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.     

Post-injury repeated administrations of minocycline improve the antinociceptive effect of morphine in chronic constriction injury model of neuropathic pain in rat

It is confirmed that pharmacological attenuation of glial cells can alleviate neuropathic pain by lowering proinflammatory cytokine expression. The present study tries to confirm that post-injury administration of glia inhibitor, minocycline, can attenuate the neuropathic pain symptoms and improves the efficacy of morphine anti-nociception in chronic constriction injury (CCI). Male Wistar rats (230-270 g) underwent surgery for induction CCI model of neuropathy. For assessment of the thermal hyperalgesia and mechanical allodynia after CCI induction, morphine (2.5, 5, 7.5, 10 and 15 mg/kg; s.c.) and saline were administered on post-operative days (PODs) 0, 6 and 14. Hargreaves and Von-Frey tests were performed before and 30 min after morphine administration, respectively. The results showed significant decrease in antinociceptive effect of morphine on POD 6 compared to POD 0 only at the dose of 5 mg/kg. On the other hand, on POD 14 the antinociceptive effect of morphine (5, 7.5, 10 and 15 mg/kg) significantly decreased in comparison with POD 0. In another set of experiments, animals received minocycline (10, 20 and 40 mg/kg; i.p.) for eight days from POD 6 to 13 and then the antinociceptive effect of single dose of morphine 5 mg/kg was tested on POD 14. Behavioral tests showed that minocycline (40 mg/kg) could effectively attenuate the thermal hyperalgesia and mechanical allodynia on POD 13. Moreover, minocycline (40, 20 mg/kg) improved the anti-hyperalgesic, and minocycline (40 mg/kg) improved the anti-allodynic effects of morphine 5 mg/kg on POD 14. It seems that the reduction of antinociceptive effect of morphine after CCI may be mediated through glia activation. Modulation of glial activity by minocycline can attenuate CCI-induced neuropathic pain. It is also shown that repeated post-injury administration of minocycline improves the antinociceptive effect of morphine in neuropathic pain.     

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.     

Antinociceptive Effect of Cyperi rhizoma and Corydalis tuber Extracts on Neuropathic Pain in Rats

In this study, we examined the antinociceptive effect of Cyperi rhizoma (CR) and Corydalis tuber (CT) extracts using a chronic constriction injury-induced neuropathic pain rat model. After the ligation of sciatic nerve, neuropathic pain behavior such as mechanical allodynia and thermal hyperalgesia were rapidly induced and maintained for 1 month. Repeated treatment of CR or CT (per oral, 10 or 30 mg/kg, twice a day) was performed either in induction (day 0~5) or maintenance (day 14~19) period of neuropathic pain state. Treatment of CR or CT at doses of 30 mg/kg in the induction and maintenance periods significantly decreased the nerve injury-induced mechanical allodynia. In addition, CR and CT at doses of 10 or 30 mg/kg alleviated thermal heat hyperalgesia when they were treated in the maintenance period. Finally, CR or CT (30 mg/kg) treated during the induction period remarkably reduced the nerve injury-induced phosphorylation of NMDA receptor NR1 subunit (pNR1) in the spinal dorsal horn. Results of this study suggest that extracts from CR and CT may be useful to alleviate neuropathic pain.     

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.     

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.     

鞘内注射米诺四环素对慢性坐骨神经结扎大鼠机械痛敏和热痛敏的影响

目的观察鞘内注射小胶质细胞抑制剂米诺四环素对慢性坐骨神经结扎大鼠机械痛敏和热痛敏的影响。方法所有大鼠术前8d鞘内置管,用机械缩足反射阈值和热缩足潜伏期来分别评价大鼠机械痛敏和热痛敏。前给药组:生理盐水10μl或米诺四环素50μg,于坐骨神经结扎前1d开始持续到术后1d(每天2次)鞘内注射,机械缩足反射阈值和热缩足潜伏期分别于术前2d,术后1,3,5,7,14d测定;后给药组:坐骨神经结扎后7d,鞘内注射1次生理盐水10μl或米诺四环素50μg,其对机械缩足反射阈值和热缩足潜伏期的影响分别于给药后0.5、1、2、4、8h测定。结果CCI大鼠从术后1d形成稳定的热痛敏和机械痛敏,前鞘内注射米诺四环素明显增加CCI大鼠MWT和TWL(P<0.05,P<0.01),相反,后鞘内注射米诺四环素对CCI大鼠MWT和TWL无明显影响。结论前鞘内注射米诺四环素明显抑制CCI大鼠机械痛敏和热痛敏,提示小胶质细胞的活化参与慢性坐骨神经结扎引发神经病理痛的形成。     

Antinociceptive efficacy of lacosamide in rat models for tumor- and chemotherapy-induced cancer pain

Pain is the most common physical symptom of cancer patients, with most patients experiencing more than one site of pain. Current treatments lack full efficacy. Based on the need for new approaches in that field the effect of systemic administration of lacosamide (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037), a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates, was examined in rats in a tumor-induced bone cancer pain model and in a chemotherapy-induced neuropathic pain model. Lacosamide inhibited tactile allodynia (20, 40 mg/kg, i.p.), thermal hyperalgesia (30 mg/kg) and reduced weight-bearing differences (40 mg/kg) in the rat model of bone cancer pain induced by injection of MRMT-1 cells into the tibia. Morphine (5 mg/kg, s.c) was effective inhibiting tactile allodynia and weight bearing but could not reduce thermal hyperalgesia. In the vincristine-induced neuropathic pain model, lacosamide attenuated thermal allodynia, on the cold plate (4 degrees C), at 10 and 30 mg/kg, and in the warm (38 degrees C) and hot plate (52 degrees C) even at 3 mg/kg. Tactile allodynia and mechanical hyperalgesia were inhibited by lacosamide at 10 and 30 mg/kg. In contrast to lacosamide, morphine (3 mg/kg, s.c.) had no effect on mechanical hyperalgesia. Lacosamide is effective as an analgesic in a bone cancer pain model as well as chemotherapy-induced neuropathic pain model in animals and even reduced hyperalgesia where morphine did not (3 or 5 mg/kg, s.c.).     

Dose-related neuropathic and anti-neuropathic effects of simvastatin in vincristine-induced neuropathic pain in rats

The present study explores the role of simvastatin in vincristine-induced neuropathic pain, which was induced by administering vincristine (100 µg/kg i.p.) for 10 days (two 5 day cycles with 2 days pause). Pain was assessed by determining mechanical hyperalgesia, mechanical dynamic allodynia, heat hyperalgesia and cold allodynia. Biochemically, myeloperoxidase (MPO) activity was measured along with serum cholesterol levels. Simvastatin (7.5, 15 and 30 mg/kg) was administered for 14 days after administration of vincristine. Simvastatin (7.5 and 15 mg/kg) reversed vincristine-induced neuropathic pain and attenuated vincristine-induced increase in MPO, without altering cholesterol levels. Simvastatin at higher dose (30 mg/kg) did not alter neuropathic pain despite decreasing MPO levels. Furthermore, administration of simvastatin (30 mg/kg i.p.) in vincristine treated rats as well as it's per se administration in normal rats reduced cholesterol levels. Per se administration of simvastatin in normal rats produced neuropathic pain. It is concluded that simvastatin attenuates neuropathic pain only at lower doses with no reduction in cholesterol levels and anti-inflammatory effects may possibly reverse neuropathic pain. However, despite reducing inflammation, simvastatin did not confer beneficial effects at higher doses at which there is reduction in cholesterol levels, suggesting the critical role of cholesterol in neuropathic pain induction.     

Attenuating effect of hydroalcoholic extract of Acorus calamus in vincristine-induced painful neuropathy in rats

The present study was designed to investigate the attenuating potential of hydroalcoholic extract of Acorus calamus in vincristine-induced neuropathic pain in rats. Vincristine (50?μg/kg, i.p. for 10 consecutive days) was administered to induce neuropathic pain in rats. Hot plate, plantar, Randall-Selitto and von Frey hair tests were performed to assess the degree of thermal and mechanical hyperalgesia and mechanical allodynia, respectively, at different time intervals, viz., 0, 1, 3, 6, 9, 12, 15, 18 and 21 days. Tissue myeloperoxidase, superoxide anion and total calcium levels were determined after day 21to assess biochemical alterations. Histopathological evaluations were also performed. Hydroalcoholic extract of Acorus calamus (HAE-AC, 100 and 200?mg/kg, p.o.) and pregabalin (10?mg/kg, p.o.) were administered for 14 consecutive days. Vincristine significantly induced peripheral neuropathic pain, manifested in thermal and mechanical hyperalgesia and mechanical allodynia, along with rises in the levels of superoxide anion, total calcium and myeloperoxidase activity. Moreover, significant histological changes were also observed. HAE-AC attenuated vincristine-induced development of painful behavioural, biochemical and histological changes in a dose-dependent manner comparable to that of pregabalin, serving as positive control. Acorus calamus prevented vincristine-induced neuropathic pain, which may be attributed to its anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory actions, among others.     

The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain

Trigeminal neuralgia is a disorder of paroxysmal and severely disabling facial pain and continues to be a real therapeutic challenge. At present there are few effective drugs. Here we have evaluated the effects of the synthetic cannabinoid WIN 55,212-2 on mechanical allodynia and thermal hyperalgesia in a rat model of trigeminal neuropathic pain produced by a chronic constriction injury (CCI) of the infraorbital branch of the trigeminal nerve (ION). Relative to sham operation controls, rats with the CCI-ION consistently displayed hyperresponsiveness to von Frey filament and heat stimulation of the vibrissal pad. Both mechanical allodynia and thermal hyperalgesia are seen both ipsilateral and contralateral to the side of nerve injury, but is significantly more severe ipsilaterally. Administration of WIN 55,212-2 (0.3-5 mg/kg i.p.) dose-dependently increased the mechanical and heat withdrawal thresholds. WIN 55,212-2 (0.3-3 mg/kg i.p.) produced no significant motor deficits in animals using the rotarod test. The effect of WIN 55,212-2 was mimicked by cannabinoid CB1 receptor agonist HU 210 and was antagonized by CB1 receptor antagonist AM 251, but not by CB2 receptor antagonist AM 630 or vanilloid receptor 1 antagonist capsazepine, suggesting the involvement of CB1 receptors. CCI-ION also induced a time-dependent upregulation of CB1 receptors primarily within the ipsilateral superficial laminae of the trigeminal caudal nucleus revealed by both Western blot and immunohistochemistry. Taken together, these results suggest that cannabinoids may be a useful therapeutic approach for the clinical management of trigeminal neuropathic pain disorders.     

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'.     

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.     

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.     

Resveratrol attenuates neuropathic pain through balancing pro-inflammatory and anti-inflammatory cytokines release in mice

Anti-inflammatory activity of resveratrol has been widely studied, while its beneficial effect on the management of neuropathic pain, a refractory chronic syndrome with pro-inflammation implicated in, is very little investigated. In the present study, the effects of different doses and various time window of administration of resveratrol were explored in a neuropathic mouse model of chronic constriction injury (CCI) of the sciatic nerve. It was demonstrated that pretreatment of resveratrol (5, 10, 20 and 40 mg/kg) for 7 consecutive days before CCI did not alleviate neuropathic pain, while it clearly relieved the pain when administrated after CCI and such pain relief effect was more pronounced when administrated right after the peak of pain symptom at day 7 after CCI, as evidenced by the alleviation of thermal hyperalgesia and mechanical allodynia. Such a beneficial effect of resveratrol was in a dose-dependent manner. Mechanistic study showed that resveratrol repressed the expression of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, and promoted the expression of anti-inflammatory cytokine IL-10 at the same time, which was further confirmed in a cell model of microglia. It was also shown that neuropathic pain inversely correlated with pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, but not with anti-inflammatory cytokine IL-10 in all experimental mice from Spearman correlation coefficient. Our study reveals that resveratrol displays a significant neuropathic pain relief effect and paved a way for novel treatment of chronic pain.     

肉毒毒素A对慢性坐骨神经结扎大鼠机械痛敏和热痛敏的影响

目的探讨肉毒毒素A(botulinum toxin type A,BoNT-A)后处理对神经病理性疼痛大鼠疼痛行为学的影响。方法建立SD大鼠右侧慢性坐骨神经结扎模型(chronic con-striction injury of sciatic nerve,CCI)。CCI术后d3始,CCI同侧肢体足底注射BoNT-A7.5、15、30U·kg-1或等容积生理盐水,或对侧肢体足底注射BoNT-A15或30U·kg-1。分别于术前、术后1、3、5、7、14d,测定大鼠的机械缩足反射阈值(MWT)和热缩足潜伏期(TWL)。结果CCI手术同侧足底皮下注射BoNT-A可以增加大鼠的MWT和TWL,对侧应用BoNT-A对MWT和TWL无影响。结论BoNT-A可以通过局部作用减轻CCI手术同侧肢体的机械痛敏和热痛敏。     

Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain

Milnacipran, a serotonin/norepinephrine reuptake inhibitor (SNRI), has shown efficacy against several chronic pain conditions, including fibromyalgia. Here, we evaluated, in rats, its anti-allodynic effects following acute or sub-chronic treatment in a model of neuropathic pain (chronic constriction injury, CCI, of the sciatic nerve). Amitriptyline, a tricyclic antidepressant active pre-clinically and clinically against neuropathic pains, was added as a comparison compound. Upon acute i.p. administration, milnacipran was potently efficacious in the CCI model. It significantly reduced thermal allodynia in the cold (4°C) plate test (MED=2.5mg/kg), and attenuated mechanical allodynia in the von Frey filaments test (MED=10mg/kg). Given sub-chronically (7day, b.i.d.), milnacipran was effective at 10mg/kgi.p. in both tests. Acute amitriptyline (10mg/kgi.p.) was efficacious against mechanical, but less so against cold allodynia; under sub-chronic conditions, it was only active against mechanical allodynia. These data show that milnacipran is as efficacious as the reference compound amitriptyline in a pre-clinical model of injury-induced neuropathy, and demonstrate for the first time that it is active acutely and sub-chronically against cold allodynia. They also suggest that milnacipran has the potential to alleviate allodynia associated with nerve compression-induced neuropathic pain in the clinic (for example following discal hernia, avulsion or cancer-induced tissue damage).     

Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats

Recent studies have shown that activation of the cannabinoid CB(1) receptor by synthetic agonists, and pharmacological elevation of endocannabinoid levels, suppress hyperalgesia and allodynia in animal models of neuropathic pain. However, the concentrations of endocannabinoids in the nervous tissues involved in pain transmission during neuropathic pain have never been measured. Here we have determined the levels of anandamide and 2-arachidonoylglycerol (2-AG), as well as of the analgesic anandamide congener, palmitoylethanolamide (PEA), in three brain areas involved in nociception, i.e. the dorsal raphe (DR), periaqueductal grey (PAG) and rostral ventral medulla (RVM), as well as in the spinal cord (SC), following chronic constriction injury (CCI) of the sciatic nerve in the rat, in comparison with sham-operated rats. After 3 days from CCI, anandamide or 2-AG levels were significantly enhanced only in the SC or PAG, respectively. After 7 days from CCI, when thermal hyperalgesia and mechanical allodynia are maximal, a strong (1.3-3-fold) increase of both anandamide and 2-AG levels was observed in the PAG, RVM and SC. At this time point, anandamide, but not 2-AG, levels were also enhanced in the DR. PEA levels were significantly decreased in the SC after 3 days, and in the DR and RVM after 7 days from CCI. These data indicate that anandamide and 2-AG, operating at both spinal and supra-spinal levels, are up-regulated during CCI of the sciatic nerve, possibly to inhibit pain. Yet to be developed substances that inhibit both endocannabinoid and PEA inactivation might be useful for the treatment of neuropathic pain.     

Role of kinin B1 and B2 receptors in a rat model of neuropathic pain

Kinin B1 and B2 receptor (R) gene expression (mRNA) is increased in the sensory system after peripheral nerve injury. This study measured the densities of B1R and B2R binding sites in the spinal cord and dorsal root ganglia (DRG) by quantitative autoradiography, and evaluated the effects of two selective non-peptide antagonists at B1R (LF22-0542) and B2R (LF16-0687) on pain behavior after partial ligation of the left sciatic nerve. Increases of B1R binding sites were seen in superficial laminae of the ipsi- and contralateral spinal cord at 2 and 14 days while B2R binding sites were increased on the ipsilateral side at 2 days and on both sides at 14 days. In DRG, B1R and B2R binding sites were significantly increased at 2 days (ipsilateral) and 14 days on both sides. Whereas tactile allodynia started to develop progressively from 2 to 25 days post-ligation, the occurrence of cold allodynia and thermal hyperalgesia became significant from day 8 and day 14 post-ligation, respectively. At day 21 after sciatic nerve ligation, thermal hyperalgesia was blocked by LF22-0542 (10 mg/kg, s.c.) and LF16-0687 (3 mg/kg, s.c.), yet both antagonists had no effect on tactile and cold allodynia. Data highlight the implication of both kinin receptors in thermal hyperalgesia but not in tactile and cold allodynia associated with peripheral nerve injury. Hence LF22-0542 and LF16-0687 present therapeutic potential for the treatment of some aspects of neuropathic pain.