Animal Models Of Neuropathic Pain Research Articles

Acute anti-allodynic action of gabapentin in dorsal horn and primary somatosensory cortex: Correlation of behavioural and physiological data

Neuropathic pain is a debilitating consequence of neuronal injury or disease. Although first line treatments include the alpha-2-delta (α2δ)-ligands, pregabalin and gabapentin (GBP), the mechanism of their anti-allodynic action is poorly understood. One specific paradox is that GBP relieves signs of neuropathic pain in animal models within 30min of an intraperitoneal (IP) injection yet its actions in vitro on spinal dorsal horn or primary afferent neurons take hours to develop. We found, using confocal Ca2+ imaging, that substantia gelatinosa neurons obtained ex vivo from rats subjected to sciatic chronic constriction injury (CCI) were more excitable than controls. We confirmed that GBP (100 mg/kg) attenuated mechanical allodynia in animals subject to CCI within 30min of IP injection.Substantia gelatinosa neurons obtained ex vivo from these animals no longer displayed CCI-induced increased excitability.Electrophysiological analysis of substantia gelatinosa neurons ex vivo suggest that rapidly developing in vivo anti-allodynic effects of GBP i) are mediated intracellularly, ii) involve actions on the neurotransmitter release machinery and iii) depend on decreased excitatory synaptic drive to excitatory neurons without major actions on inhibitory neurons or on intrinsic neuronal excitability. Experiments using in vivo Ca2+ imaging showed that 100 mg/kg GBP also suppressed the response of the S1 somatosensory cortex of CCI rats, but not that of control rats, to vibrotactile stimulation.Since the level of α2δ1 protein is increased in primary afferent fibres after sciatic CCI, we suggest this dictates the rate of GBP action; rapidly developing actions can only be seen when α2δ1 levels are elevated.

An automated method by which effects of compounds on locomotor activity and spontaneous neuropathic pain-specific movements can be simultaneously evaluated in rats with chronic-constriction nerve injury

Neuropathic pain patients are characterized by evoked pain (hyperalgesia and allodynia) and spontaneous pain, the latter of which is the predominant symptom. In animal models of neuropathic pain, effects of test compounds on spontaneous pain-related behaviors have been evaluated by direct visual observation. In addition, by performing another locomotor activity experiment in normal animals, it is also indispensable to examine whether test compounds cause motor impairment to avoid overestimation of their analgesic activities. In the present study, we developed spontaneous pain-specific and automated evaluation method by improving a previous method for measuring movements of the injured hind limb in unilateral chronic constriction nerve injury (CCI) rats. Rats with unilateral CCI were implanted with strong and weak magnets in each hind limb, respectively. Limb movements were automatically detected as spiked waveforms in electromagnetic field analyzing system. Movements in each limb were analyzed separately according to differences in their respective wave amplitudes, and aberrant movements of injured limb were specifically detected on basis of the asymmetry between injured and uninjured limb movements. Consequently, the incidence ratio of spontaneous pain in injured limb, which was not affected by individual locomotive activities, was able to be obtained as a new evaluation index. The incidence ratio of spontaneous pain revealed substantial difference between CCI and sham rats with only a small variation in the value. Further, according to the frequency of movement of the uninjured limb, it could be determined simultaneously whether a test compound causes sedative effect or not, resulting in eliminating the need for another experiment in normal animals.

The refined biomimetic NeuroDigm GEL™ Model of neuropathic pain in the mature rat.

Background: Many humans suffering with chronic pain have no clinical evidence of a lesion or disease. They are managed with a morass of drugs and invasive procedures. Opiates usually become less effective over time. In many, their persistent pain occurs after the healing of a soft tissue injury. Current animal models of neuropathic pain typically create direct neural damage with open surgeries using ligatures, neurectomies, chemicals or other forms of deliberate trauma. However, we have observed clinically that after an injury in humans, the naturally occurring process of tissue repair can cause chronic neural pain. Methods: We demonstrate how the refined biomimetic NeuroDigm GEL™ Model, in the mature male rat, gradually induces neuropathic pain behavior with a nonsurgical percutaneous implant of tissue-derived hydrogel in the musculo-fascial tunnel of the distal tibial nerve. Morphine, Celecoxib, Gabapentin and Duloxetine were each screened in the model three times each over 5 months after pain behaviors developed. A pilot study followed in which recombinant human erythropoietin was applied to the GEL neural procedure site. Results: The GEL Model gradually developed neuropathic pain behavior lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses had profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months. Histology revealed a site of focal neural remodeling, with neural regeneration, as in human biopsies. Conclusion: The refined NeuroDigm GEL™ Model induces localized neural remodeling resulting in robust neuropathic pain behavior. The analgesics responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin appears to heal the ectopic focal neural site, as demonstrated by the extinguishing of neuropathic pain behavior present for over 4 months.

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain.

Nociception - the ability to detect painful stimuli - is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a 'pacemaker for pain', in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

Neuroprotective Effect of Matrine in Mouse Model of Vincristine-Induced Neuropathic Pain.

Chemotherapy drugs such as vincristine (VCR) can cause neuropathic pain, and there is still lack of ideal strategy to treat it. The current study was designed to investigate effect of matrine (MT) on VCR-induced neuropathic pain in animal model. VCR (75μg/kg, i.p. for 10 consecutive days) was administered to induce painful neuropathy model in mice. MT (15, 30 and 60mg/kg, i.p.) and pregabalin (10mg/kg, i.p.) were administered for 11 consecutive days. Various tests were performed to assess the degree of pain at different days (1, 6, 11, 16, and 21). Von Frey hair, hot plate, cold-plate and paw pressure tests were conducted to assess the degree of mechanical allodynia, thermal hyperalgesia, cold allodynia and mechanical hyperalgesia in the hind paw respectively. The electrophysiological and histopathological changes were also analyzed. Furthermore, tissue malondialdehyde (MDA), total antioxidant capacity (T-AOC),superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total calcium (TCA), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10) were measured to investigate possible involvement of MT in inflammation and oxidative stress. Administration of MT attenuated the VCR-induced behavioral alterations as well as electrophysiological and histopathological changes in a dose dependent manner. Further, MT also attenuated the VCR-induced oxidative stress (MDA, T-AOC, GSH-Px, SOD and TCA) and inflammation (MPO, TNF-α, IL-6 and IL-10). Taken together, MT ameliorated VCR-induced painful neuropathy, which might be attributed to neuroprotective effects by subsequent reduction in oxidative stress and anti-inflammatory actions.

Exercise-induced hypoalgesia: potential mechanisms in animal models of neuropathic pain.

Physical exercise, such as forced treadmill running and swimming, can sufficiently improve mechanical allodynia and heat hyperalgesia in animal models of neuropathic pain (NPP), including partial sciatic nerve ligation, chronic constriction injury, and spinal nerve ligation models. Thus, physical exercise has been established as a low-cost, safe, and effective way to manage NPP conditions, but the exact mechanisms underlying such exercise-induced hypoalgesia (EIH) are not fully understood. A growing body of evidence has identified several factors that work at different levels of the nervous system as playing important roles in producing EIH in animal models of NPP. The objective of this review is to provide an overview of key players associated with EIH, and then to discuss our current understanding of the mechanisms underlying EIH. Relevant studies have demonstrated that physical exercise can dramatically alter the levels of inflammatory cytokines, neurotrophins, neurotransmitters, endogenous opioids, and histone acetylation at various sites in the nervous system, such as injured peripheral nerves, dorsal root ganglia, and spinal dorsal horn in animal models of NPP, thereby contributing to the production of EIH. These results suggest that EIH is produced through multiple cellular and molecular events in the pain pathway.

Genomics of the Effect of Spinal Cord Stimulation on an Animal Model of Neuropathic Pain

Few studies have evaluated single-gene changes modulated by spinal cord stimulation (SCS), providing a narrow understanding of molecular changes. Genomics allows for a robust analysis of holistic gene changes in response to stimulation. Rats were randomized into six groups to determine the effect of continuous SCS in uninjured and spared-nerve injury (SNI) animals. After behavioral assessment, tissues from the dorsal quadrant of the spinal cord (SC) and dorsal root ganglion (DRG) underwent full-genome microarray analyses. Weighted Gene Correlation Network Analysis (WGCNA), and Gene Ontology (GO) analysis identified similar expression patterns, molecular functions and biological processes for significant genes. Microarray analyses reported 20,985 gene probes in SC and 19,104 in DRG. WGCNA sorted 7449 SC and 4275 DRG gene probes into 29 and 9 modules, respectively. WGCNA provided significant modules from paired comparisons of experimental groups. GO analyses reported significant biological processes influenced by injury, as well as the presence of an electric field. The genes Tlr2, Cxcl16, and Cd68 were used to further validate the microarray based on significant response to SCS in SNI animals. They were up-regulated in the SC while both Tlr2 and Cd68 were up-regulated in the DRG. The process described provides highly significant interconnected genes and pathways responsive to injury and/or electric field in the SC and DRG. Genes in the SC respond significantly to the SCS in both injured and uninjured animals, while those in the DRG significantly responded to injury, and SCS in injured animals.

Feasibility of Human Amniotic Fluid Derived Stem Cells in Alleviation of Neuropathic Pain in Chronic Constrictive Injury Nerve Model.

PurposeThe neurobehavior of neuropathic pain by chronic constriction injury (CCI) of sciatic nerve is very similar to that in humans, and it is accompanied by a profound local inflammation response. In this study, we assess the potentiality of human amniotic fluid derived mesenchymal stem cells (hAFMSCs) for alleviating the neuropathic pain in a chronic constriction nerve injury model.Methods and MethodsThis neuropathic pain animal model was conducted by four 3–0 chromic gut ligatures loosely ligated around the left sciatic nerve in Sprague—Dawley rats. The intravenous administration of hAFMSCs with 5x105 cells was conducted for three consecutive days.ResultsThe expression IL-1β, TNF-α and synaptophysin in dorsal root ganglion cell culture was remarkably attenuated when co-cultured with hAFMSCs. The significant decrease of PGP 9.5 in the skin after CCI was restored by administration of hAFMSCs. Remarkably increased expression of CD 68 and TNF-α and decreased S-100 and neurofilament expression in injured nerve were rescued by hAFMSCs administration. Increases in synaptophysin and TNF-α over the dorsal root ganglion were attenuated by hAFMSCs. Significant expression of TNF-α and OX-42 over the dorsal spinal cord was substantially attenuated by hAFMSCs. The increased amplitude of sensory evoked potential as well as expression of synaptophysin and TNF-α expression was alleviated by hAFMSCs. Human AFMSCs significantly improved the threshold of mechanical allodynia and thermal hyperalgesia as well as various parameters of CatWalk XT gait analysis.ConclusionHuman AFMSCs administration could alleviate the neuropathic pain demonstrated in histomorphological alteration and neurobehavior possibly through the modulation of the inflammatory response.

Increased miR-132-3p expression is associated with chronic neuropathic pain

Alterations in the neuro-immune balance play a major role in the pathophysiology of chronic neuropathic pain. MicroRNAs (miRNA) can regulate both immune and neuronal processes and may function as master switches in chronic pain development and maintenance. We set out to analyze the role of miR-132-3p, first in patients with peripheral neuropathies and second in an animal model of neuropathic pain. We initially determined miR-132-3p expression by measuring its levels in white blood cells (WBC) of 30 patients and 30 healthy controls and next in sural nerve biopsies of 81 patients with painful or painless inflammatory or non-inflammatory neuropathies based on clinical diagnosis. We found a 2.6 fold increase in miR-132-3p expression in WBC of neuropathy patients compared to healthy controls (p<0.001). MiR-132-3p expression was also slightly up-regulated in sural nerve biopsies from neuropathy patients suffering from neuropathic pain compared to those without pain (1.2 fold; p<0.001).These promising findings were investigated further in an animal model of neuropathic pain, the spared nerve injury model (SNI). For this purpose miR-132-3p expression levels were measured in dorsal root ganglia and spinal cord of rats. Subsequently, miR-132-3p expression was pharmacologically modulated with miRNA antagonists or mimetics, and evoked pain and pain aversion were assessed.Spinal miR-132-3p levels were highest 10days after SNI, a time when persistent allodynia was established (p<0.05). Spinal administration of miR-132-3p antagonists via intrathecal (i.t.) catheters dose dependently reversed mechanical allodyina (p<0.001) and eliminated pain behavior in the place escape avoidance paradigm (p<0.001). Intrathecal administration of miR-132-3p mimetic dose-dependently induced pain behavior in naïve rats (p<0.001). Taken together these results indicate a pro-nociceptive effect of miR-132-3p in chronic neuropathic pain.

Liposomal Formulation to Increase Stability and Prolong Antineuropathic Activity of Verbascoside.

Verbascoside (acteoside) possesses various pharmacological properties for human health, including antioxidant, anti-inflammatory, and antineoplastic properties in addition to numerous wound healing and neuroprotective properties, with an excellent and well-known safety profile. However, its poor chemical stability, due to hydrolysis, limits its use in the clinic. To overcome these limitations, we prepared unilamellar liposomal formulations of verbascoside for parenteral administration.Two formulations were prepared: V-L1 and V-L2, where V-L2 contains phospholipid and cholesterol about 4 times higher than the V-L1 sample, and about 2 times higher than verbascoside. The mean particle size of the liposomes prepared was found to be around 120 nm with a polydispersity index < 0.2. Encapsulation efficacy resulted in 30 %. A total of 82.28 ± 1.79 % of verbascoside was released from the liposomes within 24 hours. Liposomes ameliorate the stability of verbascoside by preventing its hydrolysis.The optimized drug delivery formulation was tested in the paw pressure test in two animal models of neuropathic pain: a peripheral mononeuropathy was produced either by a chronic constriction injury of the sciatic nerve or by an intra-articular injection of sodium monoiodoacetate. The performance of the liposomal formulation was compared with that of the free drug.For evaluating the paw pressure test in chronic constriction injury rats, a liposomal formulation administered i. p. at the dosage of 100 mg/kg showed a longer lasting antihyperalgesic effect in comparison with a 100-mg/kg verbascoside saline solution, as well as in the sodium monoiodoacetate models. The effect appeared 15 min after administration and persisted for up to 60 min.

Differential expression of P2X7 receptor and IL-1β in nociceptive and neuropathic pain.

BackgroundDespite substantial progress, pathogenesis and therapy of chronic pain are still the focus of many investigations. The ATP-gated P2X7 receptor (P2X7R) has previously been shown to play a central role in animal models of nociceptive inflammatory and neuropathic pain. Recently, we found that the adaptive immune system is involved in the pathophysiology of chronic nociceptive and neuropathic pain in humans. So far, data regarding P2X7R expression patterns on cells of the adaptive immune system of pain patients are scarce. We therefore analyzed the P2X7R expression on peripheral blood lymphocytes and monocytes, as well as serum levels of IL-1β in patients suffering from chronic nociceptive and neuropathic pain in comparison to healthy volunteers in order to identify individuals who might benefit from a P2X7R modulating therapy.MethodsP2X7R messenger RNA (mRNA) and protein expression were determined in patients with either chronic nociceptive low back pain (CLBP) or neuropathic pain (NeP), and in healthy volunteers by quantitative real-time PCR (qPCR) and by fluorescence-assisted cell-sorting (FACS), respectively. IL-1β serum levels were measured with a multiplex cytokine assay.ResultsCompared to healthy volunteers, P2X7R mRNA (1.6-fold, p = 0.038) and protein levels were significantly increased on monocytes (NeP: 24.6 ± 6.2, healthy volunteers: 17.0 ± 5.4; p = 0.002) and lymphocytes (NeP: 21.8 ± 6.5, healthy volunteers: 15.6 ± 5.2; p = 0.009) of patients with NeP, but not in patients with CLBP. Similarly, IL-1β serum concentrations were significantly elevated only in NeP patients (1.4-fold, p = 0.04).ConclusionsA significant upregulation of P2X7R and increased IL-1β release seems to be a particular phenomenon in patients with NeP. P2X7R inhibitors may therefore represent a potential option for the treatment of this frequently intractable type of pain.German Clinical Trial Register (DRKS): Registration Trial DRKS00005954.

Baclofen reversed thermal place preference in rats with chronic constriction injury.

Chronic constriction injury to the sciatic nerve was used as an animal model of neuropathic pain. Instead of frequently used reflex-based tests we used an operant thermal place preference test to evaluate signs of neuropathic pain and the effect of baclofen administration in rats with neuropathy. Chronic constriction injury was induced by four loose ligations of the sciatic nerve. Thermal place preference (45 °C vs. 22 °C and 45 °C vs. 11 °C) was measured after the ligation and after the administration of baclofen in sham and experimental rats. Rats with the chronic constriction injury spent significantly less time on the colder plate compared to sham operated animals at the combination 45 °C vs. 11 °C. After administration of baclofen (10 mg/kg s.c.), the aversion to the colder plate in rats with chronic constriction injury disappeared. At the combination 45 °C vs. 22 °C, no difference in time spent on colder and/or warmer plate was found between sham and experimental animals. These findings show the importance of cold allodynia evaluation in rats with chronic constriction injury and the effectiveness of baclofen in this neuropathic pain model.

Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons

The μ-opioid receptor (MOR, encoded by Oprm1) agonists are the mainstay analgesics for treating moderate to severe pain. Nerve injury causes down-regulation of MORs in the dorsal root ganglion (DRG) and diminishes the opioid effect on neuropathic pain. However, the epigenetic mechanisms underlying the diminished MOR expression caused by nerve injury are not clear. G9a (encoded by Ehmt2), a histone 3 at lysine 9 methyltransferase, is a key chromatin regulator responsible for gene silencing. In this study, we determined the role of G9a in diminished MOR expression and opioid analgesic effects in animal models of neuropathic pain. We found that nerve injury in rats induced a long-lasting reduction in the expression level of MORs in the DRG but not in the spinal cord. Nerve injury consistently increased the enrichment of the G9a product histone 3 at lysine 9 dimethylation in the promoter of Oprm1 in the DRG. G9a inhibition or siRNA knockdown fully reversed MOR expression in the injured DRG and potentiated the morphine effect on pain hypersensitivity induced by nerve injury. In mice lacking Ehmt2 in DRG neurons, nerve injury failed to reduce the expression level of MORs and the morphine effect. In addition, G9a inhibition or Ehmt2 knockout in DRG neurons normalized nerve injury-induced reduction in the inhibitory effect of the opioid on synaptic glutamate release from primary afferent nerves. Our findings indicate that G9a contributes critically to transcriptional repression of MORs in primary sensory neurons in neuropathic pain. G9a inhibitors may be used to enhance the opioid analgesic effect in the treatment of chronic neuropathic pain.

Duloxetine and 8-OH-DPAT, but not fluoxetine, reduce depression-like behaviour in an animal model of chronic neuropathic pain

The current study assessed whether antidepressant and/or antinociceptive drugs, duloxetine, fluoxetine as well as (±)-8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), are able to reverse depression-like behaviour in animals with chronic neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve in rats was selected as neuropathic pain model. Mechanical hypersensitivity and depression-like behaviour were evaluated 4 weeks after surgery by “electronic algometer” and forced swimming test (FST), which measured the time of immobility, and active behaviours climbing and swimming. The selective noradrenergic and serotonergic uptake blocker duloxetine (20mg/kg) and the selective 5-HT1A agonist 8-OH-DPAT (0.5mg/kg) significantly reversed both mechanical hypersensitivity and depression-like behaviour in CCI animals. Duloxetine significantly reversed depression-like behaviour in CCI rats by increasing the time of climbing and swimming, while 8-OH-DPAT attenuated depression-like behaviour mainly by increasing the time of swimming. However, the selective serotonergic uptake blocker fluoxetine (20mg/kg) failed to attenuate mechanical hypersensitivity and depression-like behaviour, possibly due to confounding pro-nociceptive actions at 5-HT3 receptors. These data suggest to target noradrenergic and 5-HT1A receptors for treatment of chronic pain and its comorbidity depression.

α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors

Objectiveα-Conotoxin Vc1.1 is a small disulfide-bonded peptide from the venom of the marine cone snail Conus victoriae. Vc1.1 has antinociceptive actions in animal models of neuropathic pain, but its applicability...

A Comparison of the Effects of Burst and Tonic Spinal Cord Stimulation on Hyperalgesia and Physical Activity in an Animal Model of Neuropathic Pain.

Parameters of spinal cord stimulation (SCS) play a role in its effectiveness and may impact SCS mechanisms and outcomes. For example, SCS applied in a bursting pattern may result in better pain relief than that for tonic SCS for neuropathic pain. We tested the effectiveness of different SCS pulse frequencies given at 2 different burst frequencies in an animal model of neuropathic pain. After Sprague-Dawley rats were anesthetized, neuropathic pain was induced using the spared nerve injury model, and an epidural SCS lead was implanted in the upper lumber spinal cord. One of the 8 different SCS parameters was delivered daily for 4 days at 90% motor threshold 2 weeks after nerve injury. Four burst patterns were administered at 4- or 40-Hz frequency with a train of 4 pulses at frequencies of 60, 500, and 1000 Hz. Sham and tonic patterns at 16, 60, and 160 Hz were chosen as controls. Paw withdrawal threshold was assessed before the surgery and 15 minutes before, during, and after SCS daily for 4 days. Physical activity (distance, crossing, rearing, and grooming) was assessed before surgery, before SCS on day 1, and after SCS on day 4. Animals showed a decrease in paw withdrawal threshold and physical activity levels 2 weeks after nerve injury. During stimulation, burst SCS with pulse frequencies of 60, 500, or 1000 Hz were more effective for improving paw withdrawal threshold than sham and tonic SCS at 16 Hz. Burst SCS with higher pulse frequencies (500 and 1000 Hz) than 60-Hz SCS and burst SCS with higher pulse frequencies (1000 Hz) than 160-Hz SCS were more effective. In addition, tonic SCS at 160 Hz and burst SCS with higher pulse frequencies (500 and 1000 Hz) significantly increased the distance traveled. Burst SCS at 4 Hz with pulse frequency of 1000 Hz also increased the number of crossings when compared with sham control and tonic SCS at 16 Hz. The current study shows that a variety of SCS pulse frequencies applied with a burst frequency result in greater improvement in hyperalgesia and activity levels than tonic SCS in a neuropathic pain model during stimulation.

The endocannabinoid system and neuropathic pain.

The research of new therapeutic strategies for neuropathic pain represents a major current priority. Important drawbacks to advance in the development of these therapies are the limited translational value of the animal models now available and the elucidation of the complex neuronal and immune pathophysiological mechanisms underlying neuropathic pain. One of the neurotransmitter systems participating in neuropathic pain control that has recently raised a particular interest is the endocannabinoid system. This system is highly expressed in neurons and immune cells, and it plays a crucial role in the development of neuropathic pain. Preclinical studies have provided important findings, revealing the potential interest of the endocannabinoid system for the treatment of neuropathic pain. These studies have reported the analgesic effects of cannabinoid agonists in multiple neuropathic pain models, and they have identified specific targets within this system to develop more effective and safe analgesic compounds. However, further studies using more relevant neuropathic pain animal models are required to confirm these interesting results. Several clinical studies suggest that cannabinoids significantly reduced neuropathic pain, although most of these trials fail the required standards of quality. The different pain patient populations included in the systematic reviews also make it difficult to get adequate conclusions. Therefore, additional clinical trials that consider an adequate number of patients, the use active treatments as controls, and longer duration of administration are required to have an adequate profile of the effectiveness and safety of cannabinoids in neuropathic pain.

Agomelatine: a new opportunity to reduce neuropathic pain-preclinical evidence.

Antidepressants are first-line treatments of neuropathic pain but not all these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect norepinephrine release. Melatonin, serotonin, and norepinephrine have been involved in the pathophysiology of neuropathic pain. Yet, no study has been conducted to determine agomelatine effects on neuropathic pain in animal models. Using 3 rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, we investigated the antihypersensitivity effect of acute and repeated agomelatine administration. We then determined the influence of melatonergic, 5-HT2C, α-2 and β-1/2 adrenergic receptor antagonists in the antihypersensitivity effect of agomelatine. The effect of the combination of agomelatine + gabapentin was evaluated using an isobolographic approach. In STZ and CCI models, single doses of agomelatine significantly and dose dependently reduced mechanical hypersensitivity. After daily administrations for 2 weeks, this effect was confirmed in the CCI model and agomelatine also displayed a marked antihypersensitivity effect in the OXA model. The antihypersensitivity effect of agomelatine involved melatonergic, 5-HT2C, and α-2 adrenergic receptors but not beta adrenoceptors. The isobolographic analysis demonstrated that the combination of agomelatine + gabapentin had additive effects. Agomelatine exerts a clear-cut antihypersensitivity effect in 3 different neuropathic pain models. Its effect is mediated by melatonergic and 5-HT2C receptors and, although agomelatine has no affinity, also by α-2 adrenergic receptors. Finally, agomelatine combined with gabapentin produces an additive antihypersensitivity effect.

Nonparalytic botulinum molecules for the control of pain.

Local injections of botulinum toxins have been reported to be useful not only for the treatment of peripheral neuropathic pain and migraine but also to cause long-lasting muscle paralysis, a potentially serious side effect. Recently, a botulinum A-based molecule ("BiTox") has been synthesized that retains neuronal silencing capacity without triggering muscle paralysis. In this study, we examined whether BiTox delivered peripherally was able to reduce or prevent the increased nociceptive sensitivity found in animal models of inflammatory, surgical, and neuropathic pain. Plasma extravasation and edema were also measured as well as keratinocyte proliferation. No motor deficits were seen and acute thermal and mechanical nociceptive thresholds were unimpaired by BiTox injections. We found reduced plasma extravasation and inflammatory edema as well as lower levels of keratinocyte proliferation in cutaneous tissue after local BiTox injection. However, we found no evidence that BiTox was transported to the dorsal root ganglia or dorsal horn and no deficits in formalin-elicited behaviors or capsaicin or formalin-induced c-Fos expression within the dorsal horn. In contrast, Bitox treatment strongly reduced A-nociceptor-mediated secondary mechanical hyperalgesia associated with either complete Freund's adjuvant (CFA)-induced joint inflammation or capsaicin injection and the hypersensitivity associated with spared nerve injury. These results imply that although local release of neuromodulators from C-fibers was inhibited by BiTox injection, C-nociceptive signaling function was not impaired. Taken together with recent clinical data the results suggest that BiTox should be considered for treatment of pain conditions in which A-nociceptors are thought to play a significant role.

A comparative study of the anti-nociceptive potential of duloxetine and carbamazepine in an animal model of neuropathic pain

Background: Pain is one of the most common symptoms encountered in clinical practice. Of the various types of pain, neuropathic pain represents one of the most difficult pain states to treat, with treatments being far from satisfactory. The drugs used are not fully effective and a drug that shows good efficacy in one neuropathic pain state may be ineffective in another. This study was done to compare the antinociceptive potential of duloxetine and carbamazepine, two drugs with different mechanisms of action in an animal model of neuropathic pain.Methods: Antinociceptive effect of duloxetine (15 mg/kg intraperitoneally) and carbamazepine (20 mg/kg intraperitoneally) was evaluated in the sciatic chronic constriction injury (CCI) model of neuropathic pain in rats. Thermal hyperalgesia, evaluated by the hot plate method; and mechanical hyperalgesia, evaluated by the pinprick method were used as measures of neuropathic pain.Results: A significant degree of thermal and mechanical hyperalgesia (p ≤0.05) was produced in both the drug groups. Both drugs produced a significant decrease in thermal and mechanical hyperalgesia throughout the study period (p ≤0.01 for both drugs). In comparison to duloxetine, carbamazepine was less efficacious (p ≤0.05 at 30, 60 minutes; p ≤0.01 at 120 minutes) for thermal hyperalgesia as well as for mechanical hyperalgesia (p ≤0.05 at 30, 60 minutes; p≤0.01 at 120 minutes). Only duloxetine was able to almost completely reverse both thermal &amp; mechanical hyperalgesia to near pre-neuropathy levels.Conclusions: Duloxetine showed better antinociceptive potential as compared to carbamazepine as reflected by a more complete reduction in thermal &amp; mechanical hyperalgesia in the sciatic CCI model of neuropathic pain.