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Neuronal mechanism for neuropathic pain.

Zhuo M - Mol Pain (2007)

Bottom Line: Despite recent rapid development of neuroscience and modern techniques related to drug discovery, effective drugs based on clear basic mechanisms are still lacking.I will present the problem of neuropathic pain as a rather difficult task for neuroscientists, and we may have to wait for a long time before we fully understand how brain encode, store, and retrieve painful information after the injury.I propose that neuropathic pain as a major brain disease, rather being a clinic problem due to peripheral injury.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Faculty of Medicine, University of Toronto Centre for the study of Pain, University of Toronto, Toronto, Ontario, Canada. min.zhuo@utoronto.ca

ABSTRACT
Among different forms of persistent pain, neuropathic pain presents as a most difficult task for basic researchers and clinicians. Despite recent rapid development of neuroscience and modern techniques related to drug discovery, effective drugs based on clear basic mechanisms are still lacking. Here, I will review the basic neuronal mechanisms that maybe involved in neuropathic pain. I will present the problem of neuropathic pain as a rather difficult task for neuroscientists, and we may have to wait for a long time before we fully understand how brain encode, store, and retrieve painful information after the injury. I propose that neuropathic pain as a major brain disease, rather being a clinic problem due to peripheral injury.

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Related in: MedlinePlus

Excitatory sensory synapses contribute to pain transmission in the spinal dorsal horn and ACC. A. Synaptic currents recorded at resting membrane potentials are mostly mediated by AMPA receptors (a), some synaptic currents at dorsal horn neurons receiving high-threshold inputs are mediated by KA receptors (b). In young and adult dorsal horn neurons, some sensory synapses are 'silent' and containing only functional NMDA receptors (c). These pure NMDA synapses can be revealed when cells are hold at positive 40 mV potentials. In adult dorsal horn neurons, some pure NMDA receptor synapses can even be detected at the resting membrane potentials. When a train of stimulation is applied, neuropeptide mediated responses are recruited. Both postsynaptic NK1 and NK2 receptors contribute to substance P(SP)- and neurokinin A- (NKA) mediated excitatory postsynaptic currents. In ACC neurons, KA receptor mediated responses are detected with stimulation at greater intensities. KA receptors do not contribute to mEPSCs, indicating that KA receptors are not co-expressed with AMPA receptors in all synapses. B. Models for glutamate-containing and glutamate- and neuropeptide-mixed sensory synapses in the spinal cord dorsal horn and possible ACC neurons. At least four different synapses are found: (a) synapses receiving low-threshold sensory inputs contain only postsynaptic NMDA receptors; (b) synapses receiving low-threshold sensory inputs contain both AMPA and NMDA receptors; (c) synapses receiving both low- and high-threshold sensory inputs contain postsynaptic AMPA, KA and NMDA receptors; (d) synapses receiving low- and high-threshold sensory inputs contain AMPA, KA and NMDA receptors as well as peptidergic NK1 and NK2 receptors.
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Figure 1: Excitatory sensory synapses contribute to pain transmission in the spinal dorsal horn and ACC. A. Synaptic currents recorded at resting membrane potentials are mostly mediated by AMPA receptors (a), some synaptic currents at dorsal horn neurons receiving high-threshold inputs are mediated by KA receptors (b). In young and adult dorsal horn neurons, some sensory synapses are 'silent' and containing only functional NMDA receptors (c). These pure NMDA synapses can be revealed when cells are hold at positive 40 mV potentials. In adult dorsal horn neurons, some pure NMDA receptor synapses can even be detected at the resting membrane potentials. When a train of stimulation is applied, neuropeptide mediated responses are recruited. Both postsynaptic NK1 and NK2 receptors contribute to substance P(SP)- and neurokinin A- (NKA) mediated excitatory postsynaptic currents. In ACC neurons, KA receptor mediated responses are detected with stimulation at greater intensities. KA receptors do not contribute to mEPSCs, indicating that KA receptors are not co-expressed with AMPA receptors in all synapses. B. Models for glutamate-containing and glutamate- and neuropeptide-mixed sensory synapses in the spinal cord dorsal horn and possible ACC neurons. At least four different synapses are found: (a) synapses receiving low-threshold sensory inputs contain only postsynaptic NMDA receptors; (b) synapses receiving low-threshold sensory inputs contain both AMPA and NMDA receptors; (c) synapses receiving both low- and high-threshold sensory inputs contain postsynaptic AMPA, KA and NMDA receptors; (d) synapses receiving low- and high-threshold sensory inputs contain AMPA, KA and NMDA receptors as well as peptidergic NK1 and NK2 receptors.

Mentions: Primary afferent fibers form synapses with dorsal horn sensory neurons in the spinal cord. Some of these dorsal horn neurons send ascending projecting fibers and make synapses with neurons located at supraspinal sites, such as the thalamic nuclei. These ascending pathways are important for conveying sensory information from the periphery to the brain. Glutamate is a major neurotransmitter between primary afferent fibers and dorsal horn neurons [4,5] and postsynaptic responses are mainly mediated by glutamate α-amino-3-hydroxy-5-methyl-4-isoxalepropionate (AMPA) and kainate (KA) receptors [4-7] (see fig 1). Glutamatergic synapses are heterogeneous in the spinal dorsal horn [4,6,8,9], and at least three different types of glutamatergic synapses have been reported [4,8,10]. In some synapses receiving low threshold sensory inputs, only postsynaptic NMDA receptors are found. In synapses receiving low- or moderate intensity of sensory inputs, only AMPA receptors are detected, while in synapses that receiving high threshold inputs, both glutamatergic AMPA and KA receptor are reported.


Neuronal mechanism for neuropathic pain.

Zhuo M - Mol Pain (2007)

Excitatory sensory synapses contribute to pain transmission in the spinal dorsal horn and ACC. A. Synaptic currents recorded at resting membrane potentials are mostly mediated by AMPA receptors (a), some synaptic currents at dorsal horn neurons receiving high-threshold inputs are mediated by KA receptors (b). In young and adult dorsal horn neurons, some sensory synapses are 'silent' and containing only functional NMDA receptors (c). These pure NMDA synapses can be revealed when cells are hold at positive 40 mV potentials. In adult dorsal horn neurons, some pure NMDA receptor synapses can even be detected at the resting membrane potentials. When a train of stimulation is applied, neuropeptide mediated responses are recruited. Both postsynaptic NK1 and NK2 receptors contribute to substance P(SP)- and neurokinin A- (NKA) mediated excitatory postsynaptic currents. In ACC neurons, KA receptor mediated responses are detected with stimulation at greater intensities. KA receptors do not contribute to mEPSCs, indicating that KA receptors are not co-expressed with AMPA receptors in all synapses. B. Models for glutamate-containing and glutamate- and neuropeptide-mixed sensory synapses in the spinal cord dorsal horn and possible ACC neurons. At least four different synapses are found: (a) synapses receiving low-threshold sensory inputs contain only postsynaptic NMDA receptors; (b) synapses receiving low-threshold sensory inputs contain both AMPA and NMDA receptors; (c) synapses receiving both low- and high-threshold sensory inputs contain postsynaptic AMPA, KA and NMDA receptors; (d) synapses receiving low- and high-threshold sensory inputs contain AMPA, KA and NMDA receptors as well as peptidergic NK1 and NK2 receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1904186&req=5

Figure 1: Excitatory sensory synapses contribute to pain transmission in the spinal dorsal horn and ACC. A. Synaptic currents recorded at resting membrane potentials are mostly mediated by AMPA receptors (a), some synaptic currents at dorsal horn neurons receiving high-threshold inputs are mediated by KA receptors (b). In young and adult dorsal horn neurons, some sensory synapses are 'silent' and containing only functional NMDA receptors (c). These pure NMDA synapses can be revealed when cells are hold at positive 40 mV potentials. In adult dorsal horn neurons, some pure NMDA receptor synapses can even be detected at the resting membrane potentials. When a train of stimulation is applied, neuropeptide mediated responses are recruited. Both postsynaptic NK1 and NK2 receptors contribute to substance P(SP)- and neurokinin A- (NKA) mediated excitatory postsynaptic currents. In ACC neurons, KA receptor mediated responses are detected with stimulation at greater intensities. KA receptors do not contribute to mEPSCs, indicating that KA receptors are not co-expressed with AMPA receptors in all synapses. B. Models for glutamate-containing and glutamate- and neuropeptide-mixed sensory synapses in the spinal cord dorsal horn and possible ACC neurons. At least four different synapses are found: (a) synapses receiving low-threshold sensory inputs contain only postsynaptic NMDA receptors; (b) synapses receiving low-threshold sensory inputs contain both AMPA and NMDA receptors; (c) synapses receiving both low- and high-threshold sensory inputs contain postsynaptic AMPA, KA and NMDA receptors; (d) synapses receiving low- and high-threshold sensory inputs contain AMPA, KA and NMDA receptors as well as peptidergic NK1 and NK2 receptors.
Mentions: Primary afferent fibers form synapses with dorsal horn sensory neurons in the spinal cord. Some of these dorsal horn neurons send ascending projecting fibers and make synapses with neurons located at supraspinal sites, such as the thalamic nuclei. These ascending pathways are important for conveying sensory information from the periphery to the brain. Glutamate is a major neurotransmitter between primary afferent fibers and dorsal horn neurons [4,5] and postsynaptic responses are mainly mediated by glutamate α-amino-3-hydroxy-5-methyl-4-isoxalepropionate (AMPA) and kainate (KA) receptors [4-7] (see fig 1). Glutamatergic synapses are heterogeneous in the spinal dorsal horn [4,6,8,9], and at least three different types of glutamatergic synapses have been reported [4,8,10]. In some synapses receiving low threshold sensory inputs, only postsynaptic NMDA receptors are found. In synapses receiving low- or moderate intensity of sensory inputs, only AMPA receptors are detected, while in synapses that receiving high threshold inputs, both glutamatergic AMPA and KA receptor are reported.

Bottom Line: Despite recent rapid development of neuroscience and modern techniques related to drug discovery, effective drugs based on clear basic mechanisms are still lacking.I will present the problem of neuropathic pain as a rather difficult task for neuroscientists, and we may have to wait for a long time before we fully understand how brain encode, store, and retrieve painful information after the injury.I propose that neuropathic pain as a major brain disease, rather being a clinic problem due to peripheral injury.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Faculty of Medicine, University of Toronto Centre for the study of Pain, University of Toronto, Toronto, Ontario, Canada. min.zhuo@utoronto.ca

ABSTRACT
Among different forms of persistent pain, neuropathic pain presents as a most difficult task for basic researchers and clinicians. Despite recent rapid development of neuroscience and modern techniques related to drug discovery, effective drugs based on clear basic mechanisms are still lacking. Here, I will review the basic neuronal mechanisms that maybe involved in neuropathic pain. I will present the problem of neuropathic pain as a rather difficult task for neuroscientists, and we may have to wait for a long time before we fully understand how brain encode, store, and retrieve painful information after the injury. I propose that neuropathic pain as a major brain disease, rather being a clinic problem due to peripheral injury.

Show MeSH
Related in: MedlinePlus