Effects of milnacipran, duloxetine and indomethacin, in polyarthritic rats using the Randall-Selitto model

Milnacipran, a serotonin and noradrenalin reuptake inhibitor (SNRI), is efficacious in rodents in various models of acute or chronic pain (traumatic, neuropathic, inflammatory, visceral). However, its activity against arthritic pain has never been explored. Here, we assessed the activity of acute treatment with milnacipran in a polyarthritic rat model. Rats were injected in the tail base with complete Freund's adjuvant to induce a state of polyarthritis. Analgesic effects of acute treatment with intraperitoneal administration of milnacipran were then evaluated, using the Randall-Selitto model, against two levels of pressure applied to both hind paws (a lower one, addressing mechanical allodynia and a higher one, addressing mechanical hyperalgesia). The other SNRI duloxetine and the nonsteroidal anti-inflammatory drug indomethacin were tested as positive controls. Milnacipran was significantly and dose dependently active against the decrease of paw withdrawal threshold produced by complete Freund's adjuvant for low (minimum effective dose=5 mg/kg, range tested: 2.5-10 mg/kg) and high (minimum effective dose=10 mg/kg, range tested: 5-20 mg/kg)-pressure levels. Duloxetine (20 mg/kg, intraperitoneally) was significantly active against low pressure only. Indomethacin (3 mg/kg per os) was efficacious against both pressure levels. These rodent data suggest that milnacipran should be efficacious in painful conditions associated with chronic inflammatory states, such as arthritis.     

Pharmacological sensitivity and gene expression analysis of the tibial nerve injury model of neuropathic pain

The tibial nerve injury model is a novel, surgically uncomplicated, rat model of neuropathic pain based on a unilateral transection (neurotomy) of the tibial branch of the sciatic nerve. The aim of the present study was to describe some behavioral and molecular features of the model, and to test its sensitivity to a number of drugs which are currently used for the treatment of neuropathic pain. The model was characterized by a pronounced mechanical allodynia which was present in all subjects and a less robust thermal hyperalgesia. Mechanical allodynia developed within 2 weeks post-surgery and was reliably present for at least 9 weeks. Neurotomized rats showed no autotomy and their body weight developed normally. Gene expression in ipsilateral L5 dorsal root ganglia, analyzed by quantitative polymerase chain reaction (PCR), showed a pronounced up-regulation of galanin and vasointestinal peptide (VIP). This up-regulation developed rapidly (within 1 to 2 days following neurotomy) and remained present for at least 12 days. On the other hand, expression of calcitonin gene-related peptide (CGRP) and substance P mRNA was down-regulated 12 days following neurotomy. Mechanical allodynia was completely reversed by morphine [minimal effective dose (MED): 8 mg/kg, i.p.] and partially reversed by carbamazepine (MED: 64 mg/kg, i.p.), baclofen (MED: 3 mg/kg, i.p.) and amitriptyline (trend for efficacy at 32 mg/kg, i.p.), but not by gabapentin (50-100 mg/kg, i.p.). The finding that the tibial nerve injury model shows a robust and persistent mechanical allodynia which is sensitive to a number of established analgesics, as well as a gene expression profile which is compatible with that obtained in other models of neuropathic pain, further supports its validity as a reliable and surgically uncomplicated model for the study of neuropathic pain.     

Depression-like behavior and mechanical allodynia are reduced by bis selenide treatment in mice with chronic constriction injury: a comparison with fluoxetine, amitriptyline, and bupropion

Rationale

Neuropathic pain is associated with significant co-morbidities, including depression, which impact considerably on the overall patient experience. Pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. Neuropathic pain is characterized by hyperexcitability within nociceptive pathways and remains difficult to treat with standard analgesics.

Objectives

The present study determined the effect of bis selenide and conventional antidepressants (fluoxetine, amitriptyline, and bupropion) on neuropathic pain using mechanical allodynic and on depressive-like behavior.

Methods

Male mice were subjected to chronic constriction injury (CCI) or sham surgery and were assessed on day 14 after operation. Mice received oral treatment with bis selenide (1–5 mg/kg), fluoxetine, amitriptyline, or bupropion (10–30 mg/kg). The response frequency to mechanical allodynia in mice was measured with von Frey hairs. Mice were evaluated in the forced swimming test (FST) test for depression-like behavior.

Results

The CCI procedure produced mechanical allodynia and increased depressive-like behavior in the FST. All of the drugs produced antiallodynic effects in CCI mice and produced antidepressant effects in control mice without altering locomotor activity. In CCI animals, however, only the amitriptyline and bis selenide treatments significantly reduced immobility in the FST.

Conclusion

These data demonstrate an important dissociation between the antiallodynic and antidepressant effects in mice when tested in a model of neuropathic pain. Depressive behavior in CCI mice was reversed by bis selenide and amitriptyline but not by the conventional antidepressants fluoxetine and buproprion. Bis selenide was more potent than the other drugs tested for antidepressant-like and antiallodynic effects in mice.     

Antinociceptive efficacy of lacosamide in a rat model for painful diabetic neuropathy

Lacosamide was tested in the streptozotocin rat model of diabetic neuropathic pain in comparison to drugs which are commonly used in the treatment of diabetic neuropathic pain, i.e. antidepressants and anticonvulsants. In diabetic rats, lacosamide attenuated cold (10, 30 mg/kg, i.p.), warm (3, 10, 30 mg/kg, i.p.) and mechanical allodynia (30 mg/kg, i.p.). Streptozotocin-induced thermal and mechanical hyperalgesia were reduced by lacosamide at doses of 10 and 30 mg/kg, i.p. Morphine (3 mg/kg) showed similar efficacy on allodynia and hyperalgesia. Amitriptyline (10 mg/kg), venlafaxine (15 mg/kg), levetiracetam (180 mg/kg) and pregabalin (100 mg/kg) exhibited significant effects on thermal allodynia and mechanical hyperalgesia. Only treatment with amitriptyline (30 mg/kg, i.p.) produced full reversal of thermal allodynia comparable to lacosamide. Lamotrigine (45 mg/kg, i.p.) had no effect on both behavioral readouts. Lacosamide's potency and efficacy in reversing pain behavior might be due to its new, yet unknown mechanism of action.     

Pharmacologic investigation of the mechanism underlying cold allodynia using a new cold plate procedure in rats with chronic constriction injuries

Cold allodynia is a frequent clinical symptom of patients with neuropathic pain. Despite numerous studies of cold allodynia, using animal models of neuropathic pain, little is known about its underlying mechanisms. This study was performed to establish a method for the pharmacologic evaluation of cold allodynia using several analgesics in a chronic constriction injury (CCI) rat model of neuropathic pain. Compared with the results obtained before the CCI operation, the CCI rats placed on a cork plate at 20 degrees C exhibited a slight change in the paw withdrawal latency because of the mechanical stimulus mediated by the injured paw touching the plate. By contrast, there was a significant reduction in the paw withdrawal latency on a cold metal plate compared with that on the cork plate after the CCI surgery, with the maximum decrease occurring on postoperative day 7. This reduction is thought to specifically reflect cold-induced pain behavior. In addition, both na?ve and CCI rats showed behavioral changes at 5 and 0 degrees C, but not at 10 degrees C or higher. Interestingly, a subcutaneous morphine dose of 6 mg/kg completely inhibited cold allodynia induced at 10 degrees C on postoperative day 7. Under this condition, both the sodium channel blocker mexiletine (10 and 30 mg/kg, subcutaneously) and the calcium channel alpha2delta subunit blocker pregabalin (30 and 100 mg/kg, orally) significantly suppressed cold allodynia. Additionally, both resiniferatoxin (0.3 mg/kg, subcutaneously), an ultrapotent analog of capsaicin that desensitizes C fibers, and the VR1 channel antagonist N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide (10 and 30 mg/kg, orally) significantly prolonged the paw withdrawal latency. In conclusion, our data suggest that the activation of C fibers mediates cold allodynia.     

Exploring the potential of telmisartan in chronic constriction injury-induced neuropathic pain in rats

The present study was designed to investigate the potential of telmisartan, an angiotensin AT(1) receptor, in chronic constriction injury-induced neuropathic pain in rats. Four loose ligatures were placed around the sciatic nerve to induce chronic constriction injury and neuropathic pain. Acetone drop, pin-prick, hot plate and paint brush tests were performed to assess cold allodynia; mechanical and heat hyperalgesia; and dynamic mechanical allodynia, respectively along with assessment of spontaneous pain and postural index in terms of foot deformity. The levels of TNF-α were measured in the sciatic nerve as an index of inflammation. Chronic constriction injury was associated with development of cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia; and spontaneous pain and foot deformity along with rise in the levels of TNF-α. Telmisartan (1, 2, 5 mg/kg, p.o.) was administered for 14 days in chronic constriction injury subjected rats. Administration of telmisartan (2, 5 mg/kg) significantly attenuated chronic constriction injury-induced pain related behavior, foot deformity and rise in TNF-α level. It may be concluded that telmisartan has a potential in attenuating neuropathic pain behavior in chronic constriction injury model which may possibly be attributed to its anti-inflammatory properties.     

A comparison of the antinociceptive effects of voltage-activated Na+ channel blockers in two rat models of neuropathic pain

The pain-relieving effects of various voltage-activated Na(+) channel blockers have been evaluated in two rat models of neuropathic pain; the photochemically induced nerve injury model (Gazelius) and spared nerve injury model. Lidocaine (up to 40 mg/kg, i.p.) and lamotrigine (up to 60 mg/kg, i.p.) had no effect on mechanical or cold allodynia in either model. However, lamotrigine (10, 30 and 60 mg/kg) significantly attenuated mechanical hyperalgesia in the spared nerve injury model, while mexiletine (25 and 37.5 mg/kg, i.p.) attenuated mechanical allodynia in the Gazelius model. Tocainide (50, 75 and 100 mg/kg, i.p.) significantly reduced all types of pain behaviour measured. The present results show that these voltage-activated Na(+) channel blockers have broadly similar antinociceptive effects in these two models of neuropathic pain. They also show that these drugs can have markedly different effects on distinct neuropathic pain-related behaviours within models.     

Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain

The effects of acute, systemic administration of amitriptyline, duloxetine and mirtazapine (antidepressant drugs that variously affect extracellular noradrenaline and serotonin levels) and the selective serotonin reuptake inhibitor (SSRI) citalopram were compared in rat models of experimental pain. None of the drugs (all 3-30 mg/kg, i.p.) affected acute nociceptive responses as measured in the tail flick test. In the hot plate test, duloxetine and mirtazapine significantly increased (P<0.05) the nociceptive response latency, whereas amitriptyline and citalopram were ineffective. In the formalin test, duloxetine and citalopram significantly attenuated, whereas amitriptyline and mirtazapine increased, second phase flinching behaviour (all P<0.05). However, amitriptyline and mirtazapine reduced second phase licking behaviour. In the chronic constriction injury model of neuropathic pain, thermal hyperalgesia of the injured hindpaw was significantly attenuated by all four drugs (P<0.05); only amitriptyline and duloxetine fully reversed thermal hypersensitivity. None of the drugs tested attenuated mechanical allodynia. In contrast amitriptyline, duloxetine and mirtazapine significantly reduced mechanical hyperalgesia (P<0.05); citalopram was ineffective. No drug-related effects on motor performance in the rotarod test were observed. These results (a) highlight the difficulty in correlating antinociceptive effects of drugs from different antidepressant classes across a range of animal pain models and (b) suggest that antidepressants that variously affect both noradrenaline and serotonin levels have more potent and efficacious antinociceptive effects than SSRIs (as exemplified by citalopram), against a range of pain-like behaviours in an animal model of neuropathic pain.     

Pentoxifylline decreases allodynia and hyperalgesia in a rat model of neuropathic pain

BACKGROUND AND THE PURPOSE OF THE STUDY: Pentoxifylline (PTX) is a non-specific cytokite pain in several animal models and humans. However, long-term therapeutic effects of PTX on neuropathic pain in a rat model of chronic constriction injury (CCI) are not completely clear. This study was conducted to examine the effect of long-term administration of PTX on neuropathic pain in rats. METHODS : Neuropathic pain was induced by sciatic nerve ligation using of CCI model in rats. Rats were randomly assigned into sham, CCI-saline treated, and CCI-PTX treated (30 or 60 mg/kg ip) groups. PTX or saline administered at 30 min before CCI and daily for 14 days post-CCI. At the days of 3, 7, 11 and 14 following CCI, by using standard methods effects of thermal hyperalgesia, thermal and mechanical allodynia in all groups were examined using the standard methods. RESULTS : The CCI-saline treated group showed a significant increase in mechanical and thermal allodynia, and thermal hyperalgesia as compared with the sham group in the tested days. Administration of the higher dose of PTX (60 mg/kg/day), but not the lower dose (30 mg/kg/day) significantly reduced mechanical and thermal allodynia, as compared with the CCI-saline treated group on days of 3, 7, 11 and 14 (all P values<0.001). Also, both doses of PTX significantly reduced thermal hyperalgesia as compared with the CCI-saline treated group on these days (all P values<0.001). CONCLUSION : Results of this study show that chronic administration of PTX reduces the neuropathic pain in a rat model of CCI. Thus, this drug may have a therapeutic application in the treatment and management of neuropathic pain in humans.     

Milnacipran is active in models of irritable bowel syndrome and abdominal visceral pain in rodents

The role of antidepressants in the treatment of visceral pain has not been extensively examined. Milnacipran, a serotonin/noradrenalin reuptake inhibitor, has recently been approved in the USA for fibromyalgia, a chronic pathology characterized by diffused/chronic musculoskeletal pain, and a high prevalence of irritable bowel syndrome. Here, we determined its antinociceptive efficacy in two visceral pain tests in rodents: the acetic acid-induced writhing model in mice and the butyrate/colonic distension assay in rats, a model of irritable bowel syndrome. Acute milnacipran (5-40 mg/kgi.p.) significantly and dose-dependently reduced writhing (72.2 ± 3.2 versus 17.0 ± 4.1 writhes at 40 mg/kg). Following repeated administration (40 m/kgi.p. for 5 days), milnacipran preserved its ability to significantly reduce writhing (76 ± 8.3 versus 21.1 ± 6.7 writhes). Similarly, in the butyrate model, acute milnacipran (17.5 and 35 mg/kg, i.p.) significantly and dose-dependently increased cramps induction thresholds (from 45.7 ± 5.7 to 66.3 ± 4.8 and 75.6 ± 2.9 mm Hg, for 17.5 and 35 mg/kg, respectively) and reduced the number of cramps (from 3.0 ± 0.8 to 1.2 ± 0.8 and 0.3 ± 0.3 following inflation of an intra-rectal balloon. To summarise, milnacipran was efficacious in the writhing test, after acute and semi-chronic administration. This effect was confirmed after acute administration in a more specific model of colonic hypersensitivity induced by butyrate. This suggests that milnacipran has potential clinical application in the treatment of visceral pain, such as in irritable bowel syndrome, highly co-morbid with fibromyalgia.     

Tramadol has a better potency ratio relative to morphine in neuropathic than in nociceptive pain models

BACKGROUND AND OBJECTIVE: Treatment of neuropathic pain remains a challenge and the role of various analgesics in this setting is still debated. The effects of tramadol, an atypically acting analgesic with a combined opioid and monoaminergic mechanism of action, and morphine, a prototypical opioid, were tested in rat models of neuropathic and nociceptive pain. METHODS: Cold allodynia and mechanical hypersensitivity, symptoms of neuropathic pain, were studied in rat models of mononeuropathic pain. Cold allodynia was analyzed in the chronic constriction injury (CCI) model and mechanical hypersensitivity was analyzed in the spinal nerve ligation (SNL) model. Heat-induced rat tail-flick latencies were determined as measure for nociceptive pain. RESULTS: Cold allodynia and mechanical hypersensitivity were strongly attenuated with similar absolute potency after intravenous administration of tramadol and morphine. The doses of drug that were calculated to result in 50% pain inhibition (ED(50)) for tramadol and morphine were 2.1 and 0.9 mg/kg, respectively, in CCI rats and 4.3 and 3.7 mg/kg, respectively, in SNL rats. In the tail-flick assay of acute nociception, the potency of the two drugs differed markedly, as seen by ED(50) values of 5.5 and 0.7 mg/kg intravenously for tramadol and morphine, respectively. Accordingly, the analgesic potency ratio (ED(50) tramadol/ED(50) morphine) of both compounds differed in neuropathic (potency ratio 2.3 in CCI and 1.2 in SNL) and nociceptive pain models (potency ratio 7.8), suggesting a relative increase in potency of tramadol in neuropathic pain compared with nociceptive pain. CONCLUSION: The results of this study are consistent with clinical data supporting the efficacy of opioids in neuropathic pain conditions, and furthermore suggest an additional contribution of the monoaminergic mechanism of tramadol in the treatment of neuropathic pain states.     

Endogenous noradrenergic tone controls symptoms of allodynia in the spinal nerve ligation model of neuropathic pain

Endogenous inhibitory controls were studied in the spinal nerve ligation model of neuropathic pain. Atipamezole, a selective alpha2-adrenoceptor antagonist, produced both mechanical and cold allodynia in those rats which had not developed clear neuropathic symptoms. The same doses (50 microg i.t. or 1 mg/kg s.c.) did not increase the severity of symptoms in rats which had developed them. The opioid receptor antagonist naloxone (20 microg i.t. or 1 mg/kg s.c.) had no effect on the neuropathic symptoms. These results indicate that mechanical and cold allodynia are under endogenous noradrenergic rather than opioidergic control in this model of neuropathic pain.     

Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain

Rationale Neuropathic pain is characterised by hyperexcitability within nociceptive pathways that manifests behaviourally as allodynia and hyperalgesia and remains difficult to treat with standard analgesics. However, antidepressants have shown reasonable preclinical and clinical anti-nociceptive efficacy against signs and symptoms of neuropathic pain. Objectives To ascertain whether inhibition of serotonin (5-HT) and/or noradrenaline (NA) and/or dopamine (DA) re-uptake preferentially mediates superior anti-nociception in preclinical pain models. Methods The 5-HT re-uptake inhibitor fluoxetine (3–30 mg/kg), the NA re-uptake inhibitor reboxetine (3–30 mg/kg), the dual 5-HT and NA re-uptake inhibitor venlafaxine (3–100 mg/kg) and the dual DA and NA re-uptake inhibitor bupropion (3–30 mg/kg) were tested after intraperitoneal administration in rat models of acute, persistent and neuropathic pain. Results Reboxetine and venlafaxine dose-dependently attenuated second-phase flinching in the formalin test; fluoxetine attenuated flinching only at the highest dose tested, whereas bupropion was ineffective. In the chronic constriction injury (CCI) and spinal nerve ligation models of neuropathic pain, hindpaw mechanical allodynia was significantly attenuated by fluoxetine and particularly by bupropion. Reboxetine and venlafaxine were completely ineffective. In contrast, reboxetine and venlafaxine reversed thermal hyperalgesia in CCI rats, whereas bupropion and fluoxetine were either minimally effective or ineffective. Fluoxetine, reboxetine and venlafaxine transiently increased the tail-flick latency in uninjured animals. Anti-nociceptive doses of drugs had no effect on motor function. Conclusions Combined re-uptake inhibition of 5-HT and NA appears to confer a greater degree of anti-nociception in animal models of experimental pain than single mechanism of action inhibitors. The selective attenuation of mechanical allodynia by bupropion suggests that the additional re-uptake of DA may further augment 5-HT/NA re-uptake mediated anti-nociception after nerve injury.     

The antipsychotic drug,fluphenazine, effectively reverses mechanical allodynia in rat models of neuropathic pain

Rationale Fluphenazine is a potent antipsychotic drug used to treat schizophrenia and other psychotic symptoms. Its clinical benefit is mainly mediated by the antagonism of dopamine D2 receptors. We have recently discovered, however, that fluphenazine is also a potent sodium channel blocker, a property that may offer additional therapeutical indications, including analgesia. Objectives The present study sought to determine the analgesic effect of fluphenazine on neuropathic pain in animal models. Methods The effect of fluphenazine on mechanical allodynia was assessed in three animal neuropathic pain models, including spinal nerve ligation, chronic constriction nerve injury (CCI), and sural-spared sciatic nerve injury models. Results Systemic fluphenazine effectively attenuated mechanical allodynia in all three rat neuropathic pain models at doses (0.03–0.3 mg/kg) that approximate those used in rodent models of psychosis. In parallel with its in vivo antiallodynic effect, fluphenazine (3–30 μM) effectively suppressed the ectopic discharges in injured afferent fibers without affecting the propagation of action potentials evoked by electrical nerve stimulation in an ex vivo dorsal root ganglia (DRG)-nerve preparation excised from CCI rats. Furthermore, similar concentrations of fluphenazine significantly blocked sodium channels in DRG neurons. Conclusions The inhibitory action of fluphenazine on ectopic afferent discharges may be due to its ability to block voltage-gated sodium channels, and this may also provide a mechanistic basis for the drug’s antiallodynic effect in animal models of neuropathic pain. In summary, our study demonstrates that the classic antipsychotic drug fluphenazine has antiallodynic properties in multiple rodent models of nerve injury-induced neuropathic pain. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and treatment of neuropathic pain remains a challenge. The purpose of the present study was to examine the effect of ethosuximide, an anti-epileptic and relatively selective T-type calcium blocker and morphine, a prototypical opioid in the behavioral responses following the chronic constriction injury (CCI) model of neuropathic pain. Experiments were performed on eight groups (n=8) of male Sprague-Dawley rats (230-280 g). The animals were injected with saline, ethosuximide (100, 200, 300 mg/kg), morphine (4 mg/kg), and a combination of morphine (4 mg/kg) plus ethosuximide (100mg/kg, i.p.). The cold-and mechano-allodynia and thermal hyperalgesia were measured prior to surgery (the day 0) and 3, 5, 7, 14 and 21 days post surgery. Ethosuximide and morphine significantly decreased cold and mechano allodynia and thermal hyperalgesia. However, the co-administration of both drugs seems to be more effective than the ethosuximide or morphine alone on cold and mechano allodynia and thermal hyperalgesia .Our results suggest that ethosuximide block tactile and thermal hypersensitivity after the CCI model, also, ethosuximide potentiates the analgesic effects of morphine in neuropathic pain conditions and behavioral responses.     

Guggulipid of Commiphora mukul,with antiallodynic and antihyperalgesic activities in both sciatic nerve and spinal nerve ligation models of neuropathic pain

Abstract

Context: Guggulipid is a neutral fraction of ethyl acetate extract of gum resin of the tree Commiphora mukul Engl. (Burseraceae) and used in Ayurvedic medicine for treatment of neurological disorders.

Objectives: The present study was undertaken to assess the antiallodynic and antihyperalgesic activities of guggulipid in rats.

Materials and methods: The screening study included the CCI and L5–L6 SNL models of neuropathic pain. Guggulipid (100 and 50?mg/kg) or saline was administered intraperitoneally in a blinded, randomized manner from postoperative day (POD) 7 to 13. Paw withdrawal duration (PWD) to spontaneous pain, chemical allodynia and mechanical hyperalgesia and paw withdrawal latency (PWL) to mechanical allodynia and thermal hyperalgesia were tested before surgery, before and after guggulipid or saline administration (from POD7 to 13) and after the withdrawal of treatment (from POD14 to 20).

Results: The activity profiles of the different doses of guggulipid were found to vary with time. In CCI rats, guggulipid (100 and 50?mg/kg) significantly (p?<?0.05) reduced the spontaneous pain, mechanical allodynia and mechanical and thermal hyperalgesia responses and the LD₅₀ of guggulipid was 1600?mg/kg. In SNL rats, both doses of guggulipid were found to be ineffective in reversing the spontaneous pain but showing antiallodynic and antihyperalgesic activity.

Discussion and conclusion: The results demonstrated that guggulipid produce antinociception in the peripheral nerve injury (CCI and SNL) models of neuropathic pain. The underlying mechanisms are expected to be modulating microglial activation occurring due to peripheral nerve injury.     

Lacosamide, a new anti-epileptic, alleviates neuropathic pain-like behaviors in rat models of spinal cord or trigeminal nerve injury

The effect of systemic administration of lacosamide, a newly developed anti-epileptic, on neuropathic pain-like behaviors was examined in rats after ischemic injury to the infraorbital nerve or spinal cord using a photochemical method. In rats with infraorbital nerve injury, lacosamide reduced mechanical hypersensitivity and the effect was markedly stronger in female than in male rats. In spinal cord injured female rats 10-20 mg/kg lacosamide dose-dependently alleviated the mechanical and cold allodynia-like behaviors without causing motor impairments or marked sedation. Administration of lacosamide twice daily at 20 mg/kg for 7 days totally alleviated the allodynia-like state in spinally-injured rats with no tolerance. Following treatment cessation the cold and the static allodynia reappeared but the effect on dynamic mechanical allodynia (brushing) was maintained until day 11. Lacosamide also produced hypothermia at antinociceptive doses in rats. It is suggested that this novel compound may be useful as an analgesic for treating central and trigeminal neuropathic pain. Furthermore, there may be a gender difference to the effect of lacosamide with female rats being more responsive to the treatments.     

Lithium attenuates pain-related behavior in a rat model of neuropathic pain: possible involvement of opioid system

Lithium is a major drug for bipolar disorder and mania. Recently, many studies have shown the neuroprotective effect of lithium in different models of neurodegenerative diseases. The present study was carried out to examine the effect of lithium in a rat model of neuropathic pain induced by partial sciatic nerve ligation and the possible role of opioid system in this effect. To do so, animals received acute injection of saline, lithium (5, 10 and 15 mg/kg,) and naloxone (1 mg/kg) or the combination of naloxone (1 mg/kg) with lithium (10 mg/kg) intraperitoneally on the testing days. Thermal hyperalgesia, mechanical and cold allodynia were measured on the days 3, 5, 7, 10 and 14 after surgery. Lithium decreased thermal hyperalgesia scores with dose of 5, 10 and 15 mg/kg and cold and mechanical allodynia scores with dose of 10 and 15 mg/kg, significantly. The opioid antagonist naloxone prevented the effect of lithium on thermal hyperalgesia and mechanical allodynia while it did not show any effect on the acetone-induced cold allodynia. Our results suggest that lithium can be considered as a therapeutic potential for the treatment of some aspects of neuropathic pain and that the opioid system may be involved in the lithium-induced attenuation of thermal hyperalgesia and mechanical allodynia.     

Effects of intrathecal epigallocatechin gallate, an inhibitor of Toll-like receptor 4, on chronic neuropathic pain in rats

Numerous studies revealed that spinal inflammation and immune response play an important role in neuropathic pain. In this study, we investigated the effects of intrathecal injection of a Toll-like receptor (TLR4) inhibitor epigallocatechin gallate (EGCG) on neuropathic pain induced by chronic constriction injury of the sciatic nerve (CCI). A total of 120 rats were randomly assigned into 4 groups: sham-operated group, CCI group, CCI plus normal saline group and CCI plus EGCG group. CCI and sham surgeries were performed and both thermal hyperalgesia and mechanical allodynia were tested. Lumbar spinal cord was sampled and the mRNA and protein expressions of TLR4 and High Mobility Group 1 protein (HMGB1) were detected, the contents of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-10 (IL-10) were measured by ELISA, and immunohistochemistry for nuclear factor kappa B (NF-κB) was also carried out. When compared with the sham group, both mechanical and heat pain thresholds were significantly decreased, and the mRNA and protein expressions of TLR4 and HMGB1, the contents of TNF-α, IL-1β and IL-10 in the spinal cords and NF-κB expression in the spinal dorsal horn were markedly increased in CCI rats (P<0.05). After intrathecal injection of EGCG (1mg/kg) once daily from 1day before to 3days after CCI surgery, the expressions of TLR4, NF-κB, HMGB1, TNF-α and IL-1β were markedly decreased while the content of IL-10 in the spinal cord increased significantly accompanied by dramatical improvement of pain behaviors in CCI rats (P<0.05). These results show that the TLR4 signaling pathway plays an important role in the occurrence and development of neuropathic pain, and the therapy targeting TLR4 might be a novel strategy in the treatment of neuropathic pain.     

Curcumin exerts antinociceptive effects in a mouse model of neuropathic pain: descending monoamine system and opioid receptors are differentially involved

Curcumin, a phenolic compound present in Curcuma longa, has been reported to exert antinociceptive effects in some animal models, but the mechanisms remain to be elucidated. This work aimed to investigate the antinociceptive action of curcumin on neuropathic pain and the underlying mechanism(s). Chronic constriction injury (CCI), a canonical animal model of neuropathic pain, was produced by loosely ligating the sciatic nerve in mice and von Frey hair or hot plate test was used to assess mechanical allodynia or thermal hyperalgesia (to heat), respectively. Chronic, but not acute, curcumin treatment (5, 15 or 45 mg/kg, p.o., twice per day for three weeks) alleviated mechanical allodynia and thermal hyperalgesia in CCI mice, accompanied by increasing spinal monoamine (or metabolite) contents. Chemical ablation of descending noradrenaline (NA) by 6-hydroxydopamine (6-OHDA), or depletion of descending serotonin by p-chlorophenylalanine (PCPA), abolished curcumin's antinociceptive effect on mechanical allodynia or thermal hyperalgesia, respectively. The anti-allodynic action of curcumin on mechanical stimuli was totally blocked by chronic co-treatment with the β(2)-adrenoceptor antagonist ICI 118,551, or by acute co-treatment with the delta-opioid receptor antagonist naltrindole. Meanwhile, co-treatment with the 5-HT(1A) receptor antagonist WAY-100635 chronically, or with the irreversible mu-opioid receptor antangonist β-funaltrexamine acutely, completely abrogated the anti-hyperalgesic action of curcumin on thermal stimuli. Collectively, these findings indicate that the descending monoamine system (coupled with spinal β(2)-adrenoceptor and 5-HT(1A) receptor) is critical for the modality-specific antinociceptive effect of curcumin in neuropathic pain. Delta- and mu-opioid receptors are likely rendered as downstream targets, accordingly. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.