Met-enkephalin (ME) turnover change in rat spinal dorsal horn by adjuvant treatment and its possible role of the modulation of pain threshold

Abstract Background The underlying mechanism of chronic pain involves the plasticity in synaptic receptors and neurotransmitters. This study aimed to investigate potential roles of neuroligins (NLs) within the spinal dorsal horn of rats in a newly established bone cancer pain (BCP) model. Methods Using our rat BCP model, we assessed pain hypersensitivity over time. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to investigate NL expression, and NLs were overexpressed in the rat spinal cord using lentiviral vectors. Immunofluorescence staining and whole-cell patch-clamp recordings were deployed to investigate the role of NLs in the development of BCP. Results We observed reduced expression levels of NL1 and NL2, but not NL3, within the rat spinal cord, which were found to be associated with and essential for the development of BCP in our model. Accordingly, NL1 or NL2 overexpression in the spinal cord alleviated mechanical hypersensitivity of rats. Electrophysiological experiments indicated that NL1 and NL2 are involved in BCP via regulating γ-aminobutyric acid-ergic interneuronal synapses and the activity of glutamatergic interneuronal synapses, respectively. Conclusions Our observations unravel the role of NLs in cancer-related chronic pain and further suggest that inhibitory mechanisms are central features of BCP in the spinal dorsal horn. These results provide a new perspective and basis for subsequent studies elucidating the onset and progression of BCP.

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Bidirectional Neuron–Glia Interactions Triggered by Deficiency of Glutamate Uptake at Spinal Sensory Synapses

Journal of Neurophysiology ◽

10.1152/jn.00282.2010 ◽

2010 ◽

Vol 104 (2) ◽

pp. 713-725 ◽

Cited By ~ 19

Author(s):

Hui Nie ◽

Haijun Zhang ◽

Han-Rong Weng

Keyword(s):

Dorsal Horn ◽

Glial Cells ◽

Synaptic Input ◽

Spinal Dorsal Horn ◽

Glutamate Uptake ◽

Glutamate Transporters ◽

Spinothalamic Tract ◽

Dorsal Horn Neurons ◽

Spinal Dorsal

Bidirectional interactions between neurons and glial cells are crucial to the genesis of pathological pain. The mechanisms regulating these interactions and the role of this process in relaying synaptic input in the spinal dorsal horn remain to be established. We studied the role of glutamate transporters in the regulation of such interactions. On pharmacological blockade of glutamate transporters, slow inward currents (SICs) appeared spontaneously and/or were evoked by peripheral synaptic input in the spinal superficial dorsal horn neurons, including the spinothalamic tract neurons. We showed that the SICs were induced by the release of glutamate from glial cells. On inhibition of glutamate uptake, the stimulation-induced, synaptically released glutamate activated glial cells and caused glial cells to release glutamate. Glial-derived glutamate acted on extrasynaptic N-methyl-d-aspartate (NMDA) receptors mainly composed of NR2B receptors and generated SICs, which led to depolarization and action potential generation in superficial spinal dorsal horn neurons. Thus glutamate transporters regulate glutamatergic neuron–glia interactions at spinal sensory synapses. When glutamate uptake is impaired, glial cells function like excitatory interneurons—they are activated by peripheral synaptic input and release glutamate to activate postsynaptic neurons in spinal pain pathways.

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