Upregulation of Spinal Glutamate Receptors in Chronic Pain

Harris, Jonathan; Corsi, M.; Quartaroli, M.; Arban, Roberto; Bentivoglio, Marina

doi:10.1016/0306-4522(96)00196-0

Cited by 107 publications

(72 citation statements)

References 24 publications

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“…AMPA receptors have been shown to play a significant role in the mechanisms of neuropathic pain and spinal nociceptive processing (Mao et al, 1992a,b;Leem et al, 1996;Kondo et al, 2002;Garry et al, 2003). The AMPA receptor consists of several subunits and previous studies have indicated that spinal AMPA receptor expression was altered after either peripheral nerve injury or inflammation, which contributed to the development of pathological pain conditions in rats (Harris et al, 1996;Alvarez et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats

Lim

Sung

et al. 2006

Brain Research

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Spinal γ-aminobutyric acid (GABA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been implicated in the mechanisms of neuropathic pain after nerve injury; however, how these two receptors interact at the spinal level remains unclear. Here we show that intrathecal midazolam through activation of spinal GABAA receptors attenuated the expression and function of spinal AMPA receptors in rats following peripheral nerve injury. Thermal hyperalgesia and mechanical allodynia induced by chronic constriction nerve injury (CCI) in rats were attenuated by the short-acting benzodiazepine midazolam (20=10>5 μg > vehicle) administered intrathecally once daily for seven postoperative days. CCI-induced upregulation of AMPA receptors within the spinal cord dorsal horn was also significantly reduced by the intrathecal midazolam (10, 20 μg) treatment. The inhibitory effects of midazolam (10, 20 μg) on neuropathic pain behaviors and AMPA receptor expression were prevented by co-administration of midazolam with the GABAA receptor antagonist bicuculline (3 μg), whereas intrathecal treatment with bicuculline (1 or 3 μg) alone in naive rats induced the upregulation of spinal AMPA receptor expression and nociceptive responses, indicating a tonic regulatory effect from endogenous GABAergic activity on the AMPA receptor expression and spinal nociceptive processing. These results indicate that modulation of spinal AMPA receptor expression and function by the GABAergic activity may serve as a mechanism contributory to the spinal nociceptive processing.

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Section: Introductionmentioning

confidence: 99%

Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats

Lim

Sung

et al. 2006

Brain Research

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“…Previous immunohistochemical and in situ hybridization studies have suggested that GluR1 and GluR2 subunits are present throughout the dorsal horn, with highest levels in laminas I and II, that GluR2 is also present in the ventral horn, and that GluR3 and GluR4 are highly expressed in ventral horn, with moderate levels in deep dorsal horn and limited expression in the superficial laminas (Furuyama et al, 1993;Tölle et al, 1993;Tachibana et al, 1994;Jakowec et al, 1995a,b;Harris et al, 1996;Popratiloff et al, 1996Popratiloff et al, , 1998Morrison et al, 1998;Spike et al, 1998; Engelman et al, 1999; Shibata et al, 1999). Our findings after pepsin treatment are consistent with these reports (Fig.…”

Section: Laminar Distribution Of Ampa Subunitsmentioning

confidence: 99%

Widespread Expression of the AMPA Receptor GluR2 Subunit at Glutamatergic Synapses in the Rat Spinal Cord and Phosphorylation of GluR1 in Response to Noxious Stimulation Revealed with an Antigen-Unmasking Method

Nagy¹,

Al-Ayyan²,

Andrew³

et al. 2004

J. Neurosci.

112

154

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Glutamate, the principal excitatory neurotransmitter in the spinal cord, acts primarily through AMPA receptors. Although all four AMPA subunits are expressed by spinal neurons, we know little about their distribution at glutamatergic synapses. We used an antigenunmasking technique to reveal the synaptic distribution of glutamate receptor (GluR) 1-4 subunits with confocal microscopy. After pepsin treatment, punctate staining was seen with antibodies against each subunit: GluR2-immunoreactive puncta were distributed throughout the gray matter, whereas GluR1-immunoreactive puncta were restricted to the dorsal horn and were most numerous in laminas I-II. Punctate staining for GluR3 and GluR4 was found in all laminas but was weak in superficial dorsal horn. Colocalization studies showed that GluR2 was present at virtually all (98%) puncta that were GluR1, GluR3, or GluR4 immunoreactive and that most (Ͼ90%) immunoreactive puncta in laminas IV, V, and IX showed GluR2, GluR3, and GluR4 immunoreactivity.Evidence that these puncta represented synaptic receptors was obtained with electron microscopy and by examining the association of GluR2-and GluR1-immunoreactive puncta with glutamatergic boutons (identified with vesicular glutamate transporters or markers for unmyelinated afferents). The great majority (96%) of these boutons were associated with GluR2-immunoreactive puncta. Our findings suggest that GluR2 is almost universally present at AMPA-containing synapses, whereas GluR1 is preferentially associated with primary afferent terminals.We also found a substantial, rapid increase in staining for synaptic GluR1 subunits phosphorylated on the S845 residue in the ipsilateral dorsal horn after peripheral noxious stimulation. This finding demonstrates plastic changes, presumably contributing to central sensitization, at the synaptic level.

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“…during ventral L5 transection) (He et al, 2010;Li et al, 2002); the dorsal root ganglia sensory neurons still undergo functional changes that have been found to correlate with the development of neuropathic pain (He et al, 2010;Wu et al, 2002;Xu et al, 2006). Some of the peripheral nerve injury-induced functional changes in the dorsal root ganglia sensory neurons are believed to be important for the initiation and sustained alteration of the activity of the spinal cord neurons and in turn of the brain neurons (central sensitization) that underly chronic neuropathic pain (Harris et al, 1996;Jang et al, 2007;Lee et al, 2003;Liu and Salter, 2010;Obata et al, 2003;Ringkamp and Meyer, 2005). Second, although the dorsal root ganglia is surrounded by a thick connective tissue capsule, the dorsal root ganglia is not protected by a "blood-nerve barrier", as it is the rest of the peripheral nervous system (Abram et al, 2006;Hirakawa et al, 2004).…”

Section: Dorsal Root Ganglia As a Pharmacological Target To Avoid Thementioning

confidence: 99%

An Approach to Identify Nerve Injury-Evoked Changes that Contribute to the Development or Protect Against the Development of Sustained Neuropathic Pain

Recio-Pinto¹,

Norcini²,

Blanck³

2012

Basic Principles of Peripheral Nerve Disorders

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Upregulation of Spinal Glutamate Receptors in Chronic Pain

Cited by 107 publications

References 24 publications

Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats

Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats

Widespread Expression of the AMPA Receptor GluR2 Subunit at Glutamatergic Synapses in the Rat Spinal Cord and Phosphorylation of GluR1 in Response to Noxious Stimulation Revealed with an Antigen-Unmasking Method

An Approach to Identify Nerve Injury-Evoked Changes that Contribute to the Development or Protect Against the Development of Sustained Neuropathic Pain

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