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1.  Neuropathic pain as a process: reversal of chronification in an animal model 
Journal of Pain Research  2011;4:315-323.
Peripheral neuropathic pain arises from trauma to sensory nerves. Other types of acute neurotrauma such as stroke and spinal cord injury are treated immediately, largely to prevent secondary damage. To pursue the possibility that neuropathic pain may also be amenable to early treatment, a rat model of neuropathic pain was induced using a 2-mm polyethylene cuff implanted around one sciatic nerve. Within 24 hours, hypersensitivity to von Frey hair stimulation appeared, as indicated by decreased paw withdrawal thresholds. When the cuff was removed 24 hours after implantation, readings returned to pre-implantation levels starting as early as day 18. When the cuff was removed after 4 days, there was a period of initial hypersensitivity, and then an increase toward baseline at two time points near the end of the study; therefore, only a partial recovery toward pre-implantation values occurred. Having established that a temporal reversal can occur, the next step examined possible pharmacological reversal. The tachykinin NK1 receptor antagonist, CP-96,345, produced a minor increase in withdrawal thresholds in animals with the cuff left permanently implanted. To determine the effect of early and repeated administration of CP-96,345, it was given daily on days 1–4. The cuff was removed on day 4. Six days later, readings showed reversal of tactile hypersensitivity. We suggest that persistent neuropathic pain occurs from processes that develop over several hours and days, and that some of these processes may be prevented by early medical intervention. Thus, nerve injury in the context of chronic neuropathic pain should be treated in a similar manner to nerve injury resulting from stroke, spinal cord injury, and other types of neurotrauma. We suggest that effective medical intervention within the first few hours after nerve injury may spare a patient from a chronic debilitating pain that may be refractory to later therapies.
doi:10.2147/JPR.S17882
PMCID: PMC3191931  PMID: 22003305
neurotrauma; neuroplasticity; nerve injury; neuropathy; chronic pain; tactile hypersensitivity
2.  Progesterone prevents development of neuropathic pain in a rat model: Timing and duration of treatment are critical 
Journal of Pain Research  2011;4:91-101.
Background:
Progesterone is emerging as an important protective agent against various injuries to the nervous system. Neuroprotective and remyelinating effects have been documented for this neurosteroid, which is synthesized by, and acts on, the central and peripheral nervous systems. Neuropathic pain is a severe, persistent condition that is generally resistant to treatment, and poses major personal, social, and economic burdens. The purpose of this study was to determine if single-dose or repeated progesterone administration would alleviate tactile hypersensitivity in a rat model of neuropathic pain, and to determine if early versus late initiation of treatment has an effect on the outcome.
Methods:
Rats were unilaterally implanted with a polyethylene cuff around the sciatic nerve, and sensitivity to von Frey filament stimulation was measured over approximately 12 weeks.
Results:
Rats given progesterone starting one hour after cuff implantation, and daily until day 4, exhibited tactile hypersensitivity similar to that of vehicle-treated rats for the duration of the study. When progesterone was started one hour after cuff implantation and given daily until day 10, rats exhibited no tactile hypersensitivity in the later part of the study, after treatment had stopped. When progesterone treatment was initiated at 20 days, once the model had been fully established, and given daily for 4 or even 11 days, no differences in withdrawal thresholds were observed compared with controls. Progesterone did not have any effect on withdrawal thresholds when given as a single dose, as measured at 30, 60 and 90 minutes after administration.
Conclusion:
These results indicate that progesterone, when administered immediately after nerve injury, and for a sufficient period of time, can prevent the development of neuropathic pain, and may offer new strategies for the treatment of this highly debilitating condition.
doi:10.2147/JPR.S17009
PMCID: PMC3085268  PMID: 21559355
progesterone; neurosteroid; neuropathic pain; peripheral neuropathy; recovery; neuroprotection
3.  Antiallodynic Effect of Thalidomide and Morphine on Rat Spinal Nerve Ligation-induced Neuropathic Pain 
The Korean Journal of Pain  2010;23(3):172-178.
Background
Tumor necrosis factor-alpha and other proinflammatory cytokines are becoming well recognized as key mediators in the pathogenesis of many types of neuropathic pain. Thalidomide has profound immunomodulatory actions in addition to their originally intended pharmacological actions. There has been debate on the analgesic efficacy of opioids in neuropathic pain. The aim of this study was to investigate the effect of thalidomide and morphine on a spinal nerve ligation model in rats.
Methods
Male Sprague-Dawley rats weighing 100-120 g were used. Lumbar (L) 5 and 6 spinal nerve ligations were performed to induce neuropathic pain. For assessment of mechanical allodynia, mechanical stimulus using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of intraperitoneal thalidomide (6.25, 12.5, 25 and 50 mg/kg, respectively) and morphine (3 and 10 mg/kg, respectively) were examined on a withdrawal threshold evoked by spinal nerve ligation.
Results
After L5 and 6 spinal nerve ligation, paw withdrawal thresholds on the ipsilateral side were significantly decreased compared with pre-operative baseline and with those in the sham-operated group. Intraperitoneal thalidomide and morphine significantly increased the paw withdrawal threshold compared to controls and produced dose-responsiveness.
Conclusions
Systemic thalidomide and morphine have antiallodynic effect on neuropathic pain induced by spinal nerve ligation in rat. These results suggest that morphine and thalidomide may be alternative therapeutic approaches for neuropathic pain.
doi:10.3344/kjp.2010.23.3.172
PMCID: PMC2935978  PMID: 20830262
antinociceptive; cytokine; morphine; neuropathy; thalidomide
4.  The Effect of Urinary Trypsin Inhibitor Against Neuropathic Pain in Rat Models 
The Korean Journal of Pain  2013;26(4):356-360.
Background
Nerve injury sometimes leads to chronic neuropathic pain associated with neuroinflammation in the nervous system. In the case of chronic neuropathic pain, the inflammatory and algesic mediators become predominant and result in pain hypersensitivity following nervous system damage. It is well known that urinary trypsin inhibitor (ulinastatin, UTI) has an anti-inflammatory activity. Recently, the neuroprotective action of UTI on the nervous system after ischemic injury has been reported. Thus, we evaluated the neuroprotective effect of ulinastatin in a rat model of neuropathic pain.
Methods
Neuropathic pain was induced with L5 spinal nerve ligation (SNL) in male Sprague-Dawley rats weighing 100-120 g. The rats were divided into 3 groups, with n = 8 in each group. The rats in the control group (group 1) were administered normal saline and those in group 2 were administered UTI (50,000 U/kg) intravenously through the tail vein for 3 days from the day of SNL. Rats in group 3 were administered UTI (50,000 U/kg) intravenously from the 5th day after SNL. The paw withdrawal threshold was measured using the von Frey test for 3 days starting from the 5th day after SNL.
Results
The paw withdrawal thresholds were significantly increased in the rats of group 2 compared to the other groups (P < 0.05).
Conclusions
Ulinastatin, which was administered for 3 days after SNL, increased the paw withdrawal threshold and it could have a neuroprotective effect in the rat model of neuropathic pain.
doi:10.3344/kjp.2013.26.4.356
PMCID: PMC3800707  PMID: 24156001
neuropathic pain; rats; urinary trypsin inhibitor
5.  Activation of spinal MrgC-Gi-NR2B-nNOS signaling pathway by Mas oncogene-related gene C receptor agonist bovine adrenal medulla 8-22 attenuates bone cancer pain in mice 
Objectives: In the present study, we investigate the effects of Mas oncogene-related gene (Mrg) C receptors (MrgC) on the expression and activation of spinal Gi protein, N-methyl-D-aspartate receptor subunit 2B (NR2B), and neuronal nitric oxide synthase (nNOS) in mouse model of bone cancer pain. Methods: The number of spontaneous foot lift (NSF) and paw withdrawal mechanical threshold (PWMT) were measured after inoculation of tumor cells and intrathecal injection of MrgC agonist bovine adrenal medulla 8-22 (BAM8-22) or MrgC antagonist anti-MrgC for 14 days after operation. Expression of spinal MrgC, Gi protein, NR2B and nNOS and their phosphorylated forms after inoculation was examined by immunohistochemistry and Western blotting. Double labeling was used to identify the co-localization of NR2B or nNOS with MrgC in spinal cord dorsal horn (SCDH) neurons. The effects of intrathecal injection of BAM8-22 or anti-MrgC on nociceptive behaviors and the corresponding expression of spinal MrgC, Gi protein, NR2B and nNOS were also investigated. Results: The expression of spinal MrgC, Gi protein, NR2B, and nNOS was higher in tumor-bearing mice in comparison to sham mice or normal mice. Intrathecal injection of MrgC agonist BAM8-22 significantly alleviated bone cancer pain, up-regulated MrgC and Gi protein expression, and down-regulated the expression of spinal p-NR2B, t-nNOS and p-nNOS in SCDH on day 14 after operation, whereas administration of anti-MrgC produced the opposite effect. Meanwhile, MrgC-like immunoreactivity (IR) co-localizes with NR2B-IR or nNOS-IR in SCDH neurons. Conclusions: The present study demonstrates that MrgC-activated spinal Gi-NR2B-nNOS signaling pathway plays important roles in the development of bone cancer pain. These findings may provide a novel strategy for the treatment of bone cancer pain.
PMCID: PMC4846957  PMID: 27158400
MrgC; Gi protein; NR2B; nNOS; bone cancer pain; BAM8-22; anti-MrgC
6.  Association between extracellular signal-regulated kinase expression and the anti-allodynic effect in rats with spared nerve injury by applying immediate pulsed radiofrequency 
BMC Anesthesiology  2015;15:92.
Background
The application of pulsed radiofrequency (PRF) close to the dorsal root ganglia, or peripheral nerves, has been demonstrated to be effective for the treatment of chronic neuropathic pain conditions. The goal of this study was to investigate the analgesic effect of immediate PRF treatment after nerve injury and its possible cellular alterations in the dorsal horn of the spinal cord in rats with spared nerve injury (SNI).
Methods
Neuropathic pain was achieved in a SNI neuropathic pain model by ligating and cutting the common peroneal and tibial branches of the left sciatic nerve, leaving the sural nerve intact. Wistar rats were divided into four groups that received different treatments, i.e., SNI and PRF for 6 min at 45 V (SNI + PRF-45 V), at 60 V (SNI + PRF-60 V), SNI alone, and sham groups. After the SNI surgery, each rat was immediately given the PRF treatment (500 kHz, rate of 2 Hz, 20 ms duration, temperature below 42 °C) on the left sciatic nerve 0.3–0.4 cm proximal to the injured site. The behavioral measurements included mechanical allodynia and cold allodynia of the ipsilateral hind paw and were performed during the 28 days that followed the SNI surgery and PRF treatment. Total extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phospho-ERK1/2 were measured using Western blot in the ipsilateral spinal cord from animals in the different groups.
Results
The three groups of rats with nerve injuries manifested a lower paw withdrawal threshold (PWT) in the behavioral measurement of mechanical allodynia and a shorter painful-behavior duration in the cold allodynia test over 28 days. Mechanical allodynia measurement showed that both the PRF-45 V and PRF-60 V treatment groups exhibited a more prominent antiallodynic effect than did the SNI group from days 1 to 28 after surgery. Similarly, in comparison with the SNI group, both the SNI + PRF-45 V and SNI + PRF-60 V groups had significant inhibition on the cold allodynia measurement from days 1 to 28 after surgery. Furthermore, the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the ipsilateral spinal dorsal horn of SNI rats was effectively inhibited in the SNI + PRF-45 V and SNI + PRF-60 V groups for 28 days after surgery.
Conclusions
Immediate PRF application on the proximal nerve injury site provided a significant inhibition of neuropathic pain formation, accompanied by the inhibition of ERK activation.
doi:10.1186/s12871-015-0071-3
PMCID: PMC4467050  PMID: 26077473
Pulsed radiofrequency; Spared nerve injury; ERK1/2; Neuropathic pain
7.  Antinociceptive Effect of Memantine and Morphine on Vincristine-induced Peripheral Neuropathy in Rats 
The Korean Journal of Pain  2010;23(3):179-185.
Background
Vincristine-induced peripheral neuropathy is a major dose limiting side effect and thus effective therapeutic strategy is required. In this study, we investigated the antinociceptive effect of memantine and morphine on a vincristine-induced peripheral neuropathy model in rats.
Methods
Male Sprague-Dawley rats weighing 220-240 g were used in all experiments. Rats subsequently received daily intraperitoneal injections of either vincristine sulfate (0.1 ml/kg/day) or saline (0.1 ml/kg/day) over 12 days, immediately following behavioral testing. For assessment of mechanical allodynia, mechanical stimuli using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of N-methyl-D-aspartate receptors antagonist (memantine; 2.5, 5, 10 mg/kg intraperitoneal), opioid agonist (morphine; 2.5, 5, 10 mg/kg intraperitoneal) and vehicle (saline) on vicristine-induced neuropathy were evaluated.
Results
Mechanical allodynia developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same time. Morphine abolished the reduction in paw withdrawal threshold compared to vehicle and produced dose-responsiveness. Only the highest dose of memantine (10 mg/kg) was able to increase paw withdrawal threshold compared to vehicle.
Conclusions
Systemic morphine and memantine have an antinociceptive effect on the vincristine-induced peripheral neuropathy model in rats. These results suggest morphine and memantine may be an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.
doi:10.3344/kjp.2010.23.3.179
PMCID: PMC2935979  PMID: 20830263
antinociception; memantine; morphine; neuropathic pain; vincristine
8.  Single Administration of Melatonin Modulates the Nitroxidergic System at the Peripheral Level and Reduces Thermal Nociceptive Hypersensitivity in Neuropathic Rats 
Neuropathic pain is a severe condition with unsatisfactory treatments. Melatonin, an indolamine, seems to be a promising molecule suitable for this purpose due to its well-known anti-inflammatory, analgesic, and antioxidant effects, as well as its modulation of the nitroxidergic system. Nevertheless, the data on its mechanism of action and potentialities are currently insufficient in this pathology, especially at the peripheral level. Thus, this work evaluated the effect of a single administration of melatonin in an established mononeuropathy pain model that monitors the behaviour and the changes in the nitroxidergic system in dorsal root ganglia and skin, which are affected by nervous impairment. Experiments were carried out on Sprague Dawley rats subdivided into the sham operated (control) and the chronic constriction injured animals, a model of peripheral neuropathic pain on sciatic nerve. Single administrations of melatonin (5–10 mg/kg) or vehicle were injected intraperitoneally on the 14th day after surgery, when the mononeuropathy was established. The animals were behaviourally tested for thermal hyperalgesia. The dorsal root ganglia and the plantar skin of the hind-paws were removed and processed for the immunohistochemical detection of neuronal and inducible nitric oxide synthases. The behavioural results showed an increase of withdrawal latency during the plantar test as early as 30 min after melatonin administration. The immunohistochemical results indicated a modulation of the nitroxidergic system both at dorsal root ganglia and skin level, permitting speculate on a possible mechanism of action. We showed that melatonin may be a possible therapeutic strategy in neuropathic pain.
doi:10.3390/ijms18102143
PMCID: PMC5666825  PMID: 29036889
melatonin; neuropathic pain; rats; nitroxidergic system; skin; dorsal root ganglia
9.  NSAIDs attenuate hyperalgesia induced by TRP channel activation 
Data in Brief  2016;6:668-673.
Transient receptor potential (TRP) cation channels have been extensively investigated as targets for analgesic drug discovery. Because some non-steroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins (mediators of inflammation) and NSAIDs attenuate heat nociception and mechanical allodynia in models of inflammatory and neuropathic pain, we examined three widely used NSAIDs (diclofenac, ketorolac, and xefocam) on the activation of TRPA1 and TRPV1 channels using thermal paw withdrawal (Hargreaves) test and mechanical paw withdrawal (von Frey) test in male rats. Thermal withdrawal latencies and mechanical thresholds for both hind paws were obtained with 5, 15, 30, 45, 60, and 120 min intraplantar post-injection of TRPA1 agonizts, allyl isothiocyanate (AITC) (a natural compound of mustard oil) and cinnamaldehyde (CA), and TRPV1 agonist capsaicin or vehicle. Twenty minutes prior to the start of the experiment with TRP agonizts, diclofenac, ketorolac or xefocam were pre-injected in the same hindpaw and animals were examined by these two tests. After pretreatment of all three NSAIDs in the ipsilateral (injected) hindpaw that produced strong antinociceptive effects, AITC, CA, and capsaicin caused significant decreases in latency of the thermal withdrawal reflex compared with vehicle or the contralateral hindpaw. The same findings were observed for the paw withdrawal threshold. In approximately 30 min the effects of CA, AITC, and capsaicin returned to baseline. The data are different from our previous evidence, where TRPA1 agonizts AITC and CA and TRPV1 agonist capsaicin produced hyperalgesia for nearly 2 h and resulted in facilitation of these withdrawal reflexes (Tsagareli et al., 2010, 2013). Thus, our data showing that NSAIDs suppress thermal and mechanical hyperalgesia following TRP activation could presumably due to inactivation or desensitization of TRPA1 and TRPV1 channels by NSAIDs.
doi:10.1016/j.dib.2015.12.055
PMCID: PMC4735497  PMID: 26909384
Allodynia; Cold pain; Heat pain; Hyperalgesia; Signal transduction; Nociception
10.  Tetrahydrobiopterin prevents platelet-activating factor–induced intestinal hypoperfusion and necrosis: Role of neuronal nitric oxide synthase 
Critical care medicine  2005;33(5):1050-1056.
Objective
We reported previously that neuronal nitric oxide synthase (nNOS) is the predominant NOS in rat small intestine and is down-regulated by platelet-activating factor (PAF). The severity of the bowel injury induced by PAF is inversely related to its suppressing effect on nNOS. Here, we investigated whether intestinal perfusion is regulated by nNOS and whether tetrahydrobiopterin, a co-factor and stabilizer of nNOS, reverses PAF-induced intestinal hypoperfusion and injury.
Setting
Animal laboratory.
Design
We first examined nNOS regulation of splanchnic blood flow by measuring the perfusion of the heart, lung, ileum, and kidney in rats after a nNOS inhibitor. We then examined the protective effect of tetrahydrobiopterin on PAF-induced bowel injury, mesenteric hypoperfusion, and systemic inflammation.
Subjects
Adult male Sprague-Dawley rats.
Intervention
In part 1 of the experiment, rats were given 7-nitroindazole (a specific nNOS inhibitor, 50 mg·kg−1·day−1). In part 2 of the experiment, rats were treated with tetrahydrobiopterin (20 mg/kg) 5 mins before and 30 mins after PAF challenge (2.2 μg/kg, intravenously)
Measurements
Perfusion of the heart, lung, ileum, and kidney was measured at 1 and 4 days after 7-nitroindazole, using fluorescent microspheres. Intestinal injury and inflammation (myeloperoxidase content), blood perfusion, calcium dependent-NOS activity, and systemic inflammation (hypotension and hematocrit increase) were assessed 1 hr after PAF with and without tetrahydrobiopterin treatment.
Results
In part 1 of the experiment, 7-nitroindazole induced a long-lasting reduction of blood perfusion and inducible NOS expression selectively in the ileum but not in nonsplanchnic organs such as heart, lungs, and kidneys. In part 2, tetrahydrobiopterin protected against PAF-induced intestinal necrosis, hypoperfusion, neutrophil influx, and NOS suppression. It also reversed hypotension and hemoconcentration. Sepiapterin (2 mg/kg, stable tetrahydrobiopterin precursor) also attenuated PAF-induced intestinal injury.
Conclusions
We conclude that nNOS selectively regulates intestinal perfusion. Tetrahydrobiopterin prevents PAF-induced intestinal injury, probably by stabilizing nNOS and maintaining intestinal perfusion.
PMCID: PMC1568387  PMID: 15891335
nitric oxide synthase; platelet-activating factor; shock; intestine; intestinal perfusion; tetrahydrobiopterin
11.  Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency 
Evidence for the important role of the potent oxidant peroxynitrite in peripheral diabetic neuropathy and neuropathic pain is emerging. This study evaluated the contribution of neuronal nitric oxide synthase (nNOS) to diabetes-induced nitrosative stress in peripheral nerve and dorsal root ganglia, and peripheral nerve dysfunction and degeneration. Control and nNOS−/− mice were made diabetic with streptozotocin, and maintained for 6 weeks. Peroxynitrite injury was assessed by nitrotyrosine and poly(ADP-ribose) immunoreactivities. Peripheral diabetic neuropathy was evaluated by measurements of sciatic motor and hind-limb digital sensory nerve conduction velocities, thermal algesia, tactile allodynia, and intraepidermal nerve fiber density. Control nNOS−/− mice displayed normal motor nerve conduction velocity and thermal response latency, whereas sensory nerve conduction velocity was slightly lower compared with non-diabetic wild-type mice, and tactile response threshold and intraepidermal nerve fiber density were reduced by 47 and 38%, respectively. Both diabetic wild-type and nNOS−/− mice displayed enhanced nitrosative stress in peripheral nerve. In contrast to diabetic wild-type mice, diabetic nNOS−/− mice had near normal nitrotyrosine and poly(ADP-ribose) immunofluorescence in dorsal root ganglia. Both diabetic wild-type and nNOS−/− mice developed motor and sensory nerve conduction velocity deficits and thermal hypoalgesia although nNOS gene deficiency slightly reduced severity of the three disorders. Tactile response thresholds were similarly decreased in control and diabetic nNOS−/− mice compared with non-diabetic wild-type mice. Intraepidermal nerve fiber density was lower by 27% in diabetic nNOS−/− mice compared with the corresponding non-diabetic group, and by 20% in diabetic nNOS−/− mice compared with diabetic wild-type mice. In conclusion, nNOS is required for maintaining the normal peripheral nerve function and small sensory nerve fibre innervation. nNOS gene deficiency does not protect from development of nerve conduction deficit, sensory neuropathy and intraepidermal nerve fiber loss.
PMCID: PMC2756471  PMID: 19360314
nerve conduction; neuronal nitric oxide synthase; nitrosative stress; peripheral diabetic neuropathy; streptozotocin-diabetic mouse
12.  Intrathecal administration of human bone marrow mesenchymal stem cells genetically modified with human proenkephalin gene decrease nociceptive pain in neuropathic rats 
Molecular Pain  2017;13:1744806917701445.
Background
Mesenchymal stem cell (MSC) has been one of the potential tools in neuropathic pain therapy; however, the augmented efficacy may be expected when they are modified with human proenkephalin (hPPE) gene. In the current study, the antinociceptive effect of human bone marrow stem cells (hBMSCs) engineered with hPPE gene (hPPE-hBMSCs) on sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain in rats was investigated.
Methods
Primary-cultured hBMSCs were passaged and modified with hPPE, and the cell suspensions (6 × 106) were then intrathecally injected into a rat model of CCI. Paw mechanical withdrawal threshold and paw withdrawal thermal latency were measured before and after CCI surgery. The effects of hPPE gene transfer on hBMSCs bioactivity were analyzed in vitro and in vivo.
Results
No changes were observed in the surface phenotypes and differentiation of hBMSCs after gene transfer. The hPPE-hBMSC group showed improved paw mechanical withdrawal threshold and paw thermal withdrawal latency values on the ipsilateral side of rats with CCI from day 9 post-surgery, and the analgesic effect was reversed by naloxone. Leucine-enkephalin (L-EK) secretion was augmented in the hPPE-engineered hBMSC group.
Conclusions
The intrathecal administration of BMSCs modified with hPPE gene can effectively relieve pain caused by chronic constriction injury in rats and might be a potentially therapeutic tool for neuropathic pain in humans.
doi:10.1177/1744806917701445
PMCID: PMC5391071  PMID: 28326940
Neuropathic pain; cell transplantation; proenkephalin; human marrow stem cell; chronic constriction injury
13.  Upregulation of neuregulin-1 reverses signs of neuropathic pain in rats 
Background: Peripheral nerve injury can result in neuropathic pain, a chronic condition of unclear cause often poorly responsive to current treatments. One possibility is that nerve injury disrupts large A-fiber-mediated inhibition of C-fiber-evoked responses in spinal dorsal horn neurons, leading to central sensitization. A recent study provided a potential molecular mechanism; large dorsal root ganglion (DRG) neurons secrete neuregulin-1 (NRG1), which binds to erbB4 receptors on interneurons and promotes GABA release to inhibit C-fiber-evoked nociceptive transmission. Thus, reduced NRG1 expression following nerve injury could induce chronic pain by disinhibition. We examined if DRG expression of NRG1 is in fact reduced in a rat model of neuropathic pain and if exogenous NRG1 alleviates behavioral signs of this condition. Methods: Three neuropathic pain models were established in rats: spared nerve injury of the tibial and common peroneal nerves (SNI model), intraplantar injection of complete Freund’s adjuvant (CFA model), and subcutaneous formalin injection. NRG1 expression was assessed by immunofluorescent staining, hyperalgesia by paw withdrawal threshold to von Frey filament stimulation, and pain-like behavior by spontaneous flinching. Results: NRG1 protein immunoreactivity was reduced in the rat DRG after SNI. Intrathecal administration of neuregulin-1beta 1 (NRG1-1), a 62 amino acid NRG1 mimetic, transiently increased paw withdrawal threshold in SNI model and reduced flinching in the formalin injection model. Conclusion: Our results are consistent with a model of neuropathic pain whereby peripheral nerve injury reduces NRG1-mediated inhibition of nociceptive signaling. Modulating NRG1 may have therapeutic potential for treating neuropathic pain.
PMCID: PMC4203206  PMID: 25337235
Neuregulin-1; GABA; spinal dorsal horn; neuropathic pain; dorsal root ganglion; gate control
14.  Effect of palmitoylethanolamide on inflammatory and neuropathic pain in rats 
Korean Journal of Anesthesiology  2017;70(5):561-566.
Background
A growing body of evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators in the peripheral and central nervous systems, plays an important role in the induction and maintenance of chronic pain. Palmitoylethanolamide (PEA), which is a type of N-acylethanolamide and a lipid, has an anti-inflammatory effect. Relative to the anti-inflammatory effect, little is known about its analgesic effect in chronic pain. This study aimed to determine whether PEA relieves chronic inflammatory and neuropathic pain.
Methods
Male Sprague-Dawley rats were injured by transection of the left L5 and L6 spinal nerves to induce neuropathic pain or were injected with monoiodoacetic acid into the synovial cavity of knee joints to induce inflammatory pain. To assess the degree of pain, two kinds of stimuli - pressing von Frey filaments and wetting with acetone - were applied to the plantar surface of the rat to measure mechanical and cold sensitivity, respectively. Pain was measured by assessing behavioral responses, including paw withdrawal response threshold and paw withdrawal frequency upon stimulation.
Results
Neuropathic pain caused by spinal nerve transection (SNT) decreased the mechanical threshold and increased the frequency of response to acetone application. But, cold allodynia caused by SNT did not decrease the withdrawal frequency. Mechanical hyperalgesia caused by chronic inflammation was significantly reduced by both intraperitoneal and intra-articular injections of PEA.
Conclusions
These outcomes revealed that PEA might be effective in relieving inflammatory and neuropathic pain, especially pain induced by mechanical hyperalgesia, but not cold allodynia.
doi:10.4097/kjae.2017.70.5.561
PMCID: PMC5645590
Inflammatory pain; Neuropathic pain; Palmitoylethanolamide
15.  The antiallodynic action of pregabalin may depend on the suppression of spinal neuronal hyperexcitability in rats with spared nerve injury 
Pregabalin is an anticonvulsant agent that has recently been found to be effective for the treatment of neuropathic pain, although its mechanism of action in this respect has yet to be elucidated. The authors of this article used a rat model of neuropathic pain to examine the potential role of dorsal horn wide dynamic range neurons in the antiallodynic action of pregabalin.
BACKGROUND:
Pregabalin (PGB) is a novel antiepileptic drug and is also used as a first-line medication for the treatment of neuropathic pain. However, the mechanisms of its analgesic effects remain largely unknown.
OBJECTIVES:
To elucidate the mechanisms underlying the antiallodynic action of PGB in rats with neuropathic pain.
METHODS:
In a rat model of neuropathic pain induced by spared nerve injury, mechanical allodynia, as a behavioural sign of neuropathic pain, was assessed by measuring 50% paw withdrawal threshold with von Frey filaments. Activities of dorsal horn wide dynamic range (WDR) neurons were examined by extracellular electrophysiological recording in vivo.
RESULTS:
Spinal administration of PGB exerted a significant antiallodynic effect and a prominent inhibitory effect on the hypersensitivity of dorsal horn WDR neurons in rats with spared nerve injury.
CONCLUSION:
The antiallodynic action of PGB is likely dependent on the suppression of WDR neuron hyperexcitability in rats with neuropathic pain.
PMCID: PMC4158936  PMID: 24851240
Electrophysiology; Neuropathic pain; Pregabalin; Spinal dorsal horn; WDR neurons
16.  Impaired Expression of Neuronal Nitric Oxide Synthase in the Gracile Nucleus Is Involved in Neuropathic Changes in Zucker Diabetic Fatty Rats with and without 2,5-Hexanedione Intoxication 
Neuroscience research  2015;106:47-54.
These studies examined the influence of 2,5-hexanedione (2,5-HD) intoxication on expression of neuronal nitric oxide synthase (nNOS) in the brainstem nuclei in Zucker Diabetic Fatty (ZDF) vs. lean control (LC) rats. Functional neuropathic changes were also investigated following axonal damage and impaired axonal transport induced by the treatment. Animals were intoxicated by i.p. injection of 2,5-HD plus unilateral administration of 2,5-HD over the sciatic nerve. The mechanical thresholds and withdrawal latencies to heat and cold stimuli on the foot were measured at baseline and after intoxication. The medulla sections were examined by nNOS immunohistochemistry and NADPH-diaphorase histochemistry at the end of the treatments. The mechanical thresholds and withdrawal latencies were significantly decreased while nNOS immunostained neurons and NADPH-diaphorase positive cells were selectively reduced in the gracile nucleus at baseline in ZDF vs. LC rats. NADPH-diaphorase reactivity and nNOS positive neurons were increased in the ipsilateral gracile nucleus in LC rats following 2,5-HD intoxication, but its up-regulation was attenuated in ZDF rats. These results suggest that diabetic and chemical intoxication-induced nNOS expression is selectively reduced in the gracile nucleus in ZDF rats. Impaired axonal damage-induced nNOS expression in the gracile nucleus is involved in neuropathic pathophysiology in type II diabetic rats.
doi:10.1016/j.neures.2015.10.007
PMCID: PMC4846497  PMID: 26519861
Nitric oxide synthase; dorsal medulla; diabetic neuropathy; sensory functions; 2,5-HD intoxication; immunohistochemistry
17.  Antinociceptive effects of lacosamide on spinal neuronal and behavioural measures of pain in a rat model of osteoarthritis 
Introduction
Alterations in voltage-gated sodium channel (VGSC) function have been linked to chronic pain and are good targets for analgesics. Lacosamide (LCM) is a novel anticonvulsant that enhances the slow inactivation state of VGSCs. This conformational state can be induced by repeated neuronal firing and/or under conditions of sustained membrane depolarisation, as is expected for hyperexcitable neurones in pathological conditions such as epilepsy and neuropathy, and probably osteoarthritis (OA). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model.
Methods
OA was induced in Sprague Dawley rats by intraarticular injection of 2 mg of monosodium iodoacetate (MIA). Sham rats received saline injections. Behavioural responses to mechanical and cooling stimulation of the ipsilateral hind paw and hindlimb weight-bearing were recorded. In vivo electrophysiology experiments were performed in anaesthetised MIA or sham rats, and we recorded the effects of spinal or systemic administration of LCM on the evoked responses of dorsal horn neurones to electrical, mechanical (brush, von Frey, 2 to 60 g) and heat (40°C to 50°C) stimulation of the peripheral receptive field. The effect of systemic LCM on nociceptive behaviours was assessed.
Results
Behavioural hypersensitivity ipsilateral to knee injury was seen as a reduced paw withdrawal threshold to mechanical stimulation, an increase in paw withdrawal frequency to cooling stimulation and hind limb weight-bearing asymmetry in MIA-treated rats only. Spinal and systemic administration of LCM produced significant reductions of the electrical Aβ- and C-fibre evoked neuronal responses and the mechanical and thermal evoked neuronal responses in the MIA group only. Systemic administration of LCM significantly reversed the behavioural hypersensitive responses to mechanical and cooling stimulation of the ipsilateral hind paw, but hind limb weight-bearing asymmetry was not corrected.
Conclusions
Our in vivo electrophysiological results show that the inhibitory effects of LCM were MIA-dependent. This suggests that, if used in OA patients, LCM may allow physiological transmission but suppress secondary hyperalgesia and allodynia. The inhibitory effect on spinal neuronal firing aligned with analgesic efficacy on nociceptive behaviours and suggests that LCM may still prove worthwhile for OA pain treatment and merits further clinical investigation.
doi:10.1186/s13075-014-0509-x
PMCID: PMC4308925  PMID: 25533381
18.  Measurement of mechanical withdrawal thresholds and gait analysis using the CatWalk method in a nucleus pulposus-applied rodent model 
Background
There are some previous reports of gait analysis using a rodent pain model. Applying the CatWalk method, objective measurements of pain-related behavior could be evaluated, but this method has not been investigated using the nucleus pulposus (NP) applied model, which was developed as a model of lumber disc herniation. We aimed to measure mechanical withdrawal thresholds and analyze gait patterns using the CatWalk method for the evaluation of the pain-related behavior caused by NP application.
Methods
Twenty-four nine-week-old female Sprague-Dawley rats were randomly divided into two experimental groups, the NP group (n = 12), in which autologous NP from the tail was applied to the left L5 dorsal root ganglion, and the sham-operated group (n = 12). Measurements of mechanical withdrawal thresholds were performed using von Frey filaments touching the left footpads, and gait analysis was performed using the CatWalk method. These experiments were conducted 1 day before surgery and 7, 14, 21, and 28 days after surgery. Data were statistically analyzed using the Wilcoxon rank-sum test.
Results
The NP group showed significantly lower withdrawal thresholds than the sham group at days 14 and 21. Stand (duration of contact of a paw with the glass plate) was significantly higher in the NP group at days 7 and 14, whereas step cycle (duration between two consecutive initial contacts of the same paw) and duty cycle (stand as a percentage of step cycle) were the same at day 7. Long initial dual stance (duration of ground contact for both hind paws simultaneously, but the first one in a step cycle of a target hind paw) of the right hind paw was measured at days 7 and 14. The left hind paw per right hind paw ratio of the stand index (speed at which the paw loses contact with the glass plate) and mean intensity (mean intensity of the complete paw) changed at day 7 or 14. Phase dispersion (parameter describing the temporal relationship between placement of two paws) of the hind paws decreased at day 7.
Conclusions
Rats with applied NP showed a decreased withdrawal threshold and abnormal gait. The differences in gait parameters between the NP and sham groups were observed at an earlier time point than the withdrawal thresholds. Gait analysis could be an effective method for understanding pain caused by applied NP.
doi:10.1186/s40634-017-0105-5
PMCID: PMC5624862  PMID: 28971381
Nucleus pulposus; Lumbar disc herniation; Dorsal root ganglion; Mechanical withdrawal threshold; Gait analysis; CatWalk
19.  Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy 
BMC Neuroscience  2012;13:15.
Background
Causes of neuropathic pain following nerve injury remain unclear, limiting the development of mechanism-based therapeutic approaches. Animal models have provided some directions, but little is known about the specific sensory neurons that undergo changes in such a way as to induce and maintain activation of sensory pain pathways. Our previous studies implicated changes in the Aβ, normally non-nociceptive neurons in activating spinal nociceptive neurons in a cuff-induced animal model of neuropathic pain and the present study was directed specifically at determining any change in excitability of these neurons. Thus, the present study aimed at recording intracellularly from Aβ-fiber dorsal root ganglion (DRG) neurons and determining excitability of the peripheral receptive field, of the cell body and of the dorsal roots.
Methods
A peripheral neuropathy was induced in Sprague Dawley rats by inserting two thin polyethylene cuffs around the right sciatic nerve. All animals were confirmed to exhibit tactile hypersensitivity to von Frey filaments three weeks later, before the acute electrophysiological experiments. Under stable intracellular recording conditions neurons were classified functionally on the basis of their response to natural activation of their peripheral receptive field. In addition, conduction velocity of the dorsal roots, configuration of the action potential and rate of adaptation to stimulation were also criteria for classification. Excitability was measured as the threshold to activation of the peripheral receptive field, the response to intracellular injection of depolarizing current into the soma and the response to electrical stimulation of the dorsal roots.
Results
In control animals mechanical thresholds of all neurons were within normal ranges. Aβ DRG neurons in neuropathic rats demonstrated a mean mechanical threshold to receptive field stimulation that were significantly lower than in control rats, a prolonged discharge following this stimulation, a decreased activation threshold and a greater response to depolarizing current injection into the soma, as well as a longer refractory interval and delayed response to paired pulse electrical stimulation of the dorsal roots.
Conclusions
The present study has demonstrated changes in functionally classified Aβ low threshold and high threshold DRG neurons in a nerve intact animal model of peripheral neuropathy that demonstrates nociceptive responses to normally innocuous cutaneous stimuli, much the same as is observed in humans with neuropathic pain. We demonstrate further that the peripheral receptive fields of these neurons are more excitable, as are the somata. However, the dorsal roots exhibit a decrease in excitability. Thus, if these neurons participate in neuropathic pain this differential change in excitability may have implications in the peripheral drive that induces central sensitization, at least in animal models of peripheral neuropathic pain, and Aβ sensory neurons may thus contribute to allodynia and spontaneous pain following peripheral nerve injury in humans.
doi:10.1186/1471-2202-13-15
PMCID: PMC3292996  PMID: 22289651
Neuropathic pain; Primary afferent neuron; Hyperexcitability; Ectopic discharge; Muscle spindle neuron; Dorsal root ganglion
20.  Descending facilitatory pathways from the RVM initiate and maintain bilateral hyperalgesia after muscle insult 
Pain  2007;136(3):331-339.
The rostral ventromedial medulla (RVM) is involved in facilitation of spinal nociceptive processing and generation of hyperalgesia in inflammatory and neuropathic pain models. We hypothesized that the bilateral hyperalgesia that develops after repeated intramuscular injections of acidic saline is initiated and maintained by activation of descending facilitatory pathways from the RVM. Male Sprague-Dawley rats were implanted with intracerebral guide cannulae into the nucleus raphe magnus (NRM) or the nucleus gigantocellularis (Gi). Two injections of acidic saline into one gastrocnemius muscle 5 days apart leads to robust hyperalgesia after the second injection. Either ropivacaine (local anesthetic) or vehicle (control) was microinjected into the RVM prior to the first intramuscular acid injection, prior to the second injection, or 24h after the second injection. Mechanical withdrawal thresholds of the paw (von Frey filaments) and the muscle (tweezer) were measured before and 24h after induction of hyperalgesia. The withdrawal thresholds for both the paw (cutaneous secondary hyperalgesia) and muscle (primary hyperalgesia) were decreased 24h after the second intramuscular acid injection in the vehicle control groups. Administration of ropivacaine prior to the first intramuscular acid injection had no effect on development of either cutaneous or muscle hyperalgesia that develops after the second injection. However, neither cutaneous nor muscle hyperalgesia developed in the group treated with ropivacaine prior to the second intramuscular injection. Ropivacaine also significantly reversed the hyperalgesia in the group treated 24h after the second intramuscular acid injection. Thus, the RVM is critical for both the development and maintenance of hyperalgesia after muscle insult.
doi:10.1016/j.pain.2007.07.011
PMCID: PMC2519171  PMID: 17764841
pain; raphe magnus; gigantocellularis; facilitation
21.  The Antinociceptive and Antihyperalgesic Effects of Topical Propofol on Dorsal Horn Neurons in the Rat 
Anesthesia and analgesia  2013;116(4):932-938.
Background
Propofol (2,6-diisopropylphenol) is an IV anesthetic used for general anesthesia. Recent evidence suggests that propofol-anesthetized patients experience less postoperative pain, and that propofol has analgesic properties when applied topically. We presently investigated the antinociceptive effects of topical propofol using behavioral and single-unit electrophysiological methods in rats.
Methods
In behavioral experiments with rats, we assessed the effect of topical hindpaw application of propofol (1–25%) on heat and mechanically evoked paw withdrawals. In electrophysiology experiments we recorded from lumbar dorsal horn wide dynamic range (WDR)-type neurons in pentobarbital-anesthetized rats. We assessed the effect of topical application of propofol to the ipsilateral hindpaw on neuronal responses elicited by noxious heat, cold and mechanical stimuli. We additionally tested if propofol blocks heat sensitization of paw withdrawals and WDR neuronal responses induced by topical application of allyl isothiocyanate (AITC; mustard oil).
Results
Topical application of propofol (1–25%) significantly increased the mean latency of the thermally evoked hindpaw withdrawal reflex on the treated (but not opposite) side in a concentration-dependent manner, with no effect on mechanically evoked hindpaw withdrawal thresholds. Propofol also prevented shortening of paw withdrawal latency induced by AITC. In electrophysiological experiments, topical application of 10 and 25% propofol, but not 1% propofol or vehicle (10% intralipid), to the ipsilateral hindpaw significantly attenuated the magnitude of responses of WDR neurons to noxious heating of glabrous hindpaw skin with no significant change in thermal thresholds. Maximal suppression of noxious heat-evoked responses was achieved 15-min after application followed by recovery to the pre-propofol baseline by 30 min. Responses to skin cooling or graded mechanical stimuli were not significantly affected by any concentration of propofol. Topical application of AITC enhanced the noxious heat-evoked response of dorsal horn neurons. This enhancement of heat-evoked responses was attenuated when 10% propofol was applied topically after application of AITC.
Conclusions
The results indicate that topical propofol inhibits responses of WDR neurons to noxious heat consistent with analgesia, and reduced AITC sensitization of WDR neurons consistent with an antihyperalgesic effect. These results are consistent with clinical studies demonstrating reduced postoperative pain in surgical patients anesthetized with propofol. The mechanism of analgesic action of topical propofol is not clear, but may involve desensitization of TRPV1 or TRPA1 receptors expressed in peripheral nociceptive nerve endings, engagement of endocannabinoids, or activation of peripheral gamma-aminobutyric acid A receptors.
doi:10.1213/ANE.0b013e31827f560d
PMCID: PMC3606650  PMID: 23337417
22.  Dexmedetomidine attenuates neuropathic pain in chronic constriction injury by suppressing NR2B, NF-κB, and iNOS activation 
The effective treatment of patients suffering from neuropathic pain remains challenging. Dexmedetomidine (DEX) possesses anti-inflammatory activity. However, the role of DEX in neuropathic pain is still unclear. The aim of the present study was to examine DEX an α2-adrenoceptor agonist could improve pain hypersensitivity and reduce inflammatory in a chronic constriction injury (CCI) model of the sciatic nerve in Sprague-Dawley rats. Dex was intrathecally administrated 1-h after operation. The paw mechanical withdrawal threshold (MWT) and paw withdrawal thermal latency (PWTL) were measured on day 1 before operation and on days 1, 7, 14 and 21 after operation, respectively. On day 21, all the rats were decapitated to collect the L4-6 segments of the spinal cord to examine IL-1, TNF-α, IL-6, NR2B, NF-κB, and iNOS mRNA levels using RT-PCR. The postoperative MWT and PWTL were significantly decreased in CCI, and DEX groups as compared to those before surgery and Sham group (P < 0.05). And DEX reversed this trend (P < 0.05). Interleukin 1 (IL-1), tumor necrosis factor α (TNF-α), IL-6 mRNA expression significantly increased postsurgery in CCI group as compared to that of Sham group (P < 0.05); DEX blocked increased IL-1, TNF-α, IL-6, N-methyl-D-aspartate (NMDA) receptor 2B (NR2B), nuclear factor κB (NF-κB), and inducible isoform of nitric oxide synthase (iNOS) mRNA levels (P < 0.05). DEX may alleviate neuropathic hypersensitivity and inflammation partially by inhibiting NR2B, NF-κB, and iNOS expression in the spinal cord of rats with neuropathic pain resulting from CCI of the sciatic nerve.
doi:10.1016/j.jsps.2017.04.039
PMCID: PMC5447440
Neuropathic pain; Dexmedetomidine; Inflammation; Rat
23.  In vivo USPIO magnetic resonance imaging shows that minocycline mitigates macrophage recruitment to a peripheral nerve injury 
Molecular Pain  2012;8:49.
Background
Minocycline has proven anti-nociceptive effects, but the mechanism by which minocycline delays the development of allodynia and hyperalgesia after peripheral nerve injury remains unclear. Inflammatory cells, in particular macrophages, are critical components of the response to nerve injury. Using ultrasmall superparamagnetic iron oxide-magnetic resonance imaging (USPIO-MRI) to monitor macrophage trafficking, the purpose of this project is to determine whether minocycline modulates macrophage trafficking to the site of nerve injury in vivo and, in turn, results in altered pain thresholds.
Results
Animal experiments were approved by Stanford IACUC. A model of neuropathic pain was created using the Spared Nerve Injury (SNI) model that involves ligation of the left sciatic nerve in the left thigh of adult Sprague–Dawley rats. Animals with SNI and uninjured animals were then injected with/without USPIOs (300 μmol/kg IV) and with/without minocycline (50 mg/kg IP). Bilateral sciatic nerves were scanned with a volume coil in a 7 T magnet 7 days after USPIO administration. Fluid-sensitive MR images were obtained, and ROIs were placed on bilateral sciatic nerves to quantify signal intensity. Pain behavior modulation by minocycline was measured using the Von Frey filament test. Sciatic nerves were ultimately harvested at day 7, fixed in 10% buffered formalin and stained for the presence of iron oxide-laden macrophages. Behavioral measurements confirmed the presence of allodynia in the neuropathic pain model while the uninjured and minocycline-treated injured group had significantly higher paw withdrawal thresholds (p < 0.011). Decreased MR signal is observed in the SNI group that received USPIOs (3.3+/−0.5%) compared to the minocycline-treated SNI group that received USPIOs (15.2+/−4.5%) and minocycline-treated group that did not receive USPIOs (41.2+/−2.3%) (p < 0.04). Histology of harvested sciatic nerve specimens confirmed the presence USPIOs at the nerve injury site in the SNI group without minocycline treatment.
Conclusion
Animals with neuropathic pain in the left hindpaw show increased trafficking of USPIO-laden macrophages to the site of sciatic nerve injury. Minocycline to retards the migration of macrophages to the nerve injury site, which may partly explain its anti-nociceptive effects. USPIO-MRI is an effective in vivo imaging tool to study the role of macrophages in the development of neuropathic pain.
doi:10.1186/1744-8069-8-49
PMCID: PMC3472277  PMID: 22742763
Neuropathic pain; Macrophages; Magnetic resonance imaging; Iron-oxide nanoparticles; Spared-nerve injury model
24.  Application of the chronic constriction injury of the partial sciatic nerve model to assess acupuncture analgesia 
Journal of Pain Research  2017;10:2271-2280.
Purpose
To validate and explore the application of a rat model of chronic constriction injury to the partial sciatic nerve in investigation of acupuncture analgesia.
Methods
Chronic constriction injury of the sciatic nerve (CCI) and chronic constriction injury of the partial sciatic nerve (CCIp) models were generated by ligating either the sciatic nerve trunk or its branches in rats. Both models were evaluated via paw mechanical withdrawal latency (PMWL), paw mechanical withdrawal threshold (PMWT), nociceptive reflex-induced electromyogram (C-fiber reflex EMG), and dorsal root ganglion immunohistochemistry. Electroacupuncture (EA) was performed at GB30 to study the analgesic effects on neuropathic pain and the underlying mechanisms.
Results
Following ligation of the common peroneal and tibial nerves, CCIp rats exhibited hindlimb dysfunction, hind paw shrinkage and lameness, mirroring those of CCI rats (generated by ligating the sciatic nerve trunk). Compared to presurgery measurements, CCIp and CCI modeling significantly decreased the PMWL and PMWT. EA at GB30 increased the PMWL and PMWT in both CCI and CCIp rats. Calcitonin gene-related polypeptide and substance P expressions were apparently increased in both CCI and CCIp groups, but were not different from each other. The C-fiber reflex EMG of the biceps femoris was preserved in CCIp rats, but it could not be recorded in CCI rats on the 5th day after nerve ligation. The C-fiber reflex EMG was reduced at 0, 1, and 2 minutes after EA in CCIp rats, but only at 0 and 1 minute after EA in normal rats.
Conclusion
The CCIp model is better than the CCI model for studying acupuncture analgesia on chronic neuropathic pain and the underlying mechanisms.
doi:10.2147/JPR.S139324
PMCID: PMC5614793
neuropathic pain; chronic constriction injury; acupuncture; analgesia; C-fiber reflex
25.  Selective Activation of Cannabinoid CB2 Receptors Suppresses Neuropathic Nociception Induced by Treatment with the Chemotherapeutic Agent Paclitaxel in Rats 
Activation of cannabinoid CB2 receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB2 receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the anti-tumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p. per day) on four alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the cremophor: ethanol: saline vehicle at the same times. Two structurally distinct cannabinoid CB2 agonists—the aminoalkylindole (R,S)-AM1241 ((R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone) and the cannabilactone AM1714 (1,9-dihydroxy-3-(1′,1′-dimethylheptyl)-6H-benzo[c]chromene-6-one)—produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia following systemic administration. Pretreatment with the CB2 antagonist SR144528 (5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide), but not the CB1 antagonist SR141716 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide), blocked the anti-allodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or pre-injection thresholds, consistent with mediation by CB2. Administration of either the CB1 or CB2 antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the cremophor vehicle in lieu of paclitaxel whereas AM1714 induced a modest antinociceptive effect. Our data suggest that cannabinoid CB2 receptors may be important therapeutic targets for the treatment of chemotherapy-evoked neuropathy.
doi:10.1124/jpet.108.141994
PMCID: PMC2682949  PMID: 18664590

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