Ligation Of Sciatic Nerve In Rats Research Articles

Alamandine injection in the periaqueductal gray and rostral ventromedial medulla attenuates allodynia induced by sciatic nerve ligation in rats

Alamandine, a peptide known to interact with Mas-related G protein-coupled receptor subtype D (MrgD), has been implicated in moderating inflammatory signals. MrgD receptors are abundantly found in pain transmission pathways, but the role of alamandine/MrgD in pain modulation has not been thoroughly explored. This study aimed to investigate the effects of alamandine (10, 40, and 100 pmol) in a rat model of allodynia induced by sciatic nerve ligation, with a specific focus on examining the involvement of MrgD receptors, NMDAR1, and serotonin transporter (SERT) in the ventrolateral periaqueductal gray (vlPAG) and rostral ventromedial medulla (RVM).Microinjection of alamandine into the vlPAG at a dose of 100 pmol and into the RVM at doses of 40 and 100 pmol resulted in a significant increase in paw withdrawal threshold (PWT). Additionally, co-administration of D-Pro7-Ang-(1–7) at 50 pmol, an MrgD receptor antagonist, effectively blocked the analgesic effects of alamandine.Immunofluorescence analysis confirmed the presence of MrgD receptors in both the vlPAG and RVM regions. Importantly, an upregulation of MrgD receptor expression was observed following allodynia induction, suggesting a potential compensatory mechanism in response to pain. Our findings support the co-localization of MrgD receptors with NMDAR1 in vlPAG neurons, suggesting their ability to initiate analgesic pathways similar to those activated by NMDA receptors in the vlPAG. Furthermore, our results underscore a significant co-localization of MrgD receptors with the SERT in the RVM, underscoring their potential impact on serotonergic neurons involved in promoting analgesic effects.

Behavioral and receptor expression studies on the primary somatosensory cortex and anterior cingulate cortex oxytocin involvement in modulation of sensory and affective dimensions of neuropathic pain induced by partial sciatic nerve ligation in rats

BackgroundBrain cortical areas are involved in processing of sensory, affective and cognitive aspects of pain. In the present study, microinjection effects of oxytocin and L-368,899 (an oxytocin receptor antagonist) into the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC) were investigated on sensory and affective aspects of neuropathic pain. MethodsNeuropathic pain was induced by partial sciatic nerve ligation (PSNL). Seven days later, right and left sides of S1 and ACC were surgically implanted with guide cannulas. Sensory (day 14) and affective (day 17) dimensions were recorded using von Frey filaments and place escape avoidance paradigm, respectively. The S1 and ACC oxytocin receptor protein expression were also determined. ResultsThe S1 and ACC oxytocin suppressed PSNL-induced mechanical allodynia, whereas PSNL-induced aversion was attenuated by ACC oxytocin. In the S1, alone L-368,899 with no effect on aversion increased mechanical allodynia, whereas, in the ACC, this treatment increased both mechanical allodynia and aversion. Pre-treatment with L-368,899 prevented oxytocin-induced anti-allodynia and anti-aversion. Oxytocin and L-368,899 did not alter mechanical allodynia in intact and sham groups. All the above-mentioned treatments did not change crossing number. The density of oxytocin receptors in the S1 and ACC of PSNL group was increased 1.5-2 folds in comparison to intact and sham groups. ConclusionsThe results of the present study explained that the ACC and S1 oxytocin ameliorated sensory component of neuropathic pain, whereas affective component was attenuated only by ACC oxytocin. These effects might be related to the PSNL-increased oxytocin receptor expression in the S1 and ACC.

Alleviation of neuropathic pain by trazodone in rats

Neuropathic pain is generally characterised by an abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia). The present study was designed to investigate the effect of trazodone (5mg/kg and 10mg/kg) on peripheral neuropathic pain induced by partial sciatic nerve ligation in rats. Mechanical hyperalgesia, cold allodynia and thermal hyperalgesia were assessed by performing the pinprick, acetone, and hot plate tests, respectively. Biochemically, lipid peroxidation level and total calcium levels were measured. However, trazodone administration (5 and 10 mg/ kg i.p.) for 21days significantly diminished partial sciatic nerve ligation-induced neuropathic pain along with areduction in oxidative stress and calcium levels. The results of the present study suggest that trazodone is effective in attenuating partial sciatic nerve ligation-inducedpainful neuropathic states, which may be attributed to decreased oxidative stress and calcium levels.

Stimulating muscarinic M1 receptors in the anterior cingulate cortex reduces mechanical hypersensitivity via GABAergic transmission in nerve injury rats

Cholinergic systems modulate synaptic transmission across the neuraxis and play an important role in higher brain function including cognition, arousal and nociception. The anterior cingulate cortex (ACC) is a fundamental brain region for nociception and chronic pain, and receives cholinergic projections mainly from basal forebrain. Recently, we found that the activation of muscarinic M1 receptors in the ACC produced antinociceptive behavior in response to mechanical stimulation. However, it has not been tested whether stimulating muscarinic receptors in the ACC can reduce mechanical hypersensitivity in animal models of chronic pain.Here, we tested whether the activation of muscarinic M1 receptors in the ACC can alleviate mechanical hypersensitivity in a nerve injury model. The activation of muscarinic M1/M4 receptors by McN-A-343 injected into the contralateral side of the ACC, but not into the ventral posterolateral nucleus, was found to dose-dependently reduce mechanical hypersensitivity 7 days following partial sciatic nerve ligation in rats. The reduction of mechanical hypersensitivity by McN-A-343, was blocked by a selective muscarinic M1 antagonist, but not a M4 receptor antagonist. Importantly, the nerve injury model did not change the protein expression of muscarinic M1 receptors in the ACC. Additionally, a type A γ-aminobutyric acid (GABAA) receptor agonist injected into the ACC reduced the mechanical hypersensitivity in this injury model. Finally, a GABAA receptor antagonist blocked the reduction of mechanical hypersensitivity by McN-A-343 in the injury model. Collectively, these results suggest that activations of muscarinic M1 receptors in the ACC reduce nerve injury-induced mechanical hypersensitivity through GABAergic transmission via GABAA receptors.

Respective pharmacological features of neuropathic-like pain evoked by intrathecal BDNF versus sciatic nerve ligation in rats

Numerous reported data support the idea that Brain Derived Neurotrophic Factor (BDNF) is critically involved in both depression and comorbid pain. The possible direct effect of BDNF on pain mechanisms was assessed here and compared with behavioral/neurobiological features of neuropathic pain caused by chronic constriction injury to the sciatic nerve (CCI-SN). Sprague–Dawley male rats were either injected intrathecally with BDNF (3.0ng i.t.) or subjected to unilateral CCI-SN. Their respective responses to anti-hyperalgesic drugs were assessed using the Randall–Selitto test and both immunohistochemical and RT-qPCR approaches were used to investigate molecular/cellular mechanisms underlying hyperalgesia in both models. Long lasting hyperalgesia and allodynia were induced by i.t. BDNF in intact healthy rats like those found after CCI-SN. Acute treatment with the BDNF-TrkB receptor antagonist cyclotraxin B completely prevented i.t. BDNF-induced hyperalgesia and partially reversed this symptom in both BDNF-pretreated and CCI-SN lesioned rats. Acute administration of the anticonvulsant pregabalin, the NMDA receptor antagonist ketamine, the opioid analgesics morphine and tapentadol or the antidepressant agomelatine also transiently reversed hyperalgesia in both i.t. BDNF injected- and CCI-SN lesioned-rats. Marked induction of microglia activation markers (OX42, Iba1, P-p38), proinflammatory cytokine IL-6, NMDA receptor subunit NR2B and BDNF was found in spinal cord and/or dorsal root ganglia of CCI-SN rats. A long lasting spinal BDNF overexpression was also observed in BDNF i.t. rats, indicating an autocrine self-induction, with downstream long lasting TrkB-mediated neuropathic-like pain. Accordingly, TrkB blockade appeared as a relevant approach to alleviate not only i.t. BDNF- but also nerve lesion-evoked neuropathic pain.

Differential roles of hippocampal glutamatergic receptors in neuropathic anxiety-like behavior after partial sciatic nerve ligation in rats.

BackgroundNeuropathic pain evoked by nerve injury is frequently accompanied by deterioration of emotional behaviors, but the underlying signaling mechanisms remain elusive. Glutamate (Glu) is the major mediator of excitatory synaptic transmission throughout the brain, and abnormal activity of the glutamatergic system has been implicated in the pathophysiology of pain and associated emotional comorbidities. In this study we used the partial sciatic nerve ligation (PSNL) model of neuropathic pain in rats to characterize the development of anxiety-like behavior, the expression of glutamatergic receptors, and the phosphorylation of extracellular signal-regulated kinase (ERK) in the hippocampus, the region that encodes memories related to emotions.ResultsWe found that the mechanical withdrawal threshold was significantly reduced and an anxiety-like behavior was increased as determined via open field tests and elevated plus-maze tests at 28 days after injury. No significant differences were found in the ratio of sucrose preference and immobility time detected by sucrose preference tests and forced swimming tests respectively, possibly due to the timing factor. The expression of N-methyl-D-aspartate (NMDA) receptor subtypes NR1 and NR2B, but not NR2A, GluR1, or GluR2 (the main subtype of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] receptor) in the hippocampus of injured rats was significantly reduced. Moreover, PSNL resulted in decreased phosphorylation of ERK1/2 in the hippocampus. Intriguingly, treatment with D-serine (a co-agonist of NMDA receptor, 1 g/kg intraperitoneally) reduced the anxiety-like behavior but not the mechanical hypersensitivity induced by PSNL.ConclusionsPSNL can induce significant anxiety-like but not depression-like behavior, and trigger down-regulation of NMDA but not AMPA receptors in the hippocampus at 28 days after injury.

Analgesic properties of a peripherally acting and GalR2 receptor-preferring galanin analog in inflammatory, neuropathic, and acute pain models.

There are ongoing efforts to develop pain therapeutics with novel mechanisms of action that avoid common side effects associated with other analgesics. The anticonvulsant neuropeptide galanin is a potent regulator of neuronal excitability and has a well established role in pain modulation, making it a potential target for novel therapies. Our previous efforts focused on improving blood-brain-barrier penetration and enhancing the metabolic stability of galanin analogs to protect against seizures. More recently, we designed peripherally acting galanin analogs that reduce pain-related behaviors by acting in the periphery and exhibit preferential binding toward galanin receptor (GalR)2 over GalR1. In this study, we report preclinical studies of a monodisperse oligoethylene glycol-containing galanin analog, NAX 409-9 (previously reported as GalR2-dPEG24), in rodent analgesic and safety models. Results obtained with NAX 409-9 in these tests were compared with the representative analgesics gabapentin, ibuprofen, acetylsalicylic acid, acetaminophen, and morphine. In mice that received intraplantar carrageenan, NAX 409-9 increased paw withdrawal latency with an ED50 of 6.6 mg/kg i.p. NAX 409-9 also increased the paw withdrawal threshold to mechanical stimulation following partial sciatic nerve ligation in rats (2 mg/kg). Conversely, NAX 409-9 had no effect in the tail flick or hot plate assays (up to 24 mg/kg). Importantly, NAX 409-9 did not negatively affect gastrointestinal motility (4-20 mg/kg), respiratory rate (40-80 mg/kg), or bleed time (20 mg/kg). These studies illustrate that this nonbrain-penetrating galanin analog reduces pain behaviors in several models and does not produce some of the dose-limiting toxicities associated with other analgesics.

Dexmedetomidine reduced astrocyte connexin 43 and attenuated neuropathic pain induced by partial sciatic nerve ligation in rats (LB503)

Dexmedetomidine(DEX) has been shown to attenuate neuropathic pain (NP), but the mechanism is unclear. Astrocytes connexin 43(Cx43) is increased in subjects with NP and plays an important role in the development and maintenance of NP (Glia. 2012;60(11):1660‐70). We thus investigated the role of astroglia Cx43 in DEX‐induced anti‐nociceptive effects in rats with NP. Peripheral NP was induced by partial sciatic nerve ligation (PSNL) in SD rats. After 10 days of inducing NP, DEX was intrathecally administrated for 5 days and ipsilateral mechanical allodynia and thermal hyperalgesia were examined by Von Frey Test and Hargreaves Test. Compared with control rats, PSNL induced significant ipsilateral mechanical allodynia and thermal hyperalgesia (P<0.05) that were coincident with enhanced Cx43 and increased astroglia activation in ipsilateral lumbosacral dorsal spinal cord. DEX inhibited astroglia Cx43 expression and attenuated NP (P<0.05 vs. control). Cx43 gene knock‐down did not significantly further enhance DEX mediated attenuation of NP. We concluded that astroglia Cx43 plays a critical role in DEX mediated anti‐nociceptive effects in rats with NP.Grant Funding Source: Supported by Departmental development fund Supported by Science and Technology Planning Project of Guangdong Province(2010B060900089). The authors are grateful to Pro.Huang for critical design and revise. huanghs5480@163.com

Synergistic efficacy of tramadol and meloxicam on alleviation of pain and selected immunological variables after sciatic nerve ligation in rats

This study was performed for evaluation of the effect of pre-operative and post-operative administration of tramadol and meloxicam combination on hyperalgesia and selected inflammatory responses after sciatic nerve ligation in rats. An eighty male Wistar rats (Rattus norvegicus) were divided into two groups; preemptive analgesic group, in which the rats received analgesic agents 30min before nerve ligation. Also the nociceptive pain tests were detected before surgery, 120 and 150min post-analgesics injection. The serum IL-6 and PGE-2 concentrations were detected at 150min post-analgesics injection. The second group was post-operative analgesic group; in which the rats exposed for the nerve ligation then the rats received analgesic agents at 5 till 11day’s post-operative. Behavioral tests were performed before surgery and on each even days post-operatively. The serum concentration of IL-6 and PGE-2 was determined at 5, 10 and 14days post-operative. Tramadol and meloxicam combination had a statistically significant (P<0.05) reverse hyperalgesia while preemptive administration of tramadol and meloxicam significantly decreased (P<0.05) serum IL-6 production compared to post-operative treatment. In conclusion, the preemptive combination of tramadol and meloxicam produced a potent analgesic effect post nerve ligation in rats.

Upregulation of the GABA-transporter GAT-1 in the spinal cord contributes to pain behaviour in experimental neuropathy

Sciatic nerve ligation in rats (chronic constriction injury (CCI)) induces signs and symptoms that mimic human conditions of neuropathy. The central mechanisms that have been implicated in the pathogenesis of neuropathic pain include increased neuronal excitability, possibly a consequence of decreased availability of spinal GABA. GABA availability is regulated by the presence of the GABA-transporters (GATs). This study investigates the dorsal horn expression of the transporter GAT-1 and its functional involvement towards pain behaviour in the CCI model. Male Lewis rats (total n=37) were subjected to CCI or to a sham procedure. A sub-group of animals was treated with the GAT-1 antagonist NO-711. Behavioural testing was performed pre-surgery and at 7 days post-surgery. Testing included evaluation of mechanical allodynia using Von Frey filaments, thermal allodynia with a hot-plate test and observational testing of spontaneous pain behaviour. Subsequently, spinal protein expression of GAT-1 was assessed by Western blotting. Animals were sacrificed 7 days following surgery. CCI markedly increased mechanical and thermal allodynia and spontaneous pain behaviour after 7 days, while the sham procedure did not. GAT-1 was increased in spinal cord homogenates compared contralateral to the ligation side after 7 days. NO-711 treatment significantly reduced all tested pain behaviour. These data provide evidence for possible functional involvement of GAT-1 in the development of experimental neuropathic pain. The latter can be derived from observed analgesic effects of early treatment with NO-711, a selective GAT-1 inhibitor. The obtained insights support the clinical employment of GAT-1 inhibitors to treat neuropathic pain.

Direct evidence for the involvement of endogenous β-endorphin in the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state

Recent clinical studies have demonstrated that when opioids are used to control pain, psychological dependence is not a major problem. In this study, we further investigated the mechanisms that underlie the suppression of opioid reward under neuropathic pain in rodents. Sciatic nerve ligation suppressed a place preference induced by the selective mu-opioid receptor agonist [d-Ala(2), N-MePhe(4), Gly-ol(5)] enkephalin (DAMGO) and reduced both the increase in the level of extracellular dopamine by s.c. morphine in the nucleus accumbens and guanosine-5'-o-(3-[(35)S]thio) triphosphate ([(35)S]GTPgammaS) binding to membranes of the ventral tegmental area (VTA) induced by DAMGO. These effects were eliminated in mice that lacked the beta-endorphin gene. Furthermore, intra-VTA injection of a specific antibody to the endogenous mu-opioid peptide beta-endorphin reversed the suppression of the DAMGO-induced rewarding effect by sciatic nerve ligation in rats. These results provide molecular evidence that nerve injury results in the continuous release of endogenous beta-endorphin to cause the dysfunction of mu-opioid receptors in the VTA. This phenomenon could explain the mechanism that underlies the suppression of opioid reward under a neuropathic pain-like state.

Inhibition of the Cyclic Adenosine Monophosphate Pathway Attenuates Neuropathic Pain and Reduces Phosphorylation of Cyclic Adenosine Monophosphate Response Element-Binding in the Spinal Cord After Partial Sciatic Nerve Ligation in Rats

Recent reports have identified a role for cyclic adenosine monophosphate (cAMP) transduction in nociceptive processing. Spinal activation of the cAMP induced gene transcription through the activation of protein kinase A and cAMP response element-binding protein (CREB). Intrathecal injection of protein kinase A inhibitor reversed the mechanical hyperalgesia, whereas injection of CREB antisense attenuated tactile allodynia caused by partial sciatic nerve ligation (PSNL) in rats. In the present study, we aimed to assess the effects of spinal cAMP transduction on the nociceptive processing in a chronic neuropathic pain model. PSNL was performed in male Sprague-Dawley rats 1 wk after intrathecal catheterization. Nociception to mechanical and thermal stimuli was assessed at the hindpaw 2 h, 3, 7, and 14 days after PSNL. The effects of adenylate cyclase inhibitor, SQ22536 (0.7 mumol, intrathecal) on these nociceptions were evaluated. Changes in the expression and immunoreactivity of CREB and its phosphorylated proteins (CREB-IR and pCREB-IR) in the dorsal horn of the spinal cord were also measured. The expression of CREB-IR and pCREB-IR proteins was shown to increase for 2 wk after PSNL. The increase in pCREB was partially reversed by the blockade of the cAMP pathway in the early 3 days, with a parallel increase in mechanical and thermal withdrawal thresholds. These results revealed the possible contribution of an increase in pCREB to the PSNL-induced tactile allodynia and thermal hyperalgesia. Modulation of the cAMP pathway may be clinically relevant if early intervention can be achieved in patients with chronic neuropathic pain.

Alteration of P2X3 expression in dorsal root ganglia after sciatic nerve ligation*

Background The expressions of P2X3 receptor in dorsal root ganglia (DRG) after different peripheral nerve injuries are diverse. It indicates the different roles of P2X3 in different models-caused neuropathologic pains. Objective To observe the expressions of P2X3 in corresponding DRG after sciatic nerve ligation in rats. Design Controlled observation experiment. Setting Department of Morphology, Hunan Traditional Chinese Medical College; Department of Human Anatomy and Neurobiology, Xiangya Medical College, Central South University. Materials Thirty-five healthy adult SD rats of clean grade an d either gender, weighing (200±20)g, were involved. According to the random digits table, the involved rats were randomized into 3 groups: normal group ( n =5), sham-operated group ( n =5) and experimental group ( n =25). The experimental group were subdivided into 3,7,14,21,28 days groups according to different surviving time after operation, 5 rats at each time point. Polyclonal rabbit anti-P2X3 antibody (ABCAM company); biotinylated goat anti-rabbit IgG (Zhongshanjingqiao Biotechnical Co., Ltd., Beijing); Motic fluorescence microscope (Motic, Germany). Methods The experiments were carried out in the Department of Human Anatomy and Neurobiology, Xiangya Medical College, Central South University from June to December 2006. ▪ Rats of experimental group were created into models by ligation of right sciatic nerve according to the method of Seltzer et al. Left sciatic nerve was used as self-control. As for rats in the sham-operated group, ligation of sciatic nerve was omitted, but other procedures were the same as those in the experimental group. Rats of normal group were untouched. ▪ Rats of the normal group and sham-operated group survived for 14 days separately, and those of experimental group survived for corresponding time. After being deeply anesthetized by intraperitoneal injection of over-dose sodium pentobarbital, the rats of experimental group were transcardially perfused. L 4-6 corresponding DRG connected to sciatic nerve were taken for preparing transverse sections serially. ▪ P2X3 expression in L 4-6 DRG was detected by immunohistochemistry, immunofluorescence and image analysis techniques. Main outcome measures P2X3 expression in L 4-6 DRG of rats in each group. Results Thirty-five SD rats were involved in the final analysis. ▪ P2X3 expression in DRG: In normal DRG of rats, there were abundant P2X3 immuno-positive small- and medium-sized primary sensory neurons, especially the small ones, which mostly received the input from C fibers. There were only a few large neurons expressing P2X3. The immuno-positive products mostly were located in the cytoplasm and processes. The expression of P2X3 had a slight but significant decrease in ipsilateral L 4-6 DRG 3 days after sciatic nerve ligation, and a decreasing tendency was observed with the elongation of time. At 28 days, the expression had not returned to base line, and still maintained at a low level. ▪ P2X3 immuno-positive gray scale in DRG: P2X3 immuno-positive gray scale in ipsilateral side L 4-6 DRG was 117.74±2.38,129.12±4.86,133.56±3.79,148.75±6.90 and 150.49±5.15, respectively at 3,7,14, 21 and 28 days after sciatic nerve ligation, which was significantly higher than that in the normal group and sham-operated group (105.11±3.52,104.22±5.41, F =78.861, P < 0.05), also significantly higher than that in the contralateral side (105.53±5.85,108.54±3.70,104.07±4.16,106.55±2.02,106.29±5.19, t =3.48-13.95, P < 0.05); There were no significant differences when comparing sham-operated group or contralateral side at each time point with normal group ( P > 0.05) Conclusion P2X3 is significantly down regulated in L 4-6 DRG after sciatic nerve ligation. It may exert certain effects in neuropathic pain.

Effects of intrathecal and i.c.v. administration of neuropeptide W-23 and neuropeptide B on the mechanical allodynia induced by partial sciatic nerve ligation in rats

Neuropeptide W-23 and neuropeptide B are each an endogenous ligand of GPR7. GPR7 mRNA has been detected in regions of the cortex, the hippocampus, the hypothalamus and the spinal cord in the rat. GPR7 receptor has structural features in common with both opioid and somatostatin receptors. In the present study, the effects of intrathecal and i.c.v. application of neuropeptide W-23 and neuropeptide B on the level of mechanical allodynia induced by partial sciatic nerve ligation were tested in rats. The level of mechanical allodynia was measured using von Frey filaments. Intrathecal injection of either neuropeptide W-23 or neuropeptide B attenuated the level of mechanical allodynia in a dose dependent manner at a dose between 0.1 and 10μg, but i.c.v. injection of either neuropeptide W-23 or neuropeptide B had no effect on the level of mechanical allodynia at a dose between 3 and 30μg. The effect of intrathecal administration of either 10μg of neuropeptide W-23 or 10μg of neuropeptide B was not antagonized by i.p. injection of 1mg/kg of naloxone. Immunohistochemical examination revealed that neuropeptide W-23 was expressed mainly in the small- to medium-sized neuronal profiles in the dorsal root ganglion and that partial sciatic nerve injury decreased the percentage of neuropeptide W-23-like immunoreactivity positive neuronal profiles that were labeled by IB4. These data suggest that neuropeptide W-23 is involved in the nociceptive transmission in spinal cord and that both spinally-applied neuropeptide W-23 and spinally-applied neuropeptide B produce anti-allodynic effects in the partial sciatic nerve ligation model in rat.

Stability of neuropathic pain symptoms in partial sciatic nerve ligation in rats is affected by suture material

Many factors affect the development of neuropathic pain behavior in animal models. In this letter, we describe the differences in the development of neuropathic pain behavior observed when the partial sciatic nerve ligation (PNL) is performed with either a synthetic silk or chromic catgut ligation. To characterize nociceptive changes over time after surgery, neutral plate, hot plate, Von Frey, pinprick, acetone spray and cold plate testing was performed. The results indicated that a chromic catgut ligature caused cold allodynia, chemical hyperreactivity, mechanical hyperalgesia and hypersensitivity that remained present for the entire 56 days post-surgical observation period. With the synthetic silk ligature, comparable functional deficits were present in the initial phase after surgery, but several of these deficits diminished over time 21–28 days post-surgery. In conclusion, performing the PNL using chromic catgut suture thread gives rise to more robust sensory deficits than when synthetic silk is used. Therefore, the material that is used for the ligature in the partial sciatic ligation model has an effect on the outcome of the observed sensory abnormalities.

Contralateral, ipsilateral and bilateral treatments with the κ-opioid receptor agonist U-50,488H in mononeuropathic rats

The effect of repeated contralateral administration of the κ-opioid receptor agonist U-50,488H ( trans-(±)-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate) on nociceptive behaviour was investigated and compared with ipsilateral and bilateral treatments in a rat model of peripheral unilateral neuropathy (chronic constriction of the common sciatic nerve). Administration of 0.3 mg U-50,488H into the contralateral hindpaw on days 6 and 10 after induction of mononeuropathy increased hindpaw withdrawal latency to mechanical but not to thermal stimulation compared to saline-treated rats. No difference in pain-related behaviour was found between different peripheral (contralateral, ipsilateral and bilateral) treatments with 0.3 mg U-50,488H. Autotomy behaviour was reduced for 6 weeks after sciatic nerve ligation in rats treated contralaterally with the opioid receptor agonist. Antinociceptive effects of contralaterally administered U-50,488H were abolished by the peripherally acting opioid receptor antagonist naloxone methiodide. Our findings indicate that contralateral treatment with U-50,488H attenuates nociceptive behaviour in mononeuropathic rats. These antinociceptive effects are mediated via peripheral opioid receptors.

Stereospecific effect of pregabalin on ectopic afferent discharges and neuropathic pain induced by sciatic nerve ligation in rats.

The new anticonvulsants, gabapentin and pregabalin, are effective in the treatment of neuropathic pain. The sites and mechanisms of their analgesic action are not fully known. The authors have previously demonstrated that systemic gabapentin suppresses ectopic afferent discharges recorded from injured sciatic nerves in rats. In the current study, they further examined the stereospecific effect of pregabalin on neuropathic pain and afferent ectopic discharges in a rodent model of neuropathic pain. Tactile allodynia and thermal hyperalgesia were induced by partial ligation of the left sciatic nerve in rats. Single-unit activity of afferent ectopic discharges was recorded from the sciatic nerve proximal to the site of ligation. Intravenous injection of 10-30 mg/kg pregabalin dose-dependently attenuated tactile allodynia (n = 10) and thermal hyperalgesia (n = 8). The stereoisomer of pregabalin, R-3-isobutylgaba, had no analgesic effect in this dose range. Furthermore, intravenous injection of pregabalin, but not R-3-isobutylgaba, significantly inhibited the ectopic discharges from injured afferents in a dose-dependent manner (from 20.8 +/- 2.4 impulses/s during control to 2.3 +/- 0.7 impulses/s after treatment with 30 mg/kg pregabalin, n = 15). Pregabalin did not affect the conduction velocity of afferent fibers and the response of normal afferent nerves to mechanical stimulation. These data strongly suggest that the analgesic effect of pregabalin on neuropathic pain is likely mediated, at least in part, by its peripheral inhibitory action on the impulse generation of ectopic discharges caused by nerve injury.

Changes in post-tetanic potentiation of A-fiber dorsal horn field potentials parallel the development and disappearance of neuropathic pain after sciatic nerve ligation in rats

Significant plastic changes in spinal nociceptive processing appear to accompany peripheral nerve injury or inflammation. Using a well-established model of neuropathic pain, we have recently reported that loose ligation of the sciatic nerve was accompanied by a long-lasting post-tetanic potentiation of sciatic-evoked A-fiber superficial dorsal horn field potentials. In the present study we demonstrate that the typical disappearance of thermal hyperalgesia as a behavioral sign of neuropathic pain several weeks after loose sciatic nerve ligation is accompanied by the loss of the long-lasting potentiation. These data suggest that a significant but reversible shift in the processing of sensory information in the spinal dorsal horn follows peripheral nerve injury, and lend further support to the notion that long-lasting synaptic plasticity may contribute to the development of neuropathic pain.

Effect of xymedon on cell survival in the system sensory neuron Schwann cell.

Pyrimidine derivative xymedon inhibits neuronal death in L4-L5 spinal ganglia 30 days after ligation of rat sciatic nerve. After treatment with xymedon the number of neurons on the operated side decreased by 22.1% compared to that on the contralateral side, while in the control group this parameter decreased by 28.7%. At the same terms, the number of Schwann cells on the operated side after xymedon injection increased by 27.7% in comparison with that on the contralateral side, while in the control group this parameter decreased by 57.3%.

ラット神経因性疼痛における末梢セロトニン受容体 (5-HT_&lt;2A&gt;) 活性化の関与 : 熱性痛覚過敏および脊髄細胞傷害による評価

The mechanisms of pathological pain processes including hyperalgesia and allodynia after peripheral nerve injury have not been fully understood. Several recent studies have suggested that neuronal plasticity of spinal neuronal transmission such as glutamatergic nerve activation and its related chemical cascades may be responsible for developing pain sensitization. Therefore, it is reasonable to determine whether apoptosis results from gulutamatergic activation via acceleration of intracellular and nuclear signaling processes. Sarpogrelate HCl (MCI) is newly produced compound and that affects on Serotoninergic neurons (5-HT_<2A>). The present study was designed to investigate the response to thermal stimuli in relation to histopathological changes after chronic construction injury (CCI) in rats. In addition, the present study was evaluated whether seroninergic neurons located in peripheral site may regulate neuropathic pain produced by CCI. The left sciatic nerve of SD rat were ligated under pentobarbital anesthesia. Paw withdrawal latency (PWL), response to thermal stimuli, was measured by using the plantar testing apparatus before CCI and at 6, 8, and 10th days after CCI. Immunohistchemical stainig for apoptosis (TUNEL) and early degeneration (H-E) was performed with light microscope at the corresponding days. TUNEL stain score was counted positive neurons and HE stain score was obtained as 0 : normal neuron to 3 : more than 50% neuronal degeneration. In addition, rat was divided into the three series of study by drug administration ; 1) Saline 0.5ml i.p., 2) MCI 10mg/kg i.p. and 3) MCI+α-methyl-5HT 10mg/kg i.p., 5-HT_<2A> agonist. The hyperalgesia evoked at 6 day after sciatic nerve ligation in rats. In these rats, the apoptosis development was found more at 6 than 10 day. In contraction, the neuronal degeneration occurred more at 10 day. By administration of MCI, pain behavier, apoptosis, and neuronal degeneration was inhibited significantly. The present results demonstrate that apoptosis development was firstly found in the superficial layer of spinal cord in early state of hyperalgesia. This may be suggested that sciatic nerve injury leads to increased ascending inputs or glutamatergic nerve activation followed by derangement of intracellular signaling-intranuclear process (c-fos exprerssion) in the spinal cord which causes apoptosis leading to pain behaviour. It is also suggested that the delayed appearance of neuronal degeneration in the laminae III-IV causes dysfunction of inhibitory interneurons located in this regions and this neuronal damaged is sufficient to develop the sustained pain behaviour. In addition, MCI adoministration provokes antinociceptive effect on neuropathic pain produced by CCI and this effect was reversed by 5-HT_<2A> receptor agonist. It is suggested that the serotoninergic activation take a part of neuropathic pain, the inhibition of this activation is very important of treatment of neuropathic pain.