NMDA receptor 2B subunit-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-injured neuropathic mice

Iwata, Hidehisa; Takasusuki, Toshifumi; Yamaguchi, Shigeki; Hori, Yasushi

doi:10.1016/j.brainres.2006.12.014

Cited by 58 publications

(39 citation statements)

References 40 publications

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“…Since the vast majority of spinal cord superficial laminae neurons that contained NMDA receptors also expressed the non-NMDA receptor subtype GluR2 (Nagy et al, 2004b; Antal et al, 2008), high E2 conditions leading to increased NMDA receptor expression in dorsal horn (Tang et al, 2008) would be expected to increase the NMDA:non-NMDA current ratio and thus favoring increased neuronal excitability. An altered ratio of NMDA to non-NMDA current in spinal dorsal horn has been proposed as a mechanism for hyperalgesia and allodynia following nerve injury (Iwata et al, 2007). …”

Section: Discussionmentioning

confidence: 99%

NMDA receptor blockade reduces temporomandibular joint-evoked activity of trigeminal subnucleus caudalis neurons in an estrogen-dependent manner

2009

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Estrogen status is a risk factor in painful temporomandibular disorders (TMJD). Previously we reported that estradiol (E2) enhanced nociceptive processing of TMJ input by neurons in superficial laminae at the spinomedullary (Vc/C1-2) region; however, the mechanisms for this enhancement are not known. The present study determined if ionotropic glutamate receptors contribute to TMJ nociceptive processing in an E2-dependent manner. Ovariectomized (OvX) female rats were treated with high E2 (HE2) or low dose E2 (LE2) for 2 days and neural activity was recorded in laminae I-II at the Vc/C1-2 region. TMJ-responsive units were activated by adenosine triphosphate (ATP) injections into the joint space. ATP-evoked unit responses in HE2 rats were reduced significantly by topical application of the N-methyl-D-aspartate receptor antagonist, D(−) -2-amino-5-phosphonopentanoic acid (AP5) in a dose-related manner, while units from LE2 were not affected. Application of the non-NMDA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), inhibited the ATP-evoked responses in both groups. Spontaneous activity of TMJ units was not influenced by AP5, whereas it was reduced by DNQX similarly in both groups. The high threshold convergent cutaneous receptive field area of TMJ units was not changed by AP5, whereas DNQX caused a significant reduction in both groups. These results suggest that NMDA-dependent mechanisms contribute to the enhanced ATP-evoked responses of TMJ units in superficial laminae at the Vc/C1-2 region under high E2 conditions, while non-NMDA-dependent mechanisms modify the encoding properties of TMJ units independent of E2 status.

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Section: Discussionmentioning

confidence: 99%

NMDA receptor blockade reduces temporomandibular joint-evoked activity of trigeminal subnucleus caudalis neurons in an estrogen-dependent manner

2009

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“…The activity of NMDA receptors can be modulated by several physiological/pathophysiological factors. For example, inflammation or nerve injury in somatic tissue increases NMDA receptor subunit phosphorylation, expression and pain-related behaviors (Zou et al, 2000;Guo et al 2004;Gao et al 2005;Iwata et al 2007). Recent studies in some brain areas suggest the activity of NMDA receptors can also be modulated by gonadal hormones.…”

Section: Discussionmentioning

confidence: 99%

Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat

Tang¹,

Ji²,

Traub

2008

Pain

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Pain symptoms in several chronic pain disorders in women, including irritable bowel syndrome, fluctuate with the menstrual cycle suggesting a gonadal hormone component. In female rats, estrogens modulate visceral sensitivity although the underlying mechanism(s) are unknown. In the present study the effects of 17-β estradiol on N-methyl-D-aspartate (NMDA) receptor signaling of colorectal nociceptive processing in the spinal cord were examined. Estrogen receptor alpha and the NR1 subunit of the NMDA receptor are co-expressed in dorsal horn neurons, supporting a direct action of estradiol on NMDA receptors. Intrathecal administration of the NMDA receptor antagonist D(−)-2-amino-5-phosphonopetanoic acid (APV) dose-dependently attenuated the visceromotor response with greater potency in ovariectomized (OVx) rats compared to OVx with estradiol replacement (E2) rats. Estradiol significantly increased protein expression of NR1 in the lumbosacral spinal cord compared to OVx rats. Colorectal distention significantly increased phosphorylation of NR1ser-897, a PKA phosphorylation site on the NR1 subunit in E2, but not OVx rats. Intrathecal administration of a PKA inhibitor significantly attenuated the visceromotor response, decreased NR1 phosphorylation and increased the potency of APV to attenuate the visceromotor response compared to vehicle-treated E2 rats. These data suggest that estradiol increases spinal processing of visceral nociception by increasing NMDA receptor NR1 subunit expression and increasing site specific receptor phosphorylation on the NR1 subunit contributing to an increase in NMDA receptor activity.

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“…Presynaptic functional changes after peripheral nerve injury that increase synaptic strength include alterations in the synthesis of transmitters and neuromodulators (Obata et al 2003) and in calcium channel density (Hendrich et al 2008, Li et al 2004). Postsynaptic changes involve phosphorylation of N-methyl-D-aspartate (NMDA) subunits (Ultenius et al 2006) and increased receptor density due to trafficking and enhanced synthesis of ion channels and scaffold proteins (Cheng et al 2008, Iwata et al 2007, Miyabe et al 2006, Takasusuki et al 2007, Tao et al 2003). Drugs that attenuate central sensitization by acting on calcium channel subunits to decrease transmitter release and on NMDA channels to reduce transmitter action (Chizh et al 2007; Jorum et al 2003) are effective treatment options in neuropathic pain (Dworkin et al 2007).…”

Section: Mechanisms Of Neuropathic Painmentioning

confidence: 99%

Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage

Costigan

Scholz

Woolf

2009

Annu. Rev. Neurosci.

1,627

1,533

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Neuropathic pain is triggered by lesions to the somatosensory nervous system that alter its structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified. The pain is an expression of maladaptive plasticity within the nociceptive system, a series of changes that constitute a neural disease state. Multiple alterations distributed widely across the nervous system contribute to complex pain phenotypes. These alterations include ectopic generation of action potentials, facilitation and disinhibition of synaptic transmission, loss of synaptic connectivity and formation of new synaptic circuits, and neuroimmune interactions. Although neural lesions are necessary, they are not sufficient to generate neuropathic pain; genetic polymorphisms, gender, and age all influence the risk of developing persistent pain. Treatment needs to move from merely suppressing symptoms to a disease-modifying strategy aimed at both preventing maladaptive plasticity and reducing intrinsic risk.

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NMDA receptor 2B subunit-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-injured neuropathic mice

Cited by 58 publications

References 40 publications

NMDA receptor blockade reduces temporomandibular joint-evoked activity of trigeminal subnucleus caudalis neurons in an estrogen-dependent manner

NMDA receptor blockade reduces temporomandibular joint-evoked activity of trigeminal subnucleus caudalis neurons in an estrogen-dependent manner

Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat

Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage

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