Blockade of spinal glutamate recycling produces paradoxical antinociception in rats with orofacial inflammatory pain

Yang, Kun; Mun, Jun H.; Park, Ki D.; Ju, Jae Kyun; Kim, Seong T.; Bae, Yong Chul; Ahn, Dong Kuk

doi:10.1016/j.pnpbp.2014.10.011

Cited by 19 publications

(11 citation statements)

References 64 publications

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“…Here a selective EAAT3 inhibitor produced antinociception in SNI rats, whereas EAAT1,2 inhibitors produced pronociception, with similar diverging effects on glutamate-induced pain, mechanical allodynia, CPP and glutamate-induced c- fos expression. Our c- fos studies, explain recent results showing that intracisternal TBOA significantly increased noxious heat-induced Fos immunoreactivity in the medullary dorsal horn of naive animals, while it significantly reduced this response in animals with earlier inflammation of the vibrissa pad 41 . Thus, TBOA's c- fos reducing effects in animals with persistent pain are likely due to EAAT3 blockade, while its c- fos enhancing effects in naive animals are likely due to inhibition of EAAT1/2.…”

Section: Discussionsupporting

confidence: 87%

Intracellular mGluR5 plays a critical role in neuropathic pain

et al. 2016

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Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ∼60% is located on nuclear membranes, where activation leads to sustained Ca2+ responses. Nerve injury inducing nociceptive hypersensitivity also increases the expression of nuclear mGluR5 and receptor-mediated phosphorylated-ERK1/2, Arc/Arg3.1 and c-fos. Spinal blockade of intracellular mGluR5 reduces neuropathic pain behaviours and signalling molecules, whereas blockade of cell-surface mGluR5 has little effect. Decreasing intracellular glutamate via blocking EAAT-3, mimics the effects of intracellular mGluR5 antagonism. These findings show a direct link between an intracellular GPCR and behavioural expression in vivo. Blockade of intracellular mGluR5 represents a new strategy for the development of effective therapies for persistent pain.

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Section: Discussionsupporting

confidence: 87%

Intracellular mGluR5 plays a critical role in neuropathic pain

et al. 2016

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“…On postoperative day 4, rats were re-anesthetized, mounted on a stereotaxic frame, and a PE 10 polyethylene tubing was inserted through a small hole in the atlanto-occipital membrane and dura using a 27-gauge needle, as described previously 47 , 48 . The tip of the cannula was placed dorsal to the obex.…”

Section: Methodsmentioning

confidence: 99%

A role for the purinergic receptor P2X3 in astrocytes in the mechanism of craniofacial neuropathic pain

Mah

Lee

et al. 2017

Sci Rep

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The purinergic receptor P2X3, expressed in the central terminals of primary nociceptive neurons in the brainstem, plays an important role in pathological pain. However, little is known about expression of P2X3 in the brainstem astrocytes and its involvement in craniofacial pathologic pain. To address this issue, we investigated the expression of P2X3 in astrocytes in the trigeminal caudal nucleus (Vc) in a rat model of craniofacial neuropathic pain, chronic constriction injury of infraorbital nerve (CCI-ION). We found that 1) P2X3-immunoreactivity is observed in the brainstem astrocytes, preferentially in their fine processes, 2) the number of P2X3-positive fine astrocytic processes and the density of P2X3 in these processes were increased significantly in CCI-ION rats, compared to control rats, and 3) administration of MPEP, a specific mGluR5 antagonist, alleviated the mechanical allodynia and abolished the increase in density of P2X3 in fine astrocytic processes caused by CCI-ION. These findings reveal preferential expression of P2X3 in the fine astrocytic processes in the brainstem, propose a novel role of P2X3 in the fine astrocytic process in the mechanism of craniofacial neuropathic pain, and suggest that the expression of astrocytic P2X3 may be regulated by astrocytic mGluR5.

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“…For injection site consistency, a tube was implanted in the same vibrissa pad (3 rd row, 5 th column). The anesthetized rats were mounted individually on a stereotaxic frame (model 1404, David Kopf Instruments, Tujunga, CA) and the PE10 tube was implanted for the intracisternal injection as described previously [10111213]. The PE10 tube was inserted through a tiny hole made in the atlanto-occipital membrane and dura using a 27-gauge syringe needle.…”

Section: Methodsmentioning

confidence: 99%

Participation of central GABA_Areceptors in the trigeminal processing of mechanical allodynia in rats

Kim

Park

Yang

et al. 2017

Korean J Physiol Pharmacol

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Here we investigated the central processing mechanisms of mechanical allodynia and found a direct excitatory link with low-threshold input to nociceptive neurons. Experiments were performed on male Sprague-Dawley rats weighing 230-280 g. Subcutaneous injection of interleukin 1 beta (IL-1β) (1 ng/10 µL) was used to produce mechanical allodynia and thermal hyperalgesia. Intracisternal administration of bicuculline, a gamma aminobutyric acid A (GABAA) receptor antagonist, produced mechanical allodynia in the orofacial area under normal conditions. However, intracisternal administration of bicuculline (50 ng) produced a paradoxical anti-allodynic effect under inflammatory pain conditions. Pretreatment with resiniferatoxin (RTX), which depletes capsaicin receptor protein in primary afferent fibers, did not alter the paradoxical anti-allodynic effects produced by the intracisternal injection of bicuculline. Intracisternal injection of bumetanide, an Na-K-Cl cotransporter (NKCC 1) inhibitor, reversed the IL-1β-induced mechanical allodynia. In the control group, application of GABA (100 µM) or muscimol (3 µM) led to membrane hyperpolarization in gramicidin perforated current clamp mode. However, in some neurons, application of GABA or muscimol led to membrane depolarization in the IL-1β-treated rats. These results suggest that some large myelinated Aβ fibers gain access to the nociceptive system and elicit pain sensation via GABAA receptors under inflammatory pain conditions.

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Blockade of spinal glutamate recycling produces paradoxical antinociception in rats with orofacial inflammatory pain

Cited by 19 publications

References 64 publications

Intracellular mGluR5 plays a critical role in neuropathic pain

Intracellular mGluR5 plays a critical role in neuropathic pain

A role for the purinergic receptor P2X3 in astrocytes in the mechanism of craniofacial neuropathic pain

Participation of central GABA_Areceptors in the trigeminal processing of mechanical allodynia in rats

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Blockade of spinal glutamate recycling produces paradoxical antinociception in rats with orofacial inflammatory pain

Cited by 19 publications

References 64 publications

Intracellular mGluR5 plays a critical role in neuropathic pain

Intracellular mGluR5 plays a critical role in neuropathic pain

A role for the purinergic receptor P2X3 in astrocytes in the mechanism of craniofacial neuropathic pain

Participation of central GABAAreceptors in the trigeminal processing of mechanical allodynia in rats

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Participation of central GABA_Areceptors in the trigeminal processing of mechanical allodynia in rats