Effect of carbamazepine and gabapentin on excitability in the trigeminal subnucleus caudalis of neonatal rats using a voltage-sensitive dye imaging technique

Abstract

BackgroundThe antiepileptic drugs carbamazepine and gabapentin are effective in treating neuropathic pain and trigeminal neuralgia. In the present study, to analyze the effects of carbamazepine and gabapentin on neuronal excitation in the spinal trigeminal subnucleus caudalis (Sp5c) in the medulla oblongata, we recorded temporal changes in nociceptive afferent activity in the Sp5c of trigeminal nerve-attached brainstem slices of neonatal rats using a voltage-sensitive dye imaging technique.ResultsElectrical stimulation of the trigeminal nerve rootlet evoked changes in the fluorescence intensity of dye in the Sp5c. The optical signals were composed of two phases, a fast component with a sharp peak followed by a long-lasting component with a period of more than 500 ms. This evoked excitation was not influenced by administration of carbamazepine (10, 100 and 1,000 μM) or gabapentin (1 and 10 μM), but was increased by administration of 100 μM gabapentin. This evoked excitation was increased further in low Mg2+ (0.8 mM) conditions, and this effect of low Mg2+ concentration was antagonized by 30 μM DL-2-amino-5-phosphonopentanoic acid (AP5), a N-methyl-d-aspartate (NMDA) receptor blocker. The increased excitation in low Mg2+ conditions was also antagonized by carbamazepine (1,000 μM) and gabapentin (100 μM).ConclusionCarbamazepine and gabapentin did not decrease electrically evoked excitation in the Sp5c in control conditions. Further excitation in low Mg2+ conditions was antagonized by the NMDA receptor blocker AP5. Carbamazepine and gabapentin had similar effects to AP5 on evoked excitation in the Sp5c in low Mg2+ conditions. Thus, we concluded that carbamazepine and gabapentin may act by blocking NMDA receptors in the Sp5c, which contributes to its anti-hypersensitivity in neuropathic pain.

Gabapentin Completely Neutralized the Acute Morphine Activation in the Rat Hypothalamus: a c-Fos Study

“…It is noteworthy to mention that GBP inhibited PKC signaling pathways [48][49][50][51][52]. Gabapentin also inhibited the spinal neuronal action of NMDA receptors [53][54][55].…”

“…Previous reports showed that opioid treatment altered the expression of the NMDA receptor in the hypothalamus [57,58] and NMDA receptor antagonist and intrathecal gabapentin inhibited the morphine induced development of spinal tolerance and dependence [59,60]. Recent evidences demonstrated that gabapentin inhibited the spinal neuronal action of NMDA receptors [53][54][55]. It was postulated that the spinal NMDA receptors antagonism by GBP might have played a role in blocking morphine tolerance and enhance morphine analgesia, the interference of its supra-spinal circuits is not known.…”

Psychotropic Drugs for the Management of Chronic Pain and Itch

“…The mechanisms of interaction of carbamazepine with the glutamatergic system are not fully understood. Some studies have found that carbamazepine affects the signalling pathways that involve NMDARs [225,226,227]. This data does not exclude the fact that carbamazepine can interact directly with NMDARs.…”

Opiate‐Free Pain Therapy Using Carbamazepine‐Loaded Microparticles Provides Up to 2 Weeks of Pain Relief in a Neuropathic Pain Model

“…In the peripheral nervous system, these targeted sodium channels are predominantly expressed on sensory neurons and result in limited firing rates of those neurons . Past research has implicated carbamazepine as also affecting calcium channels, as well as NMDA receptors, though effects were observed at concentrations well above therapeutic levels and above the known carbamazepine toxicity limit of 63 μmol/L. Though numerous studies have been performed regarding the mechanism of action of carbamazepine, such as modulated activity of a transiently expressed single isoform of GABAA receptor, the primary mechanism appears to be restricting neuronal firing rates via limiting activity of selective sodium channels.…”