Involvement of Glutamate Receptors in Strychnine- and Bicuculline-induced Allodynia in Conscious Mice

Onaka, Masahiko; Minami, Toshiaki; Nishihara, Isao; Ito, Seiji

doi:10.1097/00000542-199605000-00024

Cited by 54 publications

(26 citation statements)

References 30 publications

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“…Higher doses of strychnine (>10.0 μg) may cause seizure. Consistent with previous studies (13,17,41,42), intrathecal strychnine induced marked mechanical allodynia in a dose-dependent manner ( Figure 7E). However, only the highest subconvulsive dose of strychnine (10 μg) induced thermal hyperalgesia ( Figure 7F).…”

Section: Activation Of Low-threshold Aβ Fibers Evokes Ap Output Of Nosupporting

confidence: 92%

A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

Lü

Dong²,

Gao³

et al. 2013

J. Clin. Invest.

249

302

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Neuropathic pain is characterized by mechanical allodynia induced by low-threshold myelinated Aβ-fiber activation. The original gate theory of pain proposes that inhibitory interneurons in the lamina II of the spinal dorsal horn (DH) act as "gate control" units for preventing the interaction between innocuous and nociceptive signals. However, our understanding of the neuronal circuits underlying pain signaling and modulation in the spinal DH is incomplete. Using a rat model, we have shown that the convergence of glycinergic inhibitory and excitatory Aβ-fiber inputs onto PKCγ + neurons in the superficial DH forms a feed-forward inhibitory circuit that prevents Aβ input from activating the nociceptive pathway. This feed-forward inhibition was suppressed following peripheral nerve injury or glycine blockage, leading to inappropriate induction of action potential outputs in the nociceptive pathway by Aβ-fiber stimulation. Furthermore, spinal blockage of glycinergic synaptic transmission in vivo induced marked mechanical allodynia. Our findings identify a glycinergic feed-forward inhibitory circuit that functions as a gate control to separate the innocuous mechanoreceptive pathway and the nociceptive pathway in the spinal DH. Disruption of this glycinergic inhibitory circuit after peripheral nerve injury has the potential to elicit mechanical allodynia, a cardinal symptom of neuropathic pain.

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Section: Activation Of Low-threshold Aβ Fibers Evokes Ap Output Of Nosupporting

confidence: 92%

A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

Lü

Dong²,

Gao³

et al. 2013

J. Clin. Invest.

249

302

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“…Either the blockade of inhibitory neurotransmission by GABA and glycine (34,35) or augmentation of pain transmission by the excitatory transmission by the glutamate-NO system (36, 37) is known to induce allodynia. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…GABAergic neurons are present in laminae I-III of the spinal cord, and many of the neurons with somata in laminae I-III are inhibitory interneurons containing GABA (43). We previously suggested that both PGE 2 -and bicuculline-induced allodynia were mediated through pathways that include the glutamate receptor-NO system (35)(36)(37). The induction of allodynia was considered to result from removal of tonic or evoked inhibition from pathways relaying information about innocuous stimuli and augmentation of pain transmission by the excitatory transmission by the glutamate-NO system.…”

Section: Discussionmentioning

confidence: 99%

Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-deficient mice

Eguchi

Minami²,

Shirafuji³

et al. 1999

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

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225

151

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Prostaglandin (PG) D 2 is the most abundant prostanoid produced in the central nervous system of mammals and has been implicated in the modulation of neural functions such as sleep induction, nociception, regulation of body temperature, and odor responses. We generated geneknockout mice for lipocalin-type PGD 2 synthase (L-PGDS) and found that the intrathecal administration of PGE 2 , an endogenous pain-producing substance, failed to elicit allodynia (touch-evoked pain), which is one typical phenomenon of neuropathic pain, whereas it evoked thermal hyperalgesia, in L-PGDS؊͞؊ mice. We also found that the allodynic response induced by the ␥-aminobutyric acid (GABA) A receptor antagonist bicuculline was selectively abolished in the L-PGDS؊͞؊ mice, among excitatory and inhibitory agents that induced allodynia in wild-type mice. Interestingly, simultaneous injection of a femtogram amount of PGD 2 with PGE 2 or bicuculline induced allodynia in L-PGDS؊͞؊ mice to the same extent as in wild-type mice. The PGE 2 -or bicucullineevoked allodynia in wild-type and in PGD 2 -supplemented L-PGDS؊͞؊ mice was blocked by a PGD 2 receptor antagonist given in a femtogram amount. These results reveal that endogenous PGD 2 is essential for both PGE 2 -and bicucullineinduced allodynia.Prostaglandin (PG) D 2 is the major prostanoid produced in the central nervous system (CNS) of mammals (1, 2) and has been shown to be involved in a variety of central actions, e.g., it induces sleep, decreases body temperature, and modulates odor and pain responses (3-5). Among the three enzymes catalyzing the conversion of PGH 2 to PGD 2 (6, 7), lipocalintype PGD synthase (L-PGDS) is considered to be responsible for the biosynthesis of PGD 2 in the CNS. L-PGDS is present mainly in the leptomeninges, choroid plexus, and oligodendrocytes of the CNS (8, 9), and is secreted into the cerebrospinal fluid to become ␤-trace (10, 11), a major protein component of the cerebrospinal fluid (12-14). The receptor for PGD 2 , the D type of PG (DP) receptor (15, 16), also is localized in the leptomeninges of the brain (17, 18). Therefore, PGD 2 is assumed to be produced in the membranous tissues and oligodendrocytes of the CNS; to circulate through the cerebrospinal fluid in the ventricular system, subarachnoidal space, and extracellular space in the CNS; to interact with DP receptors in the meninges; and to act as a neurohormone or an informational substance for global regulation of various CNS functions (5).Prolonged tissue damage or injury often leads to chronic pain states such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). In relation to clinically relevant hyperalgesic states, such as inflammation and neuropathic pain, there is considerable interest in the neurochemical mechanisms of hyperalgesia and allodynia (19-21). Since Vane (22) reported that aspirin-like drugs prevented the development of inflammation by blocking the synthesis of PGs, it has been widely accepted that PGs are involved in inflammation an...

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“…For example, the difference in kinetics of the GABAergic versus glycinergic IPSCs and the type of activity that recruit them may match the nature of excitatory input they control. Interestingly, metabotropic receptor antagonists attenuate bicuculline-induced allodynia but are not effective against strychnine-induced allodynia (Onaka et al, 1996). Metabotropic glutamate receptors appear to be mainly located at extrasynaptic sites (Baude et al, 1993) and may therefore be activated selectively after release of a sufficient concentration of glutamate that can spill over the synapses (Rusakov and Kullmann, 1998).…”

Section: Functional Significance Of the Difference In Gaba A Rand Glymentioning

confidence: 99%

Junctional versus Extrajunctional Glycine and GABA_AReceptor-Mediated IPSCs in Identified Lamina I Neurons of the Adult Rat Spinal Cord

1999

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Colocalization of GABA and glycine in synaptic terminals of the superficial dorsal horn raises the question of their relative contribution to inhibition of different classes of neurons in this area. To address this issue, miniature IPSCs (mIPSCs) mediated via GABA A receptors (GABA A Rs) and glycine receptors (GlyRs) were recorded from identified laminae I-II neurons in adult rat spinal cord slices. GABA A R-mediated mIPSCs had similar amplitude and rise times, but significantly slower decay kinetics than GlyR-mediated mIPSCs. Lamina I neurons appeared to receive almost exclusively GlyR-mediated mIPSCs, even after application of hypertonic solutions. Yet, all neurons responded to exogenous applications of both GABA and glycine, indicating that they expressed both GABA A Rs and GlyRs. Given that virtually all glycinergic interneurons also contain GABA, the possibility was examined that GABA A Rs may be located extrasynaptically in lamina I neurons. A slow GABA A R-mediated component was revealed in large, but not minimally evoked monosynaptic IPSCs. Administration of the benzodiazepine flunitrazepam unmasked a GABA A R component to most mIPSCs, suggesting that both transmitters were released from the same vesicle. The isolated GABA A R component of these mIPSCs had rising kinetics 10 times slower than that of the GlyR component (or of GABA A R mIPSCs in lamina II). The slow GABA A R components were prolonged by GABA uptake blockers.It is concluded that, whereas GABA and glycine are likely released from the same vesicle of transmitter in lamina I, GABA A Rs appear to be located extrasynaptically. Thus, glycine mediates most of the tonic inhibition at these synapses. This differential distribution of GABA A Rs and GlyRs confers distinct functional properties to inhibition mediated by these two transmitters in lamina I. Key words: dorsal horn; substantia gelatinosa; nociception; miniature IPSCs; slice; inhibitionThe superficial laminae I and II of the dorsal horn play a pivotal role in the integration and relay of pain-related information (Perl, 1984;Willis, 1985;Light, 1992;Craig, 1996), and thus elucidating the nature of inhibitory control in this area is crucial for our understanding of nociceptive processing. Both GABA and glycine function as inhibitory neurotransmitters in the mammalian spinal cord (for review, see Todd and Spike, 1993), and blocking either of these control mechanisms produces a hypersensitivity characteristic of neuropathic pain syndromes (Yaksh, 1989;Sivilotti and Woolf, 1994;Sherman and L oomis, 1996;Sorkin and Puig, 1996). Previous studies report the coexistence of GABA and glycine as well as their respective receptors at many synapses in the superficial dorsal horn of the rat spinal cord (van den Pol

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Involvement of Glutamate Receptors in Strychnine- and Bicuculline-induced Allodynia in Conscious Mice

Cited by 54 publications

References 30 publications

A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-deficient mice

Junctional versus Extrajunctional Glycine and GABA_AReceptor-Mediated IPSCs in Identified Lamina I Neurons of the Adult Rat Spinal Cord

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Involvement of Glutamate Receptors in Strychnine- and Bicuculline-induced Allodynia in Conscious Mice

Cited by 54 publications

References 30 publications

A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-deficient mice

Junctional versus Extrajunctional Glycine and GABAAReceptor-Mediated IPSCs in Identified Lamina I Neurons of the Adult Rat Spinal Cord

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Junctional versus Extrajunctional Glycine and GABA_AReceptor-Mediated IPSCs in Identified Lamina I Neurons of the Adult Rat Spinal Cord