Antinociceptive Effects In Neuropathic Pain Research Articles

Magnesium sulfate reduces formalin-induced orofacial pain in rats with normal magnesium serum levels.

In humans, orofacial pain has a high prevalence and is often difficult to treat. Magnesium is an essential element in biological a system which controls the activity of many ion channels, neurotransmitters and enzymes. Magnesium produces an antinociceptive effect in neuropathic pain, while in inflammatory pain results are not consistent. We examined the effects of magnesium sulfate using the rat orofacial formalin test, a model of trigeminal pain. Male Wistar rats were injected with 1.5% formalin into the perinasal area, and the total time spent in pain-related behavior (face rubbing) was quantified. We also spectrophotometrically determined the concentration of magnesium and creatine kinase activity in blood serum. Magnesium sulfate administered subcutaneously (0.005-45mg/kg) produced significant antinociception in the second phase of the orofacial formalin test in rats at physiological serum concentration of magnesium. The effect was not dose-dependent. The maximum antinociceptive effect of magnesium sulfate was about 50% and was achieved at doses of 15 and 45mg/kg. Magnesium did not affect increase the levels of serum creatine kinase activity. Preemptive systemic administration of magnesium sulfate as the only drug can be used to prevent inflammatory pain in the orofacial region. Its analgesic effect is not associated with magnesium deficiency.

The Contribution of NMDA Receptors in Antinociceptive Effect of Pregabalin: Comparison of Two Models of Pain Assessment.

BackgroundPregabalin has shown remarkable antinociceptive effects in neuropathic pain; however, its efficacy against acute and visceral pain remained controversial.ObjectivesThe present study aimed at investigating the involvement of N-methyl-D-aspartate (NMDA) receptors in the antinociceptive effect of pregabalin in both acute and visceral pain using and comparing hot plate test and writhing test in male mice.MethodsNMDA (15 and 30 mg/kg), as an agonist or MK801 (0.02 and 0.05 mg/kg) as an NMDA receptor (NMDAR) antagonist, were injected intraperitoneally either alone or 15 minutes before a dose of pregabalin that produced almost 30% antinociception (100 mg/kg in hot plate test and 5 mg/kg in writhing tests). Then, the percentage of maximal possible effect (MPE%) at the 30th and 60th minutes in hot plate test and effect percentage (E%) in writhing test were measured and compared as antinociceptive indexes.ResultsIn hot plate test, pretreatment with MK801 (0.05 mg/kg) significantly increased antinociceptive effect of 100 mg/kg pregabalin, but pretreatment with NMDA did not result in any effect. Pretreatment with MK801 in writhing test significantly increased the antinociceptive effect of 5 mg/kg pregabalin (In contrast to 30 mg/kg NMDA that significantly decreased it.). NMDA induced antinociception reduction or MK801 increased antinociception in writhing test were significantly higher than what was observed in hot plate test.ConclusionsOur results suggested that pregabalin antinociception in acute and visceral pain is mediated through NMDA receptors. Although this effect depends on the dose of NMDAR ligand, it is more pronounced in the behavioral response in the writhing test.

The Contribution of NMDA Receptors in Antinociceptive Effect of Pregabalin: Comparison of Two Models of Pain Assessment

Background: Pregabalin has shown remarkable antinociceptive effects in neuropathic pain; however, its efficacy against acute and visceral pain remained controversial. Objectives: The present study aimed at investigating the involvement of N-methyl-D-aspartate (NMDA) receptors in the antinociceptive effect of pregabalin in both acute and visceral pain using and comparing hot plate test and writhing test in male mice. Methods: NMDA (15 and 30 mg/kg), as an agonist or MK801 (0.02 and 0.05 mg/kg) as an NMDA receptor (NMDAR) antagonist, were injected intraperitoneally either alone or 15 minutes before a dose of pregabalin that produced almost 30% antinociception (100 mg/kg in hot plate test and 5 mg/kg in writhing tests). Then, the percentage of maximal possible effect (MPE%) at the 30th and 60th minutes in hot plate test and effect percentage (E%) in writhing test were measured and compared as antinociceptive indexes. Results: In hot plate test, pretreatment with MK801 (0.05 mg/kg) significantly increased antinociceptive effect of 100 mg/kg pregabalin, but pretreatment with NMDA did not result in any effect. Pretreatment with MK801 in writhing test significantly increased the antinociceptive effect of 5 mg/kg pregabalin (In contrast to 30 mg/kg NMDA that significantly decreased it.). NMDA induced antinociception reduction or MK801 increased antinociception in writhing test were significantly higher than what was observed in hot plate test. Conclusions: Our results suggested that pregabalin antinociception in acute and visceral pain is mediated through NMDA receptors. Although this effect depends on the dose of NMDAR ligand, it is more pronounced in the behavioral response in the writhing test.

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.

Nauclea latifolia Smith (Rubiaceae) exerts antinociceptive effects in neuropathic pain induced by chronic constriction injury of the sciatic nerve

Ethnopharmacological relevance: The roots of Nauclea latifolia Smith (Rubiaceae) popularly known as “koumkouma” is used in traditional Cameroonian medicine as neuropathic pain remedy and for the treatment of headache, inflammatory pain and convulsion. This study was conducted to evaluate the antinociceptive effects of the alkaloid fraction isolated from Nauclea latifolia in neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in rat. Materials and methodsBioactive-guided fractionation of the root extracts of Nauclea latifolia using the Von Frey in a rat model of neuropathic pain (Benett model), afforded a potent anti-hyperalgesic fraction IV. Further fractionation of this fraction was performed by high-performance liquid chromatography (HPLC), yielded eight sub-fractions (F1–F8) which were tested for antinociceptive effects. The alkaloid fraction (F3) collected by HPLC, exhibited potent antinociceptive effects, and the anti-allodynic and anti-hyperalgesic effects of this fraction (8, 16, 40 and 80mg/kg) were determined using the von Frey and acetone tests respectively in a rat model of neuropathic pain. Rota-rod performance and catalepsy tests were used for the assessment of motor coordination. ResultsThe alkaloid fraction (80mg/kg) administered intraperitoneally induced a completely decreased hyperalgesia 90min post-dosing. In the acetone test, the Nauclea latifolia fraction at 80mg/kg showed its maximal anti-allodynic effects 120min post-injection. The areas under the curve (AUC) of the anti-allodynic or anti-hyperalgesic effects produced by the alkaloid fraction at 80mg/kg were significantly (p<0.001) greater than the AUC of effects produced by vehicle in CCI rats. The alkaloid fraction did not exhibit any significant effects on the spontaneous locomotor activity of the mice in rota-rod performance and no sign of catalepsy was observed. ConclusionThe analysis of the effects, expressed as the time course of AUC, supports the traditional use of Nauclea latifolia in neuropathic pain therapy. The pharmacological and chemical studies are continuing in order to characterize the mechanism(s) responsible for this anti-hyperalgesic and anti-allodynic action and also to identify the active substances present in the roots extracts of Nauclea latifolia.

The analgesic effect of crotoxin on neuropathic pain is mediated by central muscarinic receptors and 5-lipoxygenase-derived mediators

Crotoxin (CTX), a neurotoxin isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, induces analgesia. In this study, we evaluated the antinociceptive effect of CTX in a model of neuropathic pain induced by rat sciatic nerve transection. Hyperalgesia was detected 2 h after nerve transection and persisted for 64 days. Immersion of proximal and distal nerve stumps in CTX solution (0.01 mM for 10 s), immediately after nerve transection, blocked hyperalgesia. The antinociceptive effect of CTX was long-lasting, since it was detected 2 h after treatment and persisted for 64 days. CTX also delayed, but did not block, neurectomy-induced neuroma formation. The effect of CTX was blocked by zileuton (100 mg/kg, p.o.) and atropine (10 mg/kg, i.p.), and reduced by yohimbine (2 mg/kg, i.p.) and methysergide (5 mg/kg, i.p.). On the other hand, indomethacin (4 mg/kg, i.v.), naloxone (1 mg/kg, i.p.), and N-methyl atropine (30 mg/kg, i.p.) did not interfere with the effect of CTX. These results indicate that CTX induces a long-lasting antinociceptive effect in neuropathic pain, which is mediated by activation of central muscarinic receptors and partially, by activation of α-adrenoceptors and 5-HT receptors. Eicosanoids derived from the lipoxygenase pathway modulate the action of crotoxin.

Crotalphine induces potent antinociception in neuropathic pain by acting at peripheral opioid receptors

Neuropathic pain is an important clinical problem and it is usually resistant to the current therapy. We have recently characterized a novel analgesic peptide, crotalphine, from the venom of the South American rattlesnake Crotalus durissus terrificus. In the present work, the antinociceptive effect of crotalphine was evaluated in an experimental model of neuropathic pain induced in rats by chronic constriction of sciatic nerve. The effect of the peptide was compared to that induced by the crude venom, which confirmed that crotalphine is responsible for the antinociceptive effect of the crotalid venom on neuropathic pain. For characterization of neuropathic pain, the presence of hyperalgesia, allodynia and spontaneous pain was assessed at different times after nerve constriction. These phenomena were detected 24 h after surgery and persisted at least for 14 days. The pharmacological treatments were performed on day 14 after surgery. Crotalphine (0.2–5 µg/kg) and the crude venom (400–1600 µg/kg) administered p.o. inhibited hyperalgesia, allodynia and spontaneous pain induced by nerve constriction. The antinociceptive effect of the peptide and crude venom was long lasting, since it was detected up to 3 days after treatment. Intraplantar injection of naloxone (1 µg/paw) blocked the antinociceptive effect, indicating the involvement of opioid receptors in this phenomenon. Gabapentin (200 mg/kg, p.o.), and morphine (5 mg/kg, s.c.), used as positive controls, blocked hyperalgesia and partially inhibited allodynia induced by nerve constriction. These data indicate that crotalphine induces a potent and long lasting opioid antinociceptive effect in neuropathic pain that surpasses that observed with standard analgesic drugs.

Possible involvement of brain-derived neurotrophic factor in the antinociceptive effect of antidepressants in neuropathic pain

Neuropathic pain, a chronic pain state caused by injury to the nervous system, usually responds poorly to standard pain treatment. Antidepressants have been used to treat neuropathic pain, and animal and clinical studies have showed beneficial effects. However, the mechanisms underlying antidepressant antinociceptive effect in neuropathic pain are still unknown. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can modulate synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems. Recent animal and human studies have demonstrated that antidepressants can increase central as well as plasma BDNF levels. In addition: (1) BDNF is produced by a subset of primary sensory neurons that are located in the dorsal root ganglion; (2) BDNF levels change in animal models of neuropathic pain; (3) BDNF can indirectly depress sensory neuron transmission in the dorsal horn. From these findings, it is proposed that BDNF may play an important role in the antidepressant antinociceptive effect in neuropathic pain. The notion of BDNF mediating the therapeutic mechanisms of antidepressant in neuropathic pain may help to select the specific type and the optimal dose of antidepressants for the treatment of neuropathic pain. Exploration of this hypothesis could provide a new direction in the treatment of neuropathic pain, as well as other pain disorders.