Antinociceptive Effects Of Gabapentin Research Articles

Anti-nociceptive effect of gabapentin in mouse models of acute and chronic pain

Purpose: To investigate the anti-nociceptive effect of gabapentin in acute and chronic pain models.
 Methods: Four mouse models of pain were used in this study. These comprised thermal tests (hot plate and tail immersion tests), and chemical tests (formalin and acetic acid-induced writhing tests). A total of seventy-two (72) albino mice weighing 25 - 40 g (mean weight = 32.5 ± 5.1 g) were used. In each test, the mice were randomly assigned to three sets of 6 mice each: control group, celecoxib group and drug treatment group. Each test was performed at intervals of 30, 60 and 90 min.
 Results: During the acute phase, there was no significant decrease in foot raising (FR) or licking and biting (L & B) episodes among the groups (p > 0.05). However, these episodes were significantly (p < 0.05) decreased in the second delayed phase, in the celecoxib and drug-treated groups, when compared with normal control group. Gabapentin significantly (p < 0.05) decreased pain response throughout the course of the thermal tests. The number of writhes within 30 min were significantly reduced in celecoxib and gabapentin-treated animals, compared with negative control group (p < 0.05). Gabapentin produced approximately 60 % protection of writhing, similar to that produced by celecoxib, the standard non-steroidal anti-inflammatory drug (NSAID) used (61 %).
 Conclusion: The results demonstrate that the gabapentin is effective against chronic inflammatory pain in mice and therefore can be potentially developed as an effective anti-inflammatory agent for humans.

Gabapentin Enhances the Morphine Anti-Nociceptive Effect in Neuropathic Pain via the Interleukin-10-Heme Oxygenase-1 Signalling Pathway in Rats

In the present study, we investigated the anti-inflammatory mechanisms by which gabapentin enhances morphine anti-nociceptive effect in neuropathic pain in rats and the interaction between the anti-nociceptive effects of gabapentin on morphine and the interleukin (IL)-10-heme-oxygenase (HO)-1 signal pathway in a rat model of neuropathic pain. The neuropathic pain model was induced via a left L5/6 spinal nerve ligation (SNL) in rats. The anti-nociceptive effect of gabapentin and IL-10 on morphine was examined over a 7-day period, and the effects of the anti-IL-10 and HO-1 inhibitor zinc protoporphyrin (ZnPP) on gabapentin/morphine co-injection were assessed. Drug administration was given over 7 days, and on day 8, both anti-inflammatory cytokine IL-10, a stress-induced protein HO-1 and pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were measured. Gabapentin attenuated morphine tolerance over 7 days of co-administration, and reduced the expression of pro-inflammatory cytokines but increased IL-10 and HO-1 expression. The effect of gabapentin on morphine was partially blocked using the anti-IL-10 antibody or the HO-1 inhibitor zinc protoporphyrin. Our findings indicated that the anti-nociceptive effects of gabapentin on morphine might be caused by activation of the IL-10-HO-1 signalling pathway, which resulted in the inhibition of the expression of pro-inflammatory cytokines in neuropathic pain in the rat spinal cord.

Antinociceptive Effect of Gabapentin in Visceral Pain is not Mediated by GABAA or Opioid Receptors

Aims: There is evidence supporting the antinociceptive effect of gabapentin in visceral pain, however, the underlying mechanism(s) is not determined yet. So this study was performed to evaluate probable involvement of opioid and GABAergic receptors in the gabapentin effects on acetic acid-induced visceral pain in mice. Place and Duration of Study: Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran, between June 2012 and March 2013. Methodology: The acetic acid test was induced by intraperitoneal injection (i.p.) of acetic acid 0.6% (10ml/kg of body weight) in male mice. Writhing reflex was measured as the number of abdominal contractions in 45min. Animals received saline (as control) or gabapentin (1, 5, 10, 25, 50, 100 or 200mg/kg/ i.p.) 40min before acetic acid. The least effective dose of gabapentin (50mg/kg i.p.) was selected for further assessments and mice were pretreated either picrotoxin (0.75, 1 and 1.5mg/kg/i.p.) as chloride Original Research Article British Journal of Medicine & Medical Research, 4(31): 5062-5073, 2014 5063 channel blocker, bicuculline (0.5, 0.75, 1.5 and 2mg/kg) as GABAA receptor antagonist or naloxone (2mg/kg/i.p.) as opioid receptor antagonist, 10min before gabapentin (50mg/kg i.p.) treatment. Separate groups received naloxone or picrotoxin (1.5mg/kg) or bicuculline (2mg/kg) alone 10min before saline in acetic acid induced visceral contractions test. Results: Gabapentin reduced acetic acid-induced writhing in dose-dependent manner. Visceral contractions following naloxone, picrotoxin and bicuculline administration prior to gabapentin was not significantly different from that of gabapentin alone. Only toxic doses of picrotoxin and bicuculline (1.5 and 2mg/kg, respectively) abolished the inhibitory effect of gabapentin. Conclusion: The effect of gabapentin on visceral nociception is not mediated through opioid and/or GABAA receptors.

Analysis of the antinociceptive interactions in two-drug combinations of gabapentin, oxcarbazepine and amitriptyline in streptozotocin-induced diabetic mice

Antiepileptic and antidepressant drugs are the primary treatments for pain relief in diabetic neuropathy. Combination therapy is a valid approach in pain treatment, where a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of two-drug combinations of gabapentin, oxcarbazepine, and amitriptyline on nociception in diabetic mice and aimed to determine the type of interaction between components. The nociceptive responses in normal and diabetic mice were assessed by the tail-flick test. The testing was performed before and three weeks after the diabetes induction with streptozotocin (150 mg/kg; i.p.), when the antinociceptive effects of gabapentin, oxcarbazepine, amitriptyline and their two-drug combinations were examined. Gabapentin (10–40 mg/kg; p.o.) and oxcarbazepine (20–80 mg/kg; p.o.) produced a significant, dose-dependent antinociception in diabetic mice while amitriptyline (5–60 mg/kg; p.o.) produced weak antinociceptive effect. In normal mice, neither of the drugs produced antinociception. Gabapentin and oxcarbazepine, co-administered in fixed-dose fractions of the ED 50 to diabetic mice, induced significant, dose-dependent antinociception. Isobolographic analysis revealed synergistic interaction. Oxcarbazepine (10–60 mg/kg; p.o.) + amitriptyline (5 mg/kg; p.o.) and gabapentin (10–30 mg/kg; p.o.) + amitriptyline (5 mg/kg; p.o.) combinations significantly and dose-dependently reduced nociception in diabetic mice. Analysis of the log dose–response curves for oxcarbazepine or gabapentin in a presence of amitriptyline and oxcarbazepine or gabapentin applied alone, revealed a synergism in oxcarbazepine–amitriptyline and additivity in gabapentin–amitriptyline combination. These findings provide new information about the combination therapy of painful diabetic neuropathy and should be explored further in patients with diabetic neuropathy.

Gabapentin enhances the analgesic response to morphine in acute model of pain in male rats

Abstract Whenever opioids as drug of choice result in inadequate analgesia, the combinational therapy would be the solution. In this study the co-administration of gabapentin with morphine is evaluated in acute model of pain. Therefore the antinociceptive effect of gabapentin (30 or 90 mg/kg, s.c.) and morphine (0.5, 1 or 3 mg/kg, s.c.) alone or in combination were measured by tail-flick test in intact adult male rats. Control rats received normal saline. Tail-flick latency time and Area Under Curve (AUC), as antinociception index were calculated for each groups. There was not any significant difference between the antinociceptive response of 0.5 mg/kg morphine and 30 mg/kg gabapentin as compared to controls, but co-administration of these subanalgesic doses increased significantly AUC as compared to morphine alone. The co-administration of gabapentin with analgesic doses of 1 and 3 mg/kg morphine had also increased significantly AUC. Therefore gabapentin enhanced the antinociceptive effect of both analgesic and subanalgesic doses of morphine in a dose dependent manner. In conclusion co-administration of gabapentin with low doses of morphine produced therapeutic analgesia which could have important clinical application.

Gabapentin enhances the analgesic response to morphine in acute model of pain in male rats

Whenever opioids as drug of choice result in inadequate analgesia, the combinational therapy would be the solution. In this study the co-administration of gabapentin with morphine is evaluated in acute model of pain. Therefore the antinociceptive effect of gabapentin (30 or 90 mg/kg, s.c.) and morphine (0.5, 1 or 3 mg/kg, s.c.) alone or in combination were measured by tail-flick test in intact adult male rats. Control rats received normal saline. Tail-flick latency time and Area Under Curve (AUC), as antinociception index were calculated for each groups. There was not any significant difference between the antinociceptive response of 0.5 mg/kg morphine and 30 mg/kg gabapentin as compared to controls, but co-administration of these subanalgesic doses increased significantly AUC as compared to morphine alone. The co-administration of gabapentin with analgesic doses of 1 and 3 mg/kg morphine had also increased significantly AUC. Therefore gabapentin enhanced the antinociceptive effect of both analgesic and subanalgesic doses of morphine in a dose dependent manner. In conclusion co-administration of gabapentin with low doses of morphine produced therapeutic analgesia which could have important clinical application.

Changes in expression of voltage-dependent ion channel subunits in dorsal root ganglia of rats with radicular injury and pain.

Changes in expression of voltage-dependent ion channel subunits were examined in the radicular pain state. Furthermore, antinociceptive effects of gabapentin on radicular pain were compared with effects on peripheral neuropathic pain. To clarify molecular substrates involved in the development of radicular pain, and to investigate the responsiveness of radicular pain to gabapentin. Peripheral nerve injuries are known to induce dynamic changes of voltage-dependent Na+ and Ca2+ channel subunits expression in dorsal root ganglion neurons. However, the expression profiles of Na+ and Ca2+ channel subunits in the radicular pain state have not been examined. Two radicular pain models and one peripheral neuropathic pain model were prepared. By using semiquantitative reverse transcriptase-polymerase chain reaction, the expression levels of several Na+ and Ca2+ channel subunits in the dorsal root ganglions of these pain model rats were investigated. The antinociceptive effects of gabapentin were examined in a behavioral study using the aforementioned pain models. All three neuropathic pain operations induced comparable mechanical allodynia and thermal hyperalgesia. The upregulation of the Na(v)1.3 Na+ channel and Ca(v)alpha2delta Ca2+ channel subunits was observed only in the peripheral nerve injury model. A downregulation of the Na(v)1.9 channel was observed in all three pain model rats. A lower dose of gabapentin was significantly more effective in alleviating the mechanical allodynia of rats with radicular pain. The reduction of Na(v)1.9 found in all three models may link to the neuropathic pain state, including radicular pain. The lower sensitivity to gabapentin in rats with peripheral neuropathic pain might be partly explained by the marked upregulation of Ca(v)alpha2delta in the dorsal root ganglions, suggesting that gabapentin may be more effective in radicular pain treatment.

Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal horn

We investigated the effects of gabapentin (GBP) on glutamatergic synaptic transmission in the dorsal horn of the rat spinal cord. Patch clamp whole cell recordings were made from superficial and deep dorsal horn neurons of rat spinal cord slices. In the majority of neurons in the superficial lamina, GBP decreased the amplitudes of evoked excitatory postsynaptic currents (evoked EPSCs) mediated by either non-NMDA or NMDA receptors. In contrast, neurons in the deep lamina showed variable effects, with a lower incidence of decrease in amplitude of evoked EPSCs and a subset of neurons showing an increase in amplitude of evoked NMDA receptor-mediated EPSCs. No enhancement of evoked non-NMDA receptor-mediated EPSCs was observed in either lamina. To determine whether the observed effects of GBP are presynaptic and/or postsynaptic, spontaneous miniature excitatory postsynaptic currents (mEPSCs) were studied. In neurons that showed a decrease in its frequency of mEPSCs by GBP, no change in the amplitude or shape accompanied the effect. On the other hand, in neurons that showed an increase in the frequency of NMDA receptor-mediated mEPSCs, the effect accompanied an increase in amplitude. These results suggest that GBP presynaptically inhibits glutamatergic synaptic transmission predominantly in the superficial lamina, while postsynaptically enhancing NMDA receptor-mediated transmission in some neurons of the deep lamina. The antinociceptive effects of GBP may involve the inhibition of the release of excitatory amino acids from presynaptic terminals.

Antinociceptive effect of gabapentin in the formalin test

Gabapentin is an adjunctive drug for the treatment of resistant partial seizures. The antinociceptive effect of this drug was assessed by using the formalin pain test in rats. Although low dose gabapentin (10 mg/kg s.c.) was unable to alter pain scores, higher doses (30 and 90 mg/kg s.c.) significantly reduced them. Results suggest that gabapentin may modulate the pain perception produced by chemical irritants like formalin in rats.