Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord

Randić, Mirjana; Jiang, Michael; Cerne, R.

doi:10.1523/jneurosci.13-12-05228.1993

Cited by 469 publications

(346 citation statements)

References 73 publications

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“…Thus, the postsynaptic depolarizations in the induction protocol apparently provided sufficient stimulus for calcium influx to support LTD, independent of NMDA receptors. This observation is consistent with a previous report that strong stimulation of sensory inputs to dorsal horn induces LTD in the presence of NMDA antagonists (49).…”

Section: Discussionsupporting

confidence: 94%

“…Low-frequency stimulation of nociceptors induces LTD, which depends on NMDA and metabotropic glutamate receptor activity (47,48). Robust stimulation of dorsal roots can induce either LTP or LTD in dorsal horn, and LTP but not LTD induction is NMDA-receptor dependent under these conditions (49). LTP of dorsal horn field potentials has been demonstrated by noxious heat, mechanical, and chemosensitive stimuli but only in spinalized rats, suggesting that supraspinal inputs regulate its induction (50).…”

Section: Discussionmentioning

confidence: 99%

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Short- and long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors

Genzen

McGehee

2003

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

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Spinal administration of nicotinic agonists can produce both hyperalgesic and analgesic effects in vivo. The cellular mechanisms underlying these behavioral phenomena are not understood. As a possible explanation for nicotinic hyperalgesia, we tested whether nicotinic acetylcholine receptors (nAChRs) could enhance excitatory transmission onto spinal cord dorsal horn neurons. Whole-cell patch-clamp recordings were performed in neonatal rat spinal cord slices. Activation of nAChRs enhanced glutamatergic synaptic transmission in 59% of dorsal horn neurons tested, and this effect was blocked by methyllycaconitine (10 nM), suggesting a key role for ␣7 nAChRs. Inhibition of acetylcholinesterase with methamidophos also enhanced transmission, demonstrating a similar effect of endogenous acetylcholine. nAChR activation also enhanced transmission by dorsal root entry zone stimulation, suggesting that ␣7 nAChRs on the central terminals of DRG afferents mediate this effect. Paired pre-and postsynaptic stimulation induced long-term potentiation of excitatory inputs to some of the dorsal horn neurons. Long-term potentiation induction was much more prevalent when nicotine was applied during stimulation. This effect also depended on both ␣7 nAChRs and N-methyl-D-aspartate glutamate receptors. Our findings demonstrate that ␣7 nAChRs can contribute to both short-and long-term enhancement of glutamatergic synaptic transmission in the spinal cord dorsal horn and provide a possible mechanism for nicotinic hyperalgesia.E ffective pain management is a major challenge for modern healthcare. Most pain medications fall under two classes of compounds, opioids and nonsteroidal antiinflammatory drugs. Recently, structural analogs of nicotine have also demonstrated strong analgesic potency (1, 2). Although these agents may provide alternate pain therapies, a number of issues remain to be resolved, such as addictive profiles and side effects, including paradoxical hyperalgesia. Considerable research has focused on the analgesic effects of nicotine and its analogs (2-7), yet the mechanisms underlying nicotinic hyperalgesia are not well understood.Hyperalgesia and͞or irritation have been observed after central injections of nicotinic agonists (8-10), systemic injections of subanalgesic doses (11), and intrathecal applications (12,13). This intrathecal effect is associated with significant increases in excitatory transmitter release (14), and both nicotinic and glutamate receptor antagonists can decrease this hyperalgesia (15, 16). Although dorsal horn neurons are excited by nicotine (17), it is not known which subtypes of nicotinic acetylcholine receptors (nAChRs) are expressed by dorsal horn neurons or on presynaptic afferent terminals. For example, nicotinic enhancement of synaptic activity has been noted in the spinal cord dorsal horn (SCDH) in mice that lack the ␣4 nAChR subunit, but the nAChR subtype(s) that mediate this effect is unknown (5).Neuronal nAChRs are pentameric ligand-gated ion channels, and molecular cloning has identified nin...

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Short- and long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors

Genzen

McGehee

2003

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

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“…LTP at glutamatergic C-fiber synapses onto lamina I projection neurons has been extensively studied as a cellular mechanism accompanying hyperalgesia (18,(46)(47)(48), but relatively little is known about plasticity at dorsal horn inhibitory synapses (49). To our knowledge, the LTP we describe here is the first example of LTP at glycinergic synapses in the mammalian CNS.…”

Section: Discussionmentioning

confidence: 82%

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Chirila

Brown

Bishop

et al. 2014

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

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Long-term potentiation (LTP) is a persistent increase in synaptic strength required for many behavioral adaptations, including learning and memory, visual and somatosensory system functional development, and drug addiction. Recent work has suggested a role for LTP-like phenomena in the processing of nociceptive information in the dorsal horn and in the generation of central sensitization during chronic pain states. Whereas LTP of glutamatergic and GABAergic synapses has been characterized throughout the central nervous system, to our knowledge there have been no reports of LTP at mammalian glycinergic synapses. Glycine receptors (GlyRs) are structurally related to GABA A receptors and have a similar inhibitory role. Here we report that in the superficial dorsal horn of the spinal cord, glycinergic synapses on inhibitory GABAergic neurons exhibit LTP, occurring rapidly after exposure to the inflammatory cytokine interleukin-1 beta. This form of LTP (GlyR LTP) results from an increase in the number and/or change in biophysical properties of postsynaptic glycine receptors. Notably, formalin-induced peripheral inflammation in vivo potentiates glycinergic synapses on dorsal horn neurons, suggesting that GlyR LTP is triggered during inflammatory peripheral injury. Our results define a previously unidentified mechanism that could disinhibit neurons transmitting nociceptive information and may represent a useful therapeutic target for the treatment of pain.G lycine mediates fast synaptic inhibition throughout the spinal cord, brainstem, and midbrain, controlling normal motor behavior and rhythm generation, somatosensory processing, auditory and retinal signaling, and coordination of reflex responses (1). Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels of the Cys-loop receptor family that together with GABA A receptors (GABA A Rs) dynamically interact with the synaptic scaffold protein gephyrin to form inhibitory synapses (1, 2). In the dorsal horn of the spinal cord, glycinergic synapses are essential for nociceptive and tactile sensory processing both during adaptive and pathological pain states (3-7). However, compared with glutamatergic and GABAergic synapses, little is known about the regulation of their synaptic strength. Several studies have examined glycine receptor trafficking in cultured neurons and in heterologous expression systems (8, 9). Intracellular Ca 2+ appears important in the stabilization of GlyRs at synapses in culture (10), and elevation of intracellular Ca 2+ can also potently increase glycine receptor single channel openings in cultured cells and in heterologous systems (11). However, the modulation of glycinergic synaptic strength in native tissue remains relatively unexplored.Following peripheral injury or inflammation, changes in tactile perception develop, including hyperalgesia (exaggerated pain upon noxious stimulation), allodynia (pain in response to innocuous stimuli), and secondary hyperalgesia (pain spreading beyond the confines of the injure...

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“…Efforts were made to minimize the number of animals used and their suffering. Slices were prepared as previously described (Randic et al, 1993;Marvizon et al, 1997;1999a, b;Sandkuhler et al, 1997). Briefly, SpragueDawley rats 3 -4-weeks old (Harlan, Indianapolis, IND) were anesthetized with isoflurane.…”

Section: Preparation Of Spinal Cord Slicesmentioning

confidence: 99%

“…An additional goal of this study was to compare the potencies of SP, NKA and NKB to produce NK1R internalization. We used spinal cord slices, a high-quality preparation developed for electrophysiology (Yoshimura & Jessell, 1990), that contains functional synapses between dorsal horn neurons and primary afferent terminals (Randic et al, 1993;Yoshimura & Nishi, 1996;Marvizon et al, 1997;Sandkuhler et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

Marvizón¹,

Wang

Lao³

et al. 2003

British J Pharmacology

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1 The ability of peptidases to restrict neurokinin 1 receptor (NK1R) activation by exogenously applied or endogenously released neurokinins was investigated by measuring NK1R internalization in rat spinal cord slices. 2 Concentration -response curves for substance P and neurokinin A were obtained in the presence and absence of 10 mM thiorphan, an inhibitor of neutral endopeptidase (EC 3.4.24.11), plus 10 mM captopril, an inhibitor of dipeptidyl carboxypeptidase (EC 3.4.15.1). These inhibitors significantly decreased the EC 50 of substance P to produce NK1R internalization from 32 to 9 nM, and the EC 50 of neurokinin A from 170 to 60 nM. 3 Substance P was significantly more potent than neurokinin A, both with and without these peptidase inhibitors. 4 In the presence of peptidase inhibitors, neurokinin B was 10 times less potent than neurokinin A and 64 times less potent than substance P (EC 50 ¼ 573 nM). 5 Several aminopeptidase inhibitors (actinonin, amastatin, bacitracin, bestatin and puromycin) failed to further increase the effect of thiorphan plus captopril on the NK1R internalization produced by 10 nM substance P. 6 Electrical stimulation of the dorsal root produced NK1R internalization by releasing endogenous neurokinins. Thiorphan plus captopril increased NK1R internalization produced by 1 Hz stimulation, but not by 30 Hz stimulation. 7 Therefore, NEN and DCP restrict NK1R activation by endogenous neurokinins when they are gradually released by low-frequency firing of primary afferents, but become saturated or inhibited when primary afferents fire at a high frequency.

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Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord

Cited by 469 publications

References 73 publications

Short- and long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors

Short- and long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

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