Block by gabapentin of the facilitation of glutamate release from rat trigeminal nucleus following activation of protein kinase C or adenylyl cyclase

Maneuf, Yannick P.; McKnight, A.T.

doi:10.1038/sj.bjp.0704227

Cited by 88 publications

(57 citation statements)

References 23 publications

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“…Although the antinociceptive mechanisms of spinal gabapentin remain unclear, several hypotheses have been suggested. It has been reported that gabapentin decreases glutamate concentrations and inhibits the release of glutamate and glutamatergic synaptic transmission presynatically (15)(16)(17). Glutamate acts on the NMDA receptor and non-NMDA receptor and shows the excitatory effect (18,19).…”

Section: Discussionmentioning

confidence: 99%

Spinal Gabapentin and Antinociception: Mechanisms of Action

2003

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Spinal gabapentin has been known to show the antinociceptive effect. Although several assumptions have been suggested, mechanisms of action of gabapentin have not been clearly established. The present study was undertaken to examine the action mechanisms of gabapentin at the spinal level. Male SD rats were prepared for intrathecal catheterization. The effect of gabapentin was assessed in the formalin test. After pretreatment with many classes of drugs, changes of effect of gabapentin were examined. General behaviors were also observed. Intrathecal gabapentin produced a suppression of the phase 2 flinching, but not phase 1 in the formalin test. The antinociceptive action of intrathecal gabapentin was reversed by intrathecal NMDA, AMPA, D-serine, CGS 15943, atropine, and naloxone. No antagonism was seen following administration of bicuculline, saclofen, prazosin, yohimbine, mecamylamine, L-leucine, dihydroergocristine, or thapsigargin. Taken together, intrathecal gabapentin attenuated only the facilitated state. At the spinal level, NMDA receptor, AMPA receptor, nonstrychnine site of NMDA receptor, adenosine receptor, muscarinic receptor, and opioid receptor may be involved in the antinociception of gabapentin, but GABA receptor, L-amino acid transporter, adrenergic receptor, nicotinic receptor, serotonin receptor, or calcium may not be involved.

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Section: Discussionmentioning

confidence: 99%

Spinal Gabapentin and Antinociception: Mechanisms of Action

2003

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“…However, the question of whether this effect is due to a direct action of gabapentin on brainstem structures or is secondary to a spinal or a peripheral action of gabapentin remains unanswered. Although an antihyperalgesic action of gabapentin has only been demonstrated at the level of the dorsal horn or the subnucleus caudalis (its functional equivalent in the trigeminal system) (57)(58)(59), the hypothesis of a direct gabapentin effect on brainstem structures is reasonable, because spinobulbo-spinal circuits are contributing to experimental central sensitization. Accordingly, gabapentin has been demonstrated to have ubiquitous effects in the central nervous system (e.g., refs.…”

Section: Gabapentin Modulation Of Fmri Brain Responses: Antihyperalgesicmentioning

confidence: 99%

Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans

Iannetti

Zambreanu

Wise

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

250

203

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Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury (secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os, in a single administration. We found that (i) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; (ii) gabapentin reduced the activation in the brainstem, only during central sensitization; (iii) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.deactivation ͉ fMRI ͉ hyperalgesia ͉ nociceptive system A fter skin injury, an increased sensitivity to mechanical stimuli occurs in a large, uninjured area surrounding the injury site (1, 2). This phenomenon is termed secondary hyperalgesia and is the consequence of neuroplastic changes leading to a state of sensitization of the central nervous system (central sensitization) (3). Secondary hyperalgesia can be experimentally induced by treating the skin with high doses of the vanilloid capsaicin (by intradermal injection or topical application).Two forms of mechanical hyperalgesia occur in the area of secondary hyperalgesia: hyperalgesia to gentle skin stroking (stroking hyperalgesia or allodynia) and hyperalgesia to punctate stimuli (punctate hyperalgesia). Although both stroking and punctate hyperalgesia are due to central sensitization, they have different psychophysical characteristics (punctate hyperalgesia is easier to establish, it encompasses a larger area and it is longer-lasting than stroking hyperalgesia). They are mediated by different primary afferents (3): stroking hyperalgesia is signaled by low-threshold mechanoreceptors (4), whereas punctate hyperalgesia is signaled by capsaicin-insensitive A-fi...

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“…Also, it is likely that the rate of cycling of ␣ 2 ␦ subunits is variable in different cell types, at different locations within the cell, and depending on the physiological state of the cell. For instance, it has been reported that GBP acutely reduced glutamate release in trigeminal neurons only after activation by protein kinase C (Maneuf and McKnight, 2001). Interestingly, protein kinase C activation has been shown to lead to an increased insertion of calcium channels of the Ca v 2 family at the plasma membrane (Zhang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

The α₂δ Ligand Gabapentin Inhibits the Rab11-Dependent Recycling of the Calcium Channel Subunit α₂δ-2

Tran-Van-Minh¹,

Dolphin²

2010

J. Neurosci.

133

135

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The ␣ 2 ␦ subunits of voltage-gated calcium channels are important modulatory subunits that enhance calcium currents and may also have other roles in synaptogenesis. The antiepileptic and antiallodynic drug gabapentin (GBP) binds to the ␣ 2 ␦-1 and ␣ 2 ␦-2 isoforms of this protein, and its binding may disrupt the binding of an endogenous ligand, required for their correct function. We have shown previously that GBP produces a chronic inhibitory effect on calcium currents by causing a reduction in the total number of ␣ 2 ␦ and ␣ 1 subunits at the cell surface. This action of GBP is likely to be attributable to a disruption of the trafficking of ␣ 2 ␦ subunits, either to or from the plasma membrane. We studied the effect of GBP on the internalization of, and insertion into the plasma membrane of ␣ 2 ␦-2 using an ␣-bungarotoxin binding site-tagged ␣ 2 ␦-2 subunit, and a fluorescent derivative of ␣-bungarotoxin. We found that GBP specifically disrupts the insertion of ␣ 2 ␦-2 from post-Golgi compartments to the plasma membrane, and this effect was prevented by a mutation of ␣ 2 ␦-2 that abolishes its binding to GBP. The coexpression of the GDP-bound Rab11 S25N mutant prevented the GBP-induced decrease in ␣ 2 ␦-2 cell surface levels, both in cell lines and in primary neurons, and the GBP-induced reduction in calcium channel currents. In contrast, the internalization of ␣ 2 ␦-2 was unaffected by GBP. We conclude that GBP acts by preventing the recycling of ␣ 2 ␦-2 from Rab11-positive recycling endosomes to the plasma membrane.

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Block by gabapentin of the facilitation of glutamate release from rat trigeminal nucleus following activation of protein kinase C or adenylyl cyclase

Cited by 88 publications

References 23 publications

Spinal Gabapentin and Antinociception: Mechanisms of Action

Spinal Gabapentin and Antinociception: Mechanisms of Action

Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans

The α₂δ Ligand Gabapentin Inhibits the Rab11-Dependent Recycling of the Calcium Channel Subunit α₂δ-2

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Block by gabapentin of the facilitation of glutamate release from rat trigeminal nucleus following activation of protein kinase C or adenylyl cyclase

Cited by 88 publications

References 23 publications

Spinal Gabapentin and Antinociception: Mechanisms of Action

Spinal Gabapentin and Antinociception: Mechanisms of Action

Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans

The α2δ Ligand Gabapentin Inhibits the Rab11-Dependent Recycling of the Calcium Channel Subunit α2δ-2

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The α₂δ Ligand Gabapentin Inhibits the Rab11-Dependent Recycling of the Calcium Channel Subunit α₂δ-2