high-threshold neurons rostral and caudal to the lesion were recorded. Effects of cumulative doses of systemic (0.1-3 mg/kg) and spinal (0.1-5 microg) administration of morphine on spontaneous activity and evoked responses to the stimuli of the neurons were evaluated. Results Spontaneous activity significantly increased in WDR neurons both rostral and caudal to the SCI site, but high-frequency background discharges with burst patterns were only observed in neurons rostral to the SCI site. Significant increases in responses to the mechanical stimuli were seen both in WDR and high-threshold neurons located both rostrally and caudally to the lesion. The responses to nonnoxious and noxious stimuli were significantly greater in caudal WDR neurons than in rostral WDR neurons. In contrast, the responses to pinch stimuli were significantly higher in rostral high-threshold neurons than those in caudal high-threshold neurons. Systemically administered morphine had a greater effect on responses to nonnoxious and noxious stimuli of rostral WDR neurons than those of caudal WDR neurons. Spinally administered morphine significantly suppressed responses of WDR neurons in SCI animals to nonnoxious stimuli compared with those in sham-operated control animals. Conclusions The findings suggest that changes in properties of spinal dorsal horn neurons after SCI are caused by different mechanisms, depending on the classification of the neurons and their segmental locations.

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