Chronic Neuropathic Pain In Rats Research Articles

Gooderoside A from Anoectochilus elatus attenuates acute and chronic pains by inhibiting NO/cGMP and IRAK4/IRAK1/TAK1 signaling pathways

Ethnopharmacological relevanceAnoectochilus elatus Lindl. was traditionally used for pain treatment and Gooderoside A (GA) was regarded as its principal constituent. Aim of the studyTo investigate whether GA can be responsible for the antinociceptive activity of A. elatus and explore its underlying mechanism. Materials and methodsAcetic acid-induced abdominal writhing and tail flick tests were employed to evaluate the antinociceptive activity of ethanolic extract of A. elatus (EEA) and GA. Formalin test was used to ascertain the antinociceptive pattern of GA. Entobarbital sodium induced sleep test was adopted to exclude its hypnotic effect, while open-field test was performed to rule out its motor impairment effect. Chronic constriction injury (CCI)-induced neuropathic pain in rats was developed to evaluate its efficacy on neuropathic pain, and BV-2 cells were used to explore the underlying mechanism. ResultsEEA and GA, significantly inhibited chemical and thermal nociception. GA suppressed nociception in formalin test in both phase I and II, whereas methylene blue and L-NAME partially reversed its efficacy. GA located inner and slightly blocked sodium channel current, and did not show any hypnotic effect or motor impairment effect. Crucially, GA markedly attenuated chronic neuropathic pain in rats, inhibited the phosphorylation of IRAK4, IRAK1 and TAK1, and suppressed MAPKs pathway in BV-2 cells. ConclusionGA relieved acute and chronic pains in vivo. The mechanism of action involves the blocking of NO/cGMP and IRAK4/IRAK1/TAK1 pathways. These results suggested GA may be a promising candidate for antinociceptive drug development.

Effects of Fe2+ Nanoparticles on Pain Responses and Neural Oscillation Following Chronic Neuropathic Pain in Rats.

Neuropathic pain, a chronic pain condition caused by nerve damage either of the peripheral or central nervous system, responds poorly to current drug treatments. The present study aimed to investigate the analgesic and anxiolytic effect of Fe2+ nanoparticles on chronic constriction injury of sciatic nerve (CCI)-induced neuropathic pain in rats. We also assessed the effects of Fe2+ nanoparticles on brain rhythmical oscillation in rats with neuropathic pain. The CCI model was induced by four loose ligations of the left sciatic nerve. Male Wistar rats were divided into four groups: control, sham, CCI, and CCI+Fe2+ nanoparticle (1 mg/kg). The Fe2+ nanoparticle was administered by gavage on the day of CCI surgery (day 0) and daily (once a day) for 21 consecutive days after CCI surgery. Behavioral studies were conducted on days -1, 3, 7, 14, and 21 after CCI. An acetone test and elevated plus maze were performed to evaluate cold allodynia and induced anxiety-like responses, respectively. A field test was conducted to evaluate innate anxiety-like behaviors. In addition, an electrophysiological study was carried out on day 21 after CCI to assess the effects of drugs on brain wave power. Application of Fe2+ significantly reduced cold allodynia in all tested days after CCI, compared to the CCI group. The obtained data demonstrated that Fe2+ nanoparticle gavage caused analgesic and anxiolytic effects on all experimental days after CCI, compared to the CCI group. The CCI surgery significantly disturbed theta, alpha, and beta power in the brain. The application of Fe2+ nanoparticles could not significantly change brain wave power. It is suggested that Fe2+ nanoparticle has analgesic and anxiolytic effects during chronic neuropathic pain in rats. Furthermore, the CCI surgery effectively disturbed brain theta, alpha, and beta power. Nonetheless, the application of Fe2+ nanoparticles could not change deregulated brain oscillation in rats.

Effect of electrical and chemical (activation versus inactivation) stimulation of the infralimbic division of the medial prefrontal cortex in rats with chronic neuropathic pain.

Neuropathic pain (NP) represents a complex disorder with sensory, cognitive, and emotional symptoms. The medial prefrontal cortex (mPFC) takes critical regulatory roles and may change functionally and morphologically during chronic NP. There needs to be a complete understanding of the neurophysiological and psychopharmacological bases of the NP phenomenon. This study aimed to investigate the participation of the infralimbic division (IFL) of the mPFC in chronic NP, as well as the role of the N-methyl-D-aspartic acid receptor (NMDAr) in the elaboration of chronic NP. Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21days of chronic constriction injury (CCI) of the sciatic nerve or Sham-procedure ("false operated"). Electrical neurostimulation of the IFL/mPFC was performed by low-frequency stimuli (20 μA, 100Hz) applied for 15s by deep brain stimulation (DBS) device 21days after CCI. Either cobalt chloride (CoCl2 at 1.0mM/200 nL), NMDAr agonist (at 0.25, 1.0, and 2.0nmol/200 nL) or physiological saline (200 nL) was administered into the IFL/mPFC. CoCl2 administrationin the IFL cortex did not alter either mechanical or cold allodynia. DBS stimulation of the IFL cortex decreased mechanical allodynia in CCI rats. Chemical stimulation of the IFL cortex by an NMDA agonist (at 2.0nmol) decreased mechanical allodynia. NMDA at any dose (0.25, 1.0, and 2.0nmol) reduced the flicking/licking duration in the cold test. These findings suggest that the IFL/mPFC and the NMDAr of the neocortex are involved in attenuating chronic NP in rats.

Expression of concern: Analgesic effects of TLR4/NF-κB signaling pathway inhibition on chronic neuropathic pain in rats following chronic constriction injury of the sciatic nerve [Biomedicine & Pharmacotherapy 107 (2018) 526–533

Expression of concern: Analgesic effects of TLR4/NF-κB signaling pathway inhibition on chronic neuropathic pain in rats following chronic constriction injury of the sciatic nerve [Biomedicine & Pharmacotherapy 107 (2018) 526–533

Targeting 5-HT2A receptors and Kv7 channels in PFC to attenuate chronic neuropathic pain in rats using a spared nerve injury model

Chronic pain remains a disabling disease with limited therapeutic options. Pyramidal neurons in the prefrontal cortex (PFC) express excitatory Gq-coupled 5-HT2A receptors (5-HT2AR) and their effector system, the inhibitory Kv7 ion channel. While recent publications show these cells innervate brainstem regions important for regulating pain, the cellular mechanisms underlying the transition to chronic pain are not well understood. The present study examined whether local blockade of 5-HT2AR or enhanced Kv7 ion channel activity in the PFC would attenuate mechanical allodynia associated with spared nerve injury (SNI) in rats. Following SNI, we show that inhibition of PFC 5-HT2ARs with M100907 or opening of PFC Kv7 channels with retigabine reduced mechanical allodynia. Parallel proteomic and RNAScope experiments evaluated 5-HT2AR/Kv7 channel protein and mRNA. Our results support the role of 5-HT2ARs and Kv7 channels in the PFC in the maintenance of chronic pain.

Licochalcone A Attenuates Chronic Neuropathic Pain in Rats by Inhibiting Microglia Activation and Inflammation.

Immune response plays a vital role in the pathogenesis of neuropathic pain. Immune response-targeted therapy becomes an effective strategy for treating neuropathic pain. Licochalcone A (Lic-A) possesses anti-inflammatory and neuroprotective effects. However, the potential of Lic-A to attenuate neuropathic pain has not been well explored. To investigate the protective effect and evaluate the underlying mechanism of Lic-A against neuropathic pain in a rat model. Chronic constriction injury (CCI) surgery was employed in rats to establish neuropathic pain model. Rats were intraperitoneally administrated with Lic-A (1.25, 2.50 and 5.00mg/kg) twice daily. Mechanical withdrawal threshold and thermal withdrawal latency were used to evaluate neuropathic pain. After administration, the lumbar spinal cord enlargement of rats was collected for ELISA, Western blot and immunofluorescence analysis. Mechanical withdrawal threshold and thermal withdrawal latency results showed that Lic-A significantly attenuated CCI-evoked neuropathic pain in dose-dependent manner. Lic-A administration also effectively blocked microglia activation. Moreover, Lic-A suppressed p38 phosphorylation and the release of inflammatory factors such as tumor necrosis factor-α, interleukin-1 and interleukin-6. Our findings provide evidence that Lic-A may have the potential to attenuate CCI-evoked neuropathic pain in rats by inhibiting microglia activation and inflammatory response.

Optogenetic stimulation of the motor cortex alleviates neuropathic pain in rats of infraorbital nerve injury with/without CGRP knock-down

BackgroundPrevious studies have reported that electrical stimulation of the motor cortex is effective in reducing trigeminal neuropathic pain; however, the effects of optical motor cortex stimulation remain unclear.ObjectiveThe present study aimed to investigate whether optical stimulation of the primary motor cortex can modulate chronic neuropathic pain in rats with infraorbital nerve constriction injury.MethodsAnimals were randomly divided into a trigeminal neuralgia group, a sham group, and a control group. Trigeminal neuropathic pain was generated via constriction of the infraorbital nerve and animals were treated via selective inhibition of calcitonin gene-related peptide in the trigeminal ganglion. We assessed alterations in behavioral responses in the pre-stimulation, stimulation, and post-stimulation conditions. In vivo extracellular recordings were obtained from the ventral posteromedial nucleus of the thalamus, and viral and α-CGRP expression were investigated in the primary motor cortex and trigeminal ganglion, respectively.ResultsWe found that optogenetic stimulation significantly improved pain behaviors in the trigeminal neuralgia animals and it provided more significant improvement with inhibited α-CGRP state than active α-CGRP state. Electrophysiological recordings revealed decreases in abnormal thalamic firing during the stimulation-on condition.ConclusionOur findings suggest that optical motor cortex stimulation can alleviate pain behaviors in a rat model of trigeminal neuropathic pain. Transmission of trigeminal pain signals can be modulated via knock-down of α-CGRP and optical motor cortex stimulation.

The Primary Motor Cortex Stimulation Attenuates Cold Allodynia in a Chronic Peripheral Neuropathic Pain Condition in <i>Rattus norvegicus</i>

Background: The primary motor cortex (M1) stimulation (MCS) is a useful tool for attenuation of the peripheral neuropathic pain in patients with pharmacologically refractory pain. Furthermore, that neurological procedure may also cause antinociception in rodents with neuropathic pain. Cold allodynia is a frequent clinical finding in patients with neuropathic pain, then, we evaluated if an adapted model of neuropathy induced by chronic constriction injury (CCI) of the ischiadicus nervus (sciatic nerve) produces cold allodynia in an animal model of chronic pain. In addition, we also investigated the effect of the electrical stimulation of the M1 on chronic neuropathic pain condition in laboratory animals. Methods: Male Wistar rats were used. An adapted model of peripheral mononeuropathy induced by CCI was carried out by placing a single loose ligature around the right sciatic nerve. The acetone test was used to evaluate the cold allodynia in CCI or Sham (without ligature) rats. The MCS (M1) was performed at low-frequency (20 μA, 100 Hz) during 15 s by deep brain stimulation (DBS-Thomas Recording device) 21 days after CCI or Sham procedures. The cold allodynia was measured before and immediately after the neurostimulation of M1 in the following time-window: 0, 15 and 30 min after MCS. Results: Cold allodynia threshold increased in animals with chronic neuropathic pain submitted to the acetone test 21 days after the CCI surgery. The M1-stimulation by DBS procedure decreased the cold allodynia immediately and until 30 min after M1-stimulation in rats with chronic neuropathic pain. Conclusion: The current proposal for a CCI model by a single loose ligature of the sciatic nerve can be employed as an experimental model of chronic neuropathic pain in rats submitted to peripheral nervous system injury. The M1-stimulation produced antinociception in rats with chronic neuropathic pain. Thus, we reinforced that the MCS decreases cold allodynia in laboratory animals submitted to persistent sciatic nerve constriction and can be a more reasonable procedure for the treatment of chronic intractable neuropathic pain.

RETRACTED: Analgesic effects of TLR4/NF-κB signaling pathway inhibition on chronic neuropathic pain in rats following chronic constriction injury of the sciatic nerve

Chronic neuropathic pain (CNP) is attributed to a lesion or disease of the somatosensory system, may be derived from the peripheral and central system. Recent study revealed that spinal cord stimulation attenuated CNP by inhibiting TLR4/NF-κB signaling pathway. The present study focuses on the potential analgesic effects of TLR4/NF-κB signaling pathway on CNP in a rat model of chronic constriction injury (CCI). We successfully established the rat model of CCI by Bennett method, and then inhibited the TLR4/NF-κB signaling pathway in rat models. Next, we measured the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) 0D, 2D, 6D, 8D and 12D after operation respectively. MTS510 100 mg/kg, an inhibitor of TLR4, was intrathecal injected into rats after 6D, 8D and 12D after operation. The experiment lasted for 12 days, and then the rats were sacrificed to collect the spinal cord tissues. Protein and mRNA expression levels of toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB), glial cell line-derived neurotrophic factor (GDNF), glial fibrillary acidic protein (GFAP) and nerve growth factor (NGF) were detected by western blot analysis and RT-qPCR, respectively. Immunohistochemistry was performed to detect GDNF, GFAP and NGF expression. With the prolongation of MTS510 treatment time, MWT and TWL were increased and finally, the MWT and TWL were close to the baseline level. The levels of TLR4, NF-κB, GDNF, and GFAP as well as NGF increased in rats treated with CCI + Immunoglobulin G1 (IgG1) or CCI + MTS510, suggesting the model establishment was successful. Besides, with the prolongation of MTS510 treatment time, the protein level and mRNA expression of NF-kB, GDNF, GFAP and NGF decreased in rats treated with CCI + IgG1 or CCI + MTS510. Moreover, the GDNF, GFAP and NGF expression in spinal cord tissue in rats treated with CCI + IgG1 or CCI + MTS510 increased obviously, while the GDNF, GFAP and NGF expression decreased in spinal cord tissue in rats treated with CCI + IgG1 or CCI + MTS510 after MTS510 treatment. Collectively, this study defines the role of TLR4 and NF-κB, and inhibition of TLR4/NF-κB signaling pathway might contribute to the alleviation of CNP and improvement of MWT and TWL in a rat model of CCI. Additionally, the results obtained from the study provided a promising basis that could aid as an experimental basis for the potential treatment of TLR4/NF-κB signaling pathway.

Effects of Repetitive Transcranial Magnetic Stimulation on Astrocytes Proliferation and nNOS Expression in Neuropathic Pain Rats.

This study investigated the effects of different frequencies of repetitive transcranial magnetic stimulation (rTMS) on chronic neuropathic pain in rats. The behavior of rats with experimental chronic neuropathic pain was observed, and the expression of neuronal nitric oxide synthase (nNOS) in the ipsilateral dorsal root ganglions (DRGs) and the activation and proliferation of astrocytes in the ipsilateral spinal dorsal horn were detected. Thirty-two male Sprague-Dawley rats were randomly divided into four groups: sham-operated group, sham-rTMS group, 1 Hz group and 20 Hz group (8 rats in each group). Chronic constriction nerve injury induced by sciatic nerve ligation was made to establish the models of the chronic neuropathic pain in rats except those in the sham-operated group. Then we applied different frequencies of rTMS to the primary motor cortex (Ml) contralateral to the pain side once daily for 10 consecutive days. Pain behavior scores were observed before and after treatment. Western blot analysis was used to detect the expression of nNOS in ipsilateral L4-6 DRGs. Double immunofluorescent labeling for glial fibrillary acidic protein (GFAP) and 5-bromo-2- deoxyuridine (BrdU) was employed to observe the activation and proliferation of astrocytes in the ipsilateral L4-6 spinal dorsal horn. After rTMS treatment, the spontaneous pain behavior scores were significantly lower in the 20 Hz group than those in the sham-rTMS group (P<0.05). Moreover, the brush-evoked pain behavior scores were significantly lower in the 20 Hz group than those in the sham-rTMS and 1 Hz group (P<0.05), suggesting that the spontaneous pain and brush-evoked pain in the 20 Hz group were significantly alleviated. Western blot analysis revealed that the expression of nNOS in ipsilateral L4-6 DRGs was significantly decreased in the 20 Hz group as compared with the sham-rTMS group and the 1 Hz group (P<0.01) after rTMS treatment. Double immunofluorescence suggested that the expression of GFAP and the co-localization with BrdU in astrocytes were less in the sham-operated group than those in the sham-rTMS group and the 1 Hz group in L4-6 spinal dorsal horn ipsilateral to the neuropathic pain. After rTMS treatment, the expression of GFAP and the co-localization with BrdU decreased in the 20 Hz group as compared with the sham-rTMS group and the 1 Hz group (P<0.05). In addition, the alleviation degree of spontaneous pain and brush-evoked pain in the 20 Hz group was negatively correlated with the expression of nNOS in ipsilateral DRGs and the number of GFAP/BrdU co-labelled astrocytes in L4-6 spinal dorsal horn ipsilateral to the neuropathic pain (P<0.05). It was suggested that high-frequency rTMS may relieve neuropathic pain through down-regulating the overexpression of nNOS in ipsilateral DRGs and inhibiting the activity and proliferation of astrocytes in L4-6 spinal dorsal horn ipsilateral to the neuropathic pain.

Parameter Optimization Analysis of Prolonged Analgesia Effect of tDCS on Neuropathic Pain Rats.

Background: Transcranial direct current stimulation (tDCS) is widely used to treat human nerve disorders and neuropathic pain by modulating the excitability of cortex. The effectiveness of tDCS is influenced by its stimulation parameters, but there have been no systematic studies to help guide the selection of different parameters.Objective: This study aims to assess the effects of tDCS of primary motor cortex (M1) on chronic neuropathic pain in rats and to test for the optimal parameter combinations for analgesia.Methods: Using the chronic neuropathic pain models of chronic constriction injury (CCI), we measured pain thresholds before and after anodal-tDCS (A-tDCS) using different parameter conditions, including stimulation intensity, stimulation time, intervention time and electrode located (ipsilateral or contralateral M1 of the ligated paw on male/female CCI models).Results: Following the application of A-tDCS over M1, we observed that the antinociceptive effects were depended on different parameters. First, we found that repetitive A-tDCS had a longer analgesic effect than single stimulus, and both ipsilateral-tDCS (ip-tDCS) and contralateral-tDCS (con-tDCS) produce a long-lasting analgesic effect on neuropathic pain. Second, the antinociceptive effects were intensity-dependent and time-dependent, high intensities worked better than low intensities and long stimulus durations worked better than short stimulus durations. Third, timing of the intervention after injury affected the stimulation outcome, early use of tDCS was an effective method to prevent the development of pain, and more frequent intervention induced more analgesia in CCI rats, finally, similar antinociceptive effects of con- and ip-tDCS were observed in both sexes of CCI rats.Conclusion: Optimized protocols of tDCS for treating antinociceptive effects were developed. These findings should be taken into consideration when using tDCS to produce analgesic effects in clinical applications.

P.1.d.002 - Differential microglial inflammatory responses in the spinal cord and brain towards chronic neuropathic pain in rats

P.1.d.002 - Differential microglial inflammatory responses in the spinal cord and brain towards chronic neuropathic pain in rats

Water-soluble lipopolymer delivery of N-methyl-D-aspartic acid receptor 2B siRNA relieves chronic neuropathic pain in rats

Water-soluble lipopolymer delivery of N-methyl-D-aspartic acid receptor 2B siRNA relieves chronic neuropathic pain in rats

Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain.

One of the main dose-limiting complications of the chemotherapeutic agent oxaliplatin (OXL) is painful neuropathy. Glial activation and nociceptive sensitization may be responsible for the mechanism of neuropathic pain. The Traditional Chinese Medicine (TCM) Wen-luo-tong (WLT) has been widely used in China to treat chemotherapy induced neuropathic pain. However, there is no study on the effects of WLT on spinal glial activation induced by OXL. In this study, a rat model of OXL-induced chronic neuropathic pain was established and WLT was administrated. Pain behavioral tests and morphometric examination of dorsal root ganglia (DRG) were conducted. Glial fibrillary acidic protein (GFAP) immunostaining was performed, glial activation was evaluated, and the excitatory neurotransmitter substance P (SP) and glial-derived proinflammatory cytokine tumor necrosis factor-α (TNF-α) were analyzed. WLT treatment alleviated OXL-induced mechanical allodynia and mechanical hyperalgesia. Changes in the somatic, nuclear, and nucleolar areas of neurons in DRG were prevented. In the spinal dorsal horn, hypertrophy and activation of GFAP-positive astrocytes were averted, and the level of GFAP mRNA decreased significantly. Additionally, TNF-α mRNA and protein levels decreased. Collectively, these results indicate that WLT reversed both glial activation in the spinal dorsal horn and nociceptive sensitization during OXL-induced chronic neuropathic pain in rats.

Differential microglial inflammatory responses in the spinal cord and brain towards the chronic neuropathic pain in rats

Accumulating evidences suggest the involvement of immune cells, especially microglia, in development of the central nervous system and persistence of neuropathic pain after peripheral nerve injuries in adulthood, but the exact roles that microglia play are unclear. In this study, by utilizing an efficient and reproducible multicolor flow cytometry-based approach, we quantitatively evaluated both microgliosis and microglial activation in the lumbar spinal cord (SC), amygdala and prefrontal cortex (PFC) of adult male Hannover-Wistar rats in response to a chronic neuropathic pain induced by ligation of the tibial and common peroneal nerves (known as the spared nerve injury (SNI) model). When comparing the SNI and sham-operated rats, we observed increased microgliosis in the ipsi-lateral lumbar SC on both post-operative day (POD) 7 and 21, and a milder increase in the contralateral side of SC on POD21. Regarding microglial activation, we unexpectedly found increased numbers of the anti-inflammatory type of microglia (CD172a+MHCII-/+) in the ipsilateral lumbar SC but an opposite change in the contra-lateral PFC on POD21. Moreover, these inflammatory responses were accompanied by the mechanical allodynia and anxiety-related behaviors of the SNI rats. Our results suggest that microglia in the SC and brain are differentially activated by the spinal nerve injury, and that microglial responses in the SC do not necessarily develop into a proinflammatory prototype as many literature suggested.

(252) Broad and highly organized changes in DNA methylation in prefrontal cortex and T cells in a model of chronic neuropathic pain in rats

Chronic pain is associated with changes in brain anatomy and function and long-term alternations in gene expression. One mechanism underlying stable, long-term programming of gene expression is DNA methylation, a dynamic ongoing process that responds to environment and experiences throughout the life cycle. Our previous data showed a decrease in global DNA methylation in the prefrontal cortex (PFC) in a model of chronic neuropathic pain. In this study, neuropathic pain (or sham surgery controls) was induced in rats using the spared nerve injury (SNI).

Analgesic Effect of Harpagophytum procumbens on Postoperative and Neuropathic Pain in Rats

Harpagophytum procumbens, also known as Devil’s Claw, has historically been used to treat a wide range of conditions, including pain and arthritis. The study was designed to investigate whether H. procumbens extracts exhibit analgesic effects in plantar incision and spared nerve injury (SNI) rats. The whole procedure was performed on male SD rats. To evaluate pain-related behavior, we performed the mechanical withdrawal threshold (MWT) test measured by von Frey filaments. Pain-related behavior was also determined through analysis of ultrasonic vocalization (USVs). The results of experiments showed MWT values of the group that was treated with 300 mg/kg H. procumbens extract increased significantly; on the contrary, the number of 22–27 kHz USVs of the treated group was reduced at 6 h and 24 h after plantar incision operation. After 21 days of continuous treatment with H. procumbens extracts at 300 mg/kg, the treated group showed significantly alleviated SNI-induced hypersensitivity responses by MWT, compared with the control group. These results suggest that H. procumbens extracts have potential analgesic effects in the case of acute postoperative pain and chronic neuropathic pain in rats.

Curcumin Could Prevent the Development of Chronic Neuropathic Pain in Rats with Peripheral Nerve Injury

BackgroundPeripheral nerve injury results in chronic neuropathic pain characterized by allodynia and/or spontaneous pain. It has been suggested that activation of mitogen-activated protein kinases such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) contribute to the neuropathic pain. ObjectivesWe investigated if curcumin could prevent the development of neuropathic pain in rats with chronic constriction injury (CCI) of the sciatic nerve. MethodsThe animals were divided into 3 groups. In the curcumin treatment group (n = 10), curcumin (50 mg/kg/d PO) was administered once daily from 1 day before CCI to 7 days after CCI. The rats in the sham group (n = 10) and CCI group (n = 10) received a control vehicle. The mechanical allodynia was assessed using von Frey at 1, 3, 5, and 7 days after nerve injury. Western blots were used to evaluate the levels of p-ERK, p-JNK, and phosphorylation of NR1 (p-NR1) subunits of N-methyl-D-aspartate in the spinal dorsal root ganglion. ResultsIn the CCI group, mechanical allodynia was observed during 7 days after nerve injury. However, curcumin treatment reversed the mechanical allodynia 7 days after nerve ligation. There were no differences in the expression of p-ERK, p-JNK, and p-NR1 between the sham and curcumin groups. However, the expression of p-ERK, p-JNK, and p-NR1 in the CCI group were higher than the sham group and curcumin group, respectively (P < 0.05). ConclusionsTreatment with curcumin during the early stages of peripheral neuropathy can prevent the development of chronic neuropathic pain.

Antiallodynia and antihyperalgesia effects of ceftriaxone in treatment of chronic neuropathic pain in rats

Neuropathic pain is a chronic and disabling syndrome with complex pathogenesis. It has been suggested that the function of glutamate transporters (GLTs) has a major role in the development of neuropathic pain. This study was performed to evaluate various doses of ceftriaxone, a beta-lactam antibiotic, on the symptoms in the rat chronic constriction injury (CCI) model of neuropathic pain. This drug has been recently introduced as a selective up-regulator and activator of GLT1. Neuropathy was induced in adult male Wistar rats and animals were treated intraperitoneally with 100-400 mg/kg of ceftriaxone for seven consecutive days immediately after surgery. Gabapentin (100 mg/kg, i.p.) was used as a reference drug. von Frey filaments, acetone drop and radiant heat methods were used to assess mechanical allodynia, thermal allodynia and thermal hyperalgesia, respectively. Ceftriaxone in the repeated doses for 7 days showed significant antiallodynic and antihyperalgesic effects especially at a dose of 200 mg/kg twice a day. The results suggest that ceftriaxone as a modulator of glutamate uptake could provide beneficial effects in the treatment of chronic neuropathic pain, especially allodynia that is less sensitive to the most available drugs.

Clonidine and dexmedetomidine's effect on the altered expressions of growth associated protein-43 mRNA in rat dorsal root ganglion during the development of chronic neuropathic pain

To explore the effects of α(2) adrenergic receptor (α(2)AR) agonists clonidine and dexmedetomidine on the injury model of peripheral nerve chronic constriction in rats. A total of 72 male SD rats weighing 180 - 250 g were randomly divided into 4 groups (n = 18 each). In sham operation group (S), the right sciatic nerves were exposed but not ligated. But, in other groups, four ligatures were placed around the right sciatic nerve according to the Bennett's method. From the instant after operation, 0.4 mg × kg(-1)× d(-1) clonidine and 50.0 µg × kg(-1)× d(-1) were injected intraperitoneally into the clonidine group (CL) and dexmedetomidine group (Dex) daily. And the same volume of normal saline was injected into the S and CCI groups (C) respectively. Mechanical and thermal pain thresholds were measured by paw withdrawal latencies at Day 1 pre-operation and Day 3, 7 and 14 post-operation. After that, the L(4-6) dorsal root ganglions to chronic constriction injured sciatic nerves were harvested. Reverse transcription-polymerase chain reaction (RT-PCR) and agarose gel electrophoresis were used to examine the expression of GAP-43 mRNA. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of groups C, CL and Dex markedly decreased and the expression of GAP-43 mRNA in dorsal root ganglions significantly increased at Days 3, 7 and 14 post-operation versus those at pre-operation and group S (P < 0.05). TWL and MWT of groups CL and Dex at Days 7 and 14 post-operation significantly increased while the expression of GAP-43 mRNA in dorsal root ganglions markedly decreased versus those of group C (P < 0.05). TWL and MWT of group Dex were significantly higher while the expression of GAP-43 mRNA in dorsal root ganglions was lower than those of group CL (P < 0.05). Compared with Day 3, TWL and MWT of groups C, CL and Dex markedly decreased while the expression of GAP-43 mRNA significantly increased in dorsal root ganglions at Day 7 (P < 0.05). Compared with Day 7, TWL and MWT of groups CL and Dex markedly increased while the expression of GAP-43 mRNA in dorsal root ganglions significantly decreased at Day 14 (P < 0.05). Clonidine and dexmedetomidine both show evident analgesic effects on chronic neuropathic pain in rats probably through a reduction of nerve regeneration. But dexmedetomidine has a better efficacy due to of its high selectivity of α(2)AR.