Central Glucocorticoid Receptors Modulate the Expression and Function of Spinal NMDA Receptors after Peripheral Nerve Injury

Abstract

Central glucocorticoid receptors (GRs) and NMDA receptors (NMDARs) have been shown to play a significant role in the mechanisms of neuropathic pain after peripheral nerve injury; however, how central GRs and NMDARs interact in this process remains unknown. Here we show that the expression and function of spinal NMDARs after peripheral nerve injury were modulated by central GRs. Chronic constriction nerve injury (CCI) in rats induced a time-dependent upregulation of NR1 and NR2 subunits of the NMDAR within the spinal cord dorsal horn ipsilateral to CCI. The upregulation of NMDARs was significantly diminished by intrathecal administration (twice daily for postoperative days 1-6) of either the GR antagonist RU38486 or an antisense oligonucleotide against GRs. Moreover, this CCI-induced expression of NMDARs was significantly attenuated in rats receiving intrathecal treatment with an interleukin-6 (IL-6) antiserum and in mice with protein kinase C␥ (PKC␥) knock-out. Because IL-6 and PKC␥ mediated the upregulation of central GRs after CCI as demonstrated previously, the results suggest that IL-6 and PKC␥ served as cellular mediators contributing to the GR-mediated expression of NMDARs after CCI. Functionally, nociceptive behaviors induced by NMDAR activation and CCI were reversed by a single intrathecal administration of the GR antagonist RU38486. Conversely, a single intrathecal injection with the noncompetitive NMDAR antagonist MK-801 reversed neuropathic pain behaviors exacerbated by the GR agonist dexamethasone in CCI rats. These data suggest that interactions between central GRs and NMDARs through genomic and nongenomic regulation may be an important mechanism critical to neuropathic pain behaviors in rats.

Hypoxia-Inducible Factor-1α Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

“…NR1 expression is regulated by physiological conditions in the CNS, including those associated with neuronal plasticity, learning, and memory (Alvarez et al, 2007;Simões et al, 2007). However, inappropriate NMDAR activation is involved in the etiology of several human diseases, including acute insults such as hypoxia (Machaalani and Waters, 2002), ischemia (Cui et al, 2007), trauma (Wang et al, 2005), epilepsy (Toro et al, 2007), and in the pathology of various chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (Choi, 1988;Lipton and Gendelman, 1995;Kaul et al, 2001;Mattson, 2004). The development of neuronal injuries mediated by HIV-1 infection or LPS infusion can be arrested by treatment with the NMDAR antagonist MK801 [(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate] or memantine (Zheng et al, 2001;Glezer et al, 2003;Kowal et al, 2004).…”

Expression of Spinal NMDA Receptor and PKCγ after Chronic Morphine Is Regulated by Spinal Glucocorticoid Receptor

“…GR is expressed in spinal cord dorsal horn neurons, which contributes to spinal nociceptive processing (DeNicola et al, 1989;Cintra et al, 1993;Wang et al, 2004Wang et al, , 2005. Activation of central GR also has been shown to regulate neuronal plastic changes after neuronal injury (Cameron and Dutia, 1999) as well as the process of learning and memory (Quirarte et al, 1997;Oitzl et al, 1998;Roosendaal et al, 1999Roosendaal et al, , 2003.…”

Comparison of Botox<sup>®</sup> or Prosigne<sup>®</sup> and Facial Nerve Blockade as Adjuvant in Chronic Migraine

“…In the current study, dexamethasone was used as an adjuvant abortive agent for the control of headache attacks, as clinically observed on the basis of the reduced frequency and intensity of headache attacks in Control patients. Steroids have been shown to interact with glucocorticoid receptors located peripherally and in the spinal cord, modulating the action of spinal N-methyl-D-aspartate receptors [25], contributing to the effect of BTX-A on the central nervous system [20]. Although the α-2 agonist clonidine is not apparently effective for the prophylaxis of migraine [26], this drug has a local anesthetic action that potentiates lidocaine [27].…”