Induction of homosynaptic long-term depression at spinal synapses of sensory Aδ-fibers requires activation of metabotropic glutamate receptors

Chen, J.; Sandkühler, Jürgen

doi:10.1016/s0306-4522(00)00080-4

Cited by 65 publications

(31 citation statements)

References 56 publications

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“…This LTDlike reduction of human pain perception was similar to LTD at the synapses between nociceptive afferents and superficial dorsal horn neurons in rats, both in magnitude and in its restriction to the conditioned pathway (Chen and Sandkühler, 2000). Pain perception during conditioning LFS exhibited a biphasic time course.…”

Section: Perceptual Correlate Of Homosynaptic Ltdsupporting

confidence: 51%

Perceptual Correlates of Nociceptive Long-Term Potentiation and Long-Term Depression in Humans

Klein¹,

Magerl²,

Hopf³

et al. 2004

J. Neurosci.

333

383

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Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are ubiquitous mechanisms of synaptic plasticity, but their functional relevance in humans remains obscure. Here we report that a long-term increase in perceived pain to electrical test stimuli was induced by high-frequency electrical stimulation (HFS) (5 ϫ 1 sec at 100 Hz) of peptidergic cutaneous afferents (27% above baseline, undiminished for Ͼ3 hr). In contrast, a long-term decrease in perceived pain (27% below baseline, undiminished for 1 hr) was induced by low-frequency stimulation (LFS) (17 min at 1 Hz). Pain testing with punctate mechanical probes (200 m diameter) in skin adjacent to the HFS-LFS conditioning skin site revealed a marked twofold to threefold increase in pain sensitivity (secondary hyperalgesia, undiminished for Ͼ3 hr) after HFS but also a moderate secondary hyperalgesia (30% above baseline) after strong LFS. Additionally, HFS but not LFS caused pain to light tactile stimuli in adjacent skin (allodynia). In summary, HFS and LFS stimulus protocols that induce LTP or LTD in spinal nociceptive pathways in animal experiments led to similar LTP-and LTD-like changes in human pain perception (long-term hyperalgesia or hypoalgesia) mediated by the conditioned pathway. Additionally, secondary hyperalgesia and allodynia in adjacent skin induced by the HFS protocol and, to a minor extent, also by the LFS protocol, suggested that these perceptual changes encompassed an LTP-like heterosynaptic facilitation of adjacent nociceptive pathways by a hitherto unknown mechanism.

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Section: Perceptual Correlate Of Homosynaptic Ltdsupporting

confidence: 51%

Perceptual Correlates of Nociceptive Long-Term Potentiation and Long-Term Depression in Humans

Klein¹,

Magerl²,

Hopf³

et al. 2004

J. Neurosci.

333

383

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“…Numerous other reports have demonstrated LTD and LTP expression in dorsal horn. 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).…”

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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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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“…Dorsal root stimulation under the given experimental conditions was assessed quantitatively. A ␦ -and C-fiber-evoked EPSCs were distinguished with two measurements: the conduction velocity of afferent fibers and stimulus threshold [23,24,29,30] . The conduction velocity was calculated from the length of dorsal root and the latency between EPSC and the preceding stimulus artifact, with central delay considered to be 1 ms.…”

Section: Patch-clamp Recording and Dorsal Root Stimulationmentioning

confidence: 99%

“…The present study was based mainly on A ␦ -fiber-evoked monosynaptic responses. Synaptic responses evoked by stimulating A ␦ -fibers were considered as monosynaptic ones, if their poststimulus latency remained constant and no failures were observed during high-rate (10 or 20 Hz) repetitive stimulation [23,24,29,30] . Regular stimulus trains containing 10 pulses of different rates and random stimulus trains with Poissondistributed pulses were delivered to dorsal roots.…”

Section: Patch-clamp Recording and Dorsal Root Stimulationmentioning

confidence: 99%

Short-Term Plasticity at Primary Afferent Synapse in Rat Spinal Dorsal Horn and Its Biological Function

Wan

Zhong²,

Wang³

et al. 2006

Neurosignals

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Short-term plasticity (STP) is an important element of information processing in neuronal networks. As the first synaptic relay between primary afferent fibers (PAFs) and central neurons, primary afferent synapses in spinal dorsal horn (DH) are essential to the initial processing of somatosensory information. In this research, we examined the STP between Aδ-PAFs and spinal DH neurons by patch-clamp recording. Our results showed that depression dominated the STP at primary afferent synapses. The curves of STP had no significant changes in the presence of bicuculline, CTZ or AP-5. Lowering extracellular Ca²⁺ concentration ([Ca²⁺]_o) from 2.4 to 0.8 mM reduced the depression of synaptic responses at all stimulus rates, while raising [Ca²⁺]_o from 2.4 to 4.0 mM increased the synaptic depression. Increasing the bath temperature from 24 to 32°C clearly reduced the depression of all responses. These results indicate that the observed STP is of presynaptic origin and depends on transmitter release. By fitting the experimental data recorded under different conditions, a model of STP was used to quantitatively characterize the observed STP and to analyze the possible mechanisms underlying the effects of [Ca²⁺]_o and temperature. Furthermore, using a model neuron receiving synaptic inputs, we found that with this form of STP, postsynaptic DH neurons could detect rate changes in both rapidly- and slowly-firing afferents with equal sensitivity. The present study links the intrinsic STP properties of primary afferent synapses with their role in processing neural information, and provides a basis for further research on the STP in spinal DH and its biological function under in vivo conditions.

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Induction of homosynaptic long-term depression at spinal synapses of sensory Aδ-fibers requires activation of metabotropic glutamate receptors

Cited by 65 publications

References 56 publications

Perceptual Correlates of Nociceptive Long-Term Potentiation and Long-Term Depression in Humans

Perceptual Correlates of Nociceptive Long-Term Potentiation and Long-Term Depression in Humans

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

Short-Term Plasticity at Primary Afferent Synapse in Rat Spinal Dorsal Horn and Its Biological Function

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