Enhanced 3,5-dihydroxyphenylglycine-induced sustained nociceptive behaviors in rats with neuropathy or chronic inflammation

Scotland, Phoebe E.; Coderre, Terence J.

doi:10.1016/j.bbr.2007.07.003

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…3) A third mechanism is that SNI increases mGluR activation of G q/11 thus leading to increased Ca 2+ mobilization. Peripheral inflammation causes trafficking of group I mGluRs to the plasma membrane in the spinal dorsal horn neurons [36] and behavioral studies indicates a greater response to group I mGluR agonists in CCI compared to control, suggesting that group I mGluRs contribute to neuropathic pain [72]. 4) A fourth possible mechanism is that SNI induced a switch from GluR2-containing to GluR2-lacking AMPARs; this would allow for increased Ca 2+ entry through the AMPA receptor pore.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Nerve Injury Increases Glutamate-Evoked Calcium Mobilization in Adult Spinal Cord Neurons

et al. 2012

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BackgroundCentral sensitization in the spinal cord requires glutamate receptor activation and intracellular Ca2+ mobilization. We used Fura-2 AM bulk loading of mouse slices together with wide-field Ca2+ imaging to measure glutamate-evoked increases in extracellular Ca2+ to test the hypotheses that: 1. Exogenous application of glutamate causes Ca2+ mobilization in a preponderance of dorsal horn neurons within spinal cord slices taken from adult mice; 2. Glutamate-evoked Ca2+ mobilization is associated with spontaneous and/or evoked action potentials; 3. Glutamate acts at glutamate receptor subtypes to evoked Ca2+ transients; and 4. The magnitude of glutamate-evoked Ca2+ responses increases in the setting of peripheral neuropathic pain.ResultsBath-applied glutamate robustly increased [Ca2+]i in 14.4 ± 2.6 cells per dorsal horn within a 440 x 330 um field-of-view, with an average time-to-peak of 27 s and decay of 112 s. Repeated application produced sequential responses of similar magnitude, indicating the absence of sensitization, desensitization or tachyphylaxis. Ca2+ transients were glutamate concentration-dependent with a Kd = 0.64 mM. Ca2+ responses predominantly occurred on neurons since: 1) Over 95% of glutamate-responsive cells did not label with the astrocyte marker, SR-101; 2) 62% of fura-2 AM loaded cells exhibited spontaneous action potentials; 3) 75% of cells that responded to locally-applied glutamate with a rise in [Ca2+]i also showed a significant increase in AP frequency upon a subsequent glutamate exposure; 4) In experiments using simultaneous on-cell recordings and Ca2+ imaging, glutamate elicited a Ca2+ response and an increase in AP frequency. AMPA/kainate (CNQX)- and AMPA (GYKI 52466)-selective receptor antagonists significantly attenuated glutamate-evoked increases in [Ca2+]i, while NMDA (AP-5), kainate (UBP-301) and class I mGluRs (AIDA) did not. Compared to sham controls, peripheral nerve injury significantly decreased mechanical paw withdrawal threshold and increased glutamate-evoked Ca2+ signals.ConclusionsBulk-loading fura-2 AM into spinal cord slices is a successful means for determining glutamate-evoked Ca2+ mobilization in naïve adult dorsal horn neurons. AMPA receptors mediate the majority of these responses. Peripheral neuropathic injury potentiates Ca2+ signaling in dorsal horn.

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Section: Discussionmentioning

confidence: 99%

Peripheral Nerve Injury Increases Glutamate-Evoked Calcium Mobilization in Adult Spinal Cord Neurons

et al. 2012

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“…The present findings extend our knowledge of the modulation of NMDA current by CFA-induced inflammation and the intracellular mechanisms of mGlu receptor-produced potentiation of NMDA current. Previous studies have documented the contribution of group I mGlu receptors to central sensitization and behavioral hyperalgesia (Adwanikar et al, 2004; Guo et al, 2004; Neugebauer, 2002; Scotland et al, 2007). The present study further demonstrates that the involvement of group I mGlu receptors in persistent pain requires subsequent activation of NMDA receptors.…”

Section: Discussionmentioning

confidence: 99%

“…While groups II and III mGlu receptors are dominantly located presynaptically, group I mGlu receptors are expressed primarily on postsynaptic membranes, although a presynaptic localization has also been observed (Jia et al, 1999; Neugebauer 2002; Shigemoto et al, 1997). Group I mGlu receptors are distributed in the superficial spinal dorsal horn (Berthele et al, 1999; Guo et al, 2004), and implicated in a variety of pain conditions (Adwanikar et al, 2004; Guo et al, 2004; Neugebauer, 2002; Scotland and Coderre, 2007). It has been well established that the N -methyl-D-aspartate (NMDA) receptor, a subtype of ionotropic glutamate receptors, plays an important role in synaptic plasticity, dorsal horn hyperexcitability and hyperalgesia (Dubner and Ruda, 1992; Guo and Huang, 2001; Ren et al, 1992; Woolf and Thompson, 1991).…”

Section: Introductionmentioning

confidence: 99%

Activation of group I mGlu receptors contributes to facilitation of NMDA receptor membrane current in spinal dorsal horn neurons after hind paw inflammation in rats

Yang

Takeuchi

Feng

et al. 2011

European Journal of Pharmacology

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The interaction between the group I metabotropic glutamate (mGlu) receptors and N-methyl-D-aspartate (NMDA) receptors plays a critical role in spinal hyperexcitability and hyperalgesia. The cellular mechanisms underlying this interaction remain unknown. Utilizing an ex vivo spinal slice preparation from young adult rats, we investigated the group I mGlu receptor modulation of NMDA receptor-mediated current in superficial dorsal horn neurons by patch clamp recording after complete Freund’s adjuvant (CFA)-induced hind paw inflammation. We show that NMDA receptor-mediated dorsal root stimulation-evoked EPSC (eEPSC) and NMDA-induced current was enhanced in the inflamed rats, compared to naïve rats and this effect was attenuated by AIDA (1 mM), a group I mGlu receptor antagonist. There were also increases in the frequency and amplitude of miniature excitatory postsynaptic currents in the presence of tetrodotoxin, suggesting enhanced presynaptic glutamate release probability and postsynaptic membrane responsiveness in inflamed rats. DHPG (10 µM), a selective group I mGlu receptor agonist, further facilitated NMDA receptor-mediated eEPSC and NMDA-induced current in inflamed rats. The DHPG-produced facilitation of NMDA-induced current was blocked by intracellular dialysis of GDP-beta-S (1 mM), a G protein antagonist, and BAPTA (15 mM), an intracellular calcium chelating agent; and by pretreatment with U73,122 (10 µM), a PLC inhibitor, or 2-APB (100 µM), an IP3-receptor antagonist. These findings support the hypothesis that signal transduction coupling between group I mGlu receptors and NMDA receptors underlies the activation of NMDA receptors in spinal hyperexcitability and hyperalgesia.

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“…Animals were habituated to the testing environment in 9.5 ϫ 21 ϫ 25 cm Plexiglas boxes on an elevated perforated plastic surface for a minimum of 30 min before all behavioral tests. A blind observer conducted behavioral testing according to a modification of the up/down method (33), as previously described (34). Baseline mechanical withdrawal thresholds were obtained and unilateral CFA administration followed (50 L of 1:1 saline and heat-killed and dried Mycobacterium tuberculosis, 0.5 mg/mL, suspended in 85% paraffin oil and 15% mannide monooleate, Sigma).…”

Section: Tg Cultures and Cho Cell Preparationmentioning

confidence: 99%

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Patwardhan¹,

Scotland

Akopian³

et al. 2009

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

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196

191

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Transient receptor potential vanilloid 1 (TRPV1) plays a major role in hyperalgesia and allodynia and is expressed both in the peripheral and central nervous systems (CNS). However, few studies have evaluated mechanisms by which CNS TRPV1 mediates hyperalgesia and allodynia after injury. We hypothesized that activation of spinal cord systems releases endogenous TRPV1 agonists that evoke the development of mechanical allodynia by this receptor. Using in vitro superfusion, the depolarization of spinal cord triggered the release of oxidized linoleic acid metabolites, such as 9-hydroxyoctadecadienoic acid (9-HODE) that potently activated spinal TRPV1, leading to the development of mechanical allodynia. Subsequent calcium imaging and electrophysiology studies demonstrated that synthetic oxidized linoleic acid metabolites, including 9-HODE, 13-HODE, and 9 and 13-oxoODE, comprise a family of endogenous TRPV1 agonists. In vivo studies demonstrated that intrathecal application of these oxidized linoleic acid metabolites rapidly evokes mechanical allodynia. Finally, intrathecal neutralization of 9-and 13-HODE by antibodies blocks CFA-evoked mechanical allodynia. These data collectively reveal a mechanism by which an endogenous family of lipids activates TRPV1 in the spinal cord, leading to the development of inflammatory hyperalgesia. These findings may integrate many pain disorders and provide an approach for developing analgesic drugs.inflammation ͉ pain T ransient receptor potential vanilloid 1 (TRPV1) plays a pivotal role in many pain models, leading to the development of hyperalgesia and/or allodynia (1-2). TRPV1 is expressed in the peripheral as well as central nervous systems (CNS) including several areas involved in nociceptive transmission (3). Numerous studies have demonstrated that peripheral TRPV1 is activated by noxious heat and protons and is regulated by endogenous ligands (2), contributing to peripheral mechanisms of heat hyperalgesia (4). However, TRPV1 is also expressed in the CNS, where comparatively little is known about the role of this receptor in mediating central pain mechanisms.Recent studies have used TRPV1 antagonists to evaluate the role of CNS TRPV1 in inflammatory hyperalgesia. Interestingly, the systemic/spinal administration of TRPV1 antagonists blocks inflammation-induced heat hyperalgesia, as well as mechanical allodynia (5-6). These findings were unexpected since TRPV1 is not activated by mechanical stimuli, suggesting that spinal TRPV1 activation leads to central sensitization to both thermal and mechanical stimuli (7-8). Based upon these observations, we hypothesized that the afferent barrage resulting from peripheral tissue injury leads to generation of endogenous TRPV1 ligands in the spinal cord that activate TRPV1 in the CNS resulting in central sensitization. Results Depolarization of Spinal Cord Results in the Release of EndogenousTRPV1 Ligands. To evaluate the hypothesis that endogenous TRPV1 agonists are released from spinal cord neurons, freshly isolated male rat spinal cords w...

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Enhanced 3,5-dihydroxyphenylglycine-induced sustained nociceptive behaviors in rats with neuropathy or chronic inflammation

Cited by 5 publications

References 39 publications

Peripheral Nerve Injury Increases Glutamate-Evoked Calcium Mobilization in Adult Spinal Cord Neurons

Peripheral Nerve Injury Increases Glutamate-Evoked Calcium Mobilization in Adult Spinal Cord Neurons

Activation of group I mGlu receptors contributes to facilitation of NMDA receptor membrane current in spinal dorsal horn neurons after hind paw inflammation in rats

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

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