Ca2+ channel α2δ ligands: novel modulators of neurotransmission

Dooley, David; Taylor, Charles P.; Donevan, Sean D.; Feltner, Douglas E.

doi:10.1016/j.tips.2006.12.006

Cited by 355 publications

(227 citation statements)

References 55 publications

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“…The interaction between α2δ subunits of voltage-gated Ca 2＋ channel and the drugs explains the mechanism of action for their therapeutic effects for several clinical disorders, including epilepsy, pain from diabetic neuropathy, postherpetic neuralgia and fibromyalgia, and generalized anxiety disorder (Dooley et al, 2007). Gabapentin also inhibits the plasma membrane trafficking of β 4a-bound Ca v 2.1 complexes according to a recent report (Mich and Horne, 2008).…”

Section: Discussionmentioning

confidence: 97%

Gabapentin Attenuates the Activation of Transient Receptor Potential A1 by Cinnamaldehyde

2009

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Gabapentin is used as an effective drug for relieving pain, but the main mechanism is still unclear. Recently, voltage-gated Ca 2＋ channel subunits are suggested for the main target for the analgesic action of gabapentin. We wonder whether gabapentin directly modulates other specific ion channels peripherally expressed in the sensory neurons. To test this, we used a heterologous expression system in which the cell lines transiently expressed thermosensitive transient receptor potential ion channels (thermoTRPs) as well as the primary cultured mouse trigeminal neurons. The application of gabapentin reduced the increases in the intracellular Ca 2＋ level caused by TRPA1 activation in the heterologous expression system whereas the responses via actions of other thermoTRPs were not dramatically affected by the gabapentin treatment. Gabapentin also attenuated the TRPA1-mediated intracellular Ca 2＋ increases in the cultured trigeminal neurons. These findings suggest TRPA1 in the peripheral sensory neurons as a novel target for the analgesic of gabapentin.

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Section: Discussionmentioning

confidence: 97%

Gabapentin Attenuates the Activation of Transient Receptor Potential A1 by Cinnamaldehyde

2009

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“…Eight of our 10 patients used either gabapentin or pregabalin, which act on voltage-sensitive calcium channels (37). In anesthetized rats, gabapentin modulates the BOLD signal in several areas involved in nociceptive processing, for example, by increasing activity in thalamus and periaqueductal gray matter and decreasing it in amygdala (38).…”

Section: Discussionmentioning

confidence: 99%

Aberrant temporal and spatial brain activity during rest in patients with chronic pain

Malinen

Vartiainen²,

Hlushchuk³

et al. 2010

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

166

169

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In the absence of external stimuli, human hemodynamic brain activity displays slow intrinsic variations. To find out whether such fluctuations would be altered by persistent pain, we asked 10 patients with unrelenting chronic pain of different etiologies and 10 sex-and agematched control subjects to rest with eyes open during 3-T functional MRI. Independent component analysis was used to identify functionally coupled brain networks. Time courses of an independent component comprising the insular cortices of both hemispheres showed stronger spectral power at 0.12 to 0.25 Hz in patients than in control subjects, with the largest difference at 0.16 Hz. A similar but weaker effect was seen in the anterior cingulate cortex, whereas activity of the precuneus and early visual cortex, used as a control site, did not differ between the groups. In the patient group, seed pointbased correlation analysis revealed altered spatial connectivity between insulae and anterior cingulate cortex. The results imply both temporally and spatially aberrant activity of the affective painprocessing areas in patients suffering from chronic pain. The accentuated 0.12-to 0.25-Hz fluctuations in the patient group might be related to altered activity of the autonomic nervous system. functional MRI | insula | resting state | autonomic nervous system | human A cute pain has an important protective function and is supported by a well-known brain network comprising the insular cortex, anterior cingulate cortex (ACC), primary and secondary somatosensory cortex, and thalamus (1). When pain becomes chronic, its physiological protective function is lost. Chronic pain decreases the quality of life and interferes with the cognitive, affective, and physical functioning. Although one-fifth of the Western population suffers from chronic pain (2), the underlying brain activity is poorly understood.Extensive meta-analyses (1, 3, 4) indicate that the brain areas related to chronic and acute pain differ to some extent, but no single brain-activity pattern is specific to chronic pain. Morphometric analyses suggest gray-matter loss in many chronic pain conditions, indicating that chronic pain may alter brain structure (5), but in a reversible manner (6).Previous studies on the brain basis of chronic pain have concentrated on abnormal activation sites and strengths following external stimulation. Studies of resting-state brain activity by means of functional magnetic resonance imaging (fMRI) have shown that the connectivity within the default-mode network (7) is altered in chronic pain, together with reduced task-related deactivation within this network (8, 9). Recently, the spectra of the default-mode network were shown to contain more power at 0.05 to 0.1 Hz in patients suffering from diabetic neuropathic pain than in healthy control subjects (9).In the present study, we focused on the resting-state fluctuations and functional connectivity of the affective pain-processing areas, the insula and ACC, in chronic pain. Specifically, we recorded spontaneous fMRI sig...

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“…channel (VGCC) in the CNS [21][22][23]. They inhibit presynaptic neurotransmitter release from hyperexcitable or abnormal neurons by blocking trafficking of the a 2 d-1 subunit to the presynaptic membrane [24][25][26][27]. Experimentally, expression of a 2 d-1, but not a 2 d-2 (another binding site of GBP), is significantly increased in both the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord in animal models of peripheral neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

Yang

et al. 2016

Neurosci. Bull.

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The a 2 d-1 subunit of the voltage-gated Ca 2? channel (VGCC) is a molecular target of gabapentin (GBP), which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the a 2 d-1 subunit to the presynaptic membrane, resulting in decreased neurotransmitter release. We previously showed that GBP has an antiallodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated administration in a rat model of central post-stroke pain (CPSP) hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the a 2 d-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the a 2 d-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of a 2 d-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the a 2 d-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor a 2 d-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.Keywords Central post-stroke pain Á Calcium channel a 2 d subunit Á Gabapentinoid Á Thalamic hemorrhagic stroke Á Thalamus Á Spinal dorsal horn

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Ca2+ channel α2δ ligands: novel modulators of neurotransmission

Cited by 355 publications

References 55 publications

Gabapentin Attenuates the Activation of Transient Receptor Potential A1 by Cinnamaldehyde

Gabapentin Attenuates the Activation of Transient Receptor Potential A1 by Cinnamaldehyde

Aberrant temporal and spatial brain activity during rest in patients with chronic pain

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

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