Cold Allodynia In Rats Research Articles

The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis

Osteoarthritis represents a leading cause of disability with limited treatment options. Furthermore, it is frequently accompanied by cardiovascular and cognitive disorders, which can be exacerbated by osteoarthritis or drugs used for its treatment. Here, we examined the behavioral and cardiac effects of the novel antidepressant vortioxetine in an osteoarthritis model, and compared them to duloxetine (an established osteoarthritis treatment). Osteoarthritis was induced in male and female rats with an intraarticular sodium-monoiodoacetate injection. Antidepressants were orally administered for 28 days following induction. During this period the acetone, burrowing and novel-object-recognition tests (NORT) were used to assess the effects of antidepressants on pain hypersensitivity (cold allodynia), animal well-being and cognitive performance, respectively. Following behavioral experiments, heart muscles were collected for assessment of redox status/histology. Antidepressant treatment dose-dependently reduced cold allodynia in rats with osteoarthritis. Duloxetine (but not vortioxetine) depressed burrowing behavior in osteoarthritic rats in a dose-related manner. Osteoarthritis induction reduced cognitive performance in NORT, which was dose-dependently alleviated by vortioxetine (duloxetine improved performance only in female rats). Furthermore, duloxetine (but not vortioxetine) increased oxidative stress parameters in the heart muscles of female (but not male) rats and induced histological changes in cardiomyocytes indicative of oxidative damage. Vortioxetine displayed comparable efficacy to duloxetine in reducing pain hypersensitivity. Furthermore, vortioxetine (unlike duloxetine) dose-dependently improved cognitive performance and had no adverse effect on burrowing behavior (animal surrogate of well-being) and cardiac redox status/histology. Our results indicate that vortioxetine could be a potential osteoarthritis treatment (with better characteristics compared to duloxetine).

Chinese Tuina remodels the synaptic structure in neuropathic pain rats by downregulating the expression of N-methyl D-aspartate receptor subtype 2B and postsynaptic density protein-95 in the spinal cord dorsal horn.

To investigate whether the Chinese massage system, Tuina, exerts analgesic effects in a rat model of chronic constriction injury (CCI) by remodeling the synaptic structure in the spinal cord dorsal horn (SCDH). Sixty-nine male Sprague-Dawley rats were randomly and evenly divided into the normal group, sham group, CCI group, CCI + Tuina group, CCI + MK-801 [an -methyl D-aspartate receptor subtype 2B (NR2B) antagonist] group, and CCI + MK-801 + Tuina group. The neuropathic pain model was established using CCI with right sciatic nerve ligation. Tuina was administered 4 d after CCI surgery, using pressing manipulation for 10 min, once daily. Motor function was observed with the inclined plate test, and pain behaviors were observed by the Von Frey test and acetone spray test. At 19 d after surgery, the L3-L5 spinal cord segments were removed. Glutamate, interleukin 1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels were detected by enzyme-linked immunosorbent assay. The protein expression levels of NR2B and postsynaptic density protein-95 (PSD-95) were detected by Western blot, and the synaptic structure was observed by transmission electron microscopy (TEM). CCI reduced motor function and caused mechanical and cold allodynia in rats, increased glutamate concentration and TNF-α and IL-1β levels, and increased expression of synapse-related proteins NR2B and PSD-95 in the SCDH. TEM revealed that the synaptic structure of SCDH neurons was altered. Most of these disease-induced changes were reversed by Tuina and intrathecal injection of MK-801 ( < 0.05 or < 0.01). For the majority of experiments, no significant differences were found between the CCI + MK-801 and CCI + MK-801 + Tuina groups. Chinese Tuina can alleviate pain by remodeling the synaptic structure, and NR2B and PSD-95 receptors in the SCDH may be among its targets.

High-CBD Cannabis Vapor Attenuates Opioid Reward and Partially Modulates Nociception in Female Rats

Chronic pain patients report analgesic effects when using cannabidiol (CBD), a phytocannabinoid found in whole-plant cannabis extract (WPE). Several studies suggest that cannabis-derived products may serve as an analgesic adjunct or alternative to opioids, and importantly, CBD may also attenuate the abuse potential of opioids. Vaping is a popular route of administration among people who use cannabis, however both the therapeutic and hazardous effects of vaping are poorly characterized. Despite the fact that chronic pain is more prevalent in women, the ability of inhaled high-CBD WPE to relieve pain and reduce opioid reward has not been studied in females. Here, we present a comprehensive analysis of high-CBD WPE vapor inhalation in female rats. We found that WPE was modestly efficacious in reversing neuropathy-induced cold allodynia in rats with spared nerve injury (SNI). Chronic exposure to WPE did not affect lung cytoarchitecture or estrous cycle, and it did not induce cognitive impairment, social withdrawal or anxiolytic effects. WPE inhalation prevented morphine-induced conditioned place preference and reinstatement. Similarly, WPE exposure reduced fentanyl self-administration in rats with and without neuropathic pain. We also found that WPE vapor lacks of reinforcing effects compared to the standard excipient used in most vapor administration research. Combined, these results suggest that although high-CBD vapor has modest analgesic effects, it has a robust safety profile, no abuse potential, and it significantly reduces opioid reward in females. Clinical studies examining high-CBD WPE as an adjunct treatment during opioid use disorder are highly warranted.

Cortical Neurostimulation and N-Methyl-D-Aspartate Glutamatergic Receptor Activation in the Dysgranular Layer of the Posterior Insular Cortex Modulate Chronic Neuropathic Pain

Background and AimsThe dysgranula parts of the posterior insular cortex (PIC) stimulation (PICS) has been investigated as a new putative cortical target for nonpharmacologic therapies in patients with chronic and neuropathic pain (NP). This work investigates the neural bases of insula neurostimulation–induced antinociception and glutamatergic neurochemical mechanisms recruited by the PICS in animals with neuropathy. Materials and MethodsMale Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham procedure (“false operated”). Either the Cascade Blue 3000 MW lysine-fixable dextran (CBD) or the biotinylated dextran amine 3000 MW (BDA) neural tract tracer was microinjected into the PIC. The electrical PICS was performed at a low frequency (20 μA, 100 Hz) for 15 seconds by a deep brain stimulation device. PIC N-methyl-D-aspartate (NMDA) receptors (NMDAR) blockade with the selective antagonist LY235959 (at 2, 4, and 8 nmol/200 nL) followed by PICS was investigated in rats with CCI. ResultsPIC sends projections to the caudal pontine reticular nucleus, alpha part of the parvicellular reticular nucleus, dorsomedial tegmental area, and secondary somatosensory cortex (S2). PICS decreased both mechanical and cold allodynia in rats with chronic NP. Blockade of NMDAR in the PIC with LY235959 at 8 nmol attenuated PICS-produced antinociception. ConclusionNeuroanatomic projections from the PIC to pontine reticular nuclei and S2 may contribute to chronic NP signaling. PICS attenuates the chronic NP, and the NMDA glutamatergic system in the PIC may be involved in PICS-induced antinociception in rodents with NP conditions.

A novel gabapentin analogue assuages neuropathic pain response in chronic sciatic nerve constriction model in rats

Gabapentin (GBP) is an established drug that has been used in the management of symptoms of neuropathy but it is associated with unwanted side effects such as sedation and motor incoordination. The goal of the study was to find out a drug with greater efficacy and safety for the treatment of neuropathic pain. Our previously synthesized GABA analogue (Gabapentsal, GPS) was tested (25-100 mg/kg, i.p) in chronic constriction injury (CCI) induced nociceptive model of static allodynia, dynamic allodynia, thermal hyperalgesia, mechanical hyperalgesia and cold allodynia in rats (Sprague Dawley). Open field and rotarod tests were performed to assess the impact of GPS on the motor performance of the animals. GBP (100 mg/kg, i.p) was used as a standard for comparison. GPS dose dependently reduced static (P <0.001) and dynamic allodynia (P <0.001), thermal hyperalgesia (P <0.001), mechanical hyperalgesia (P < 0.001) and cold allodynia (P < 0.001). In comparison to GBP, GPS failed to alter any significantly the motor performance of rats in both the open field and rotarod assays. These results suggest that GPS is effective in alleviating nociception in CCI neuropathic pain model but free from the side effect of motor discoordination seen in the treatment with GBP. In conclusion, GPS may prove to be a prospectively more effective and safer option in the management of neuropathic syndromes.

Gabapentin and Duloxetine Prevent Oxaliplatin- and Paclitaxel-Induced Peripheral Neuropathy by Inhibiting Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Phosphorylation in Spinal Cords of Mice.

Chemotherapy-induced peripheral neuropathy is a common factor in limiting therapy which can result in therapy cessation or dose reduction. Gabapentin, a calcium channel inhibitor, and duloxetine, a serotonin noradrenaline reuptake inhibitor, are used to treat a variety of pain conditions such as chronic low back pain, postherpetic neuralgia, and diabetic neuropathy. It has been reported that administration of gabapentin suppressed oxaliplatin- and paclitaxel-induced mechanical hyperalgesia in rats. Moreover, duloxetine has been shown to suppress oxaliplatin-induced cold allodynia in rats. However, the mechanisms by which these drugs prevent oxaliplatin- and paclitaxel-induced neuropathy remain unknown. Behavioral assays were performed using cold plate and the von Frey test. The expression levels of proteins were examined using western blot analysis. In this study, we investigated the mechanisms by which gabapentin and duloxetine prevent oxaliplatin- and paclitaxel-induced neuropathy in mice. We found that gabapentin and duloxetine prevented the development of oxaliplatin- and paclitaxel-induced cold and mechanical allodynia. In addition, our results revealed that gabapentin and duloxetine suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the spinal cord of mice. Moreover, PD0325901 prevented the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 activation in the spinal cord of mice. In summary, our findings suggest that gabapentin, duloxetine, and PD0325901 prevent the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 phosphorylation in mice. Therefore, inhibiting ERK1/2 phosphorylation could be an effective preventive strategy against oxaliplatin- and paclitaxel-induced neuropathy.

High-fat diet increases pain behaviors in rats with or without obesity

Obesity is associated with increased risk for chronic pain. Basic mechanisms for this association are poorly understood. Using a milder version of a radicular pain model, local inflammation of the dorsal root ganglion (DRG), we observed marked increases in mechanical and cold allodynia in rats of both sexes that were maintained on a high-fat diet (HFD) for 6 weeks prior to DRG inflammation. Notably, this increase in pain-related behaviors occurred in both Long-Evans and Sprague-Dawley rats despite the fact that the 6-week HFD exposure induced obesity (e.g., increased insulin, leptin, weight, and percent body fat) in the Long-Evans, but not Sprague-Dawley, strains. This suggested that HFD, rather than obesity per se, increased pain behaviors. Increased pain behaviors were observed even after a much shorter (1 week) exposure to the HFD but the effect was smaller. HFD also increased behavioral responses and paw swelling to paw injection of complete Freund’s adjuvant, a model of peripheral inflammatory pain. No change was detected in plasma cytokine levels in HFD rats. However, increased macrophage infiltration of the DRG was observed in response to the HFD, absent any pain model. The results suggest that HFD can increase pain even when it does not cause obesity.

Spinal activation of the NPY Y1 receptor reduces mechanical and cold allodynia in rats with chronic constriction injury

Neuropeptide tyrosine (NPY) and its associated receptors Y1R and Y2R have been previously implicated in the spinal modulation of neuropathic pain induced by total or partial sectioning of the sciatic nerve. However, their role in chronic constrictive injuries of the sciatic nerve has not yet been described. In the present study, we analyzed the consequences of pharmacological activation of spinal Y1R, by using the specific Y1R agonist Leu31Pro34-NPY, in rats with chronic constriction injury (CCI). CCI and sham-injury rats were implanted with a permanent intrathecal catheter (at day 7 after injury), and their response to the administration of different doses (2.5, 5, 7, 10 or 20μg) of Leu31Pro34-NPY (at a volume of 10μl) through the implanted catheter, recorded 14days after injury. Mechanical allodynia was tested by means of the up-and-down method, using von Frey filaments. Cold allodynia was tested by application of an acetone drop to the affected hindpaw. Intrathecal Leu31Pro34-NPY induced an increase of mechanical thresholds in rats with CCI, starting at doses of 5μg and becoming stronger with higher doses. Intrathecal Leu31Pro34 also resulted in reductions in the frequency of withdrawal to cold stimuli, although the effect was somewhat more moderate and mostly observed for doses of 7μg and higher. We thus show that spinal activation of the Y1R is able to reduce neuropathic pain due to a chronic constrictive injury and, together with other studies, support the use of a spinal Y1R agonist as a therapeutic agent against chronic pain induced by peripheral neuropathy.

CXCR1/2 pathways in paclitaxel-induced neuropathic pain.

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of neuropathic pain that represents a frequent and serious consequence of chemotherapy agents. Over the last years, significant progress has been achieved in elucidating the underlying pathogenesis of CIPN. The interference of taxanes with microtubule has been proposed as a mechanism that leads to altered axonal transport and to permanent neurological damages. The inflammatory process activated by chemotherapeutic agents has been considered as a potential trigger of nociceptive process in CIPN.In this study we investigated the effect of reparixin, an inhibitor of CXCR1/CXCR2, in suppressing the development of paclitaxel-induced nociception in rats. Moreover, reparixin activity in reversing the neurotoxic effects induced by paclitaxel or GRO/KC in F11 cells was also analyzed.Reparixin administered by continuous infusion ameliorated paclitaxel-induced mechanical and cold allodynia in rats. In F11 cells, reparixin was able to inhibit the increase of acetyladed α-tubulin induced both by paclitaxel and GRO/KC. The subsequent experiments were performed in order to dissect the signal transduction pathways under GRO/KC control, eventually modulated by paclitaxel and/or reparixin. To this aim we found that reparixin significantly counteracted p-FAK, p-JAK2/p-STAT3, and PI3K-p-cortactin activation induced either by paclitaxel or GRO/KC.Overall the present results have identified IL-8/CXCR1/2 pathway as a mechanism involved in paclitaxel-induced peripheral neuropathy. In particular, the obtained data suggest that the inhibition of CXCR1/2 combined with standard taxane therapy, in addition to potentiating the taxane anti-tumor activity can reduce chemotherapy-induced neurotoxicity, thus giving some insight for the development of novel treatments.

The Suppressive Effects of Cinnamomi Cortex and Its Phytocompound Coumarin on Oxaliplatin-Induced Neuropathic Cold Allodynia in Rats.

Oxaliplatin, a chemotherapy drug, induces acute peripheral neuropathy characterized by cold allodynia, spinal glial activation and increased levels of pro-inflammatory cytokines. Herein, we determined whether Cinnamomi Cortex (C. Cortex), a widely used medicinal herb in East Asia for cold-related diseases, could attenuate oxaliplatin-induced cold allodynia in rats and the mechanisms involved. A single oxaliplatin injection (6 mg/kg, i.p.) induced significant cold allodynia signs based on tail immersion tests using cold water (4 °C). Daily oral administration of water extract of C. Cortex (WECC) (100, 200, and 400 mg/kg) for five consecutive days following an oxaliplatin injection dose-dependently alleviated cold allodynia with only a slight difference in efficacies between the middle dose at 200 mg/kg and the highest dose at 400 mg/kg. WECC at 200 mg/kg significantly suppressed the activation of astrocytes and microglia and decreased the expression levels of IL-1β and TNF in the spinal cord after injection with oxaliplatin. Furthermore, oral administration of coumarin (10 mg/kg), a major phytocompound of C. Cortex, markedly reduced cold allodynia. These results indicate that C. Cortex has a potent anti-allodynic effect in oxaliplatin-injected rats through inhibiting spinal glial cells and pro-inflammatory cytokines. We also suggest that coumarin might play a role in the anti-allodynic effect of C. Cortex.

Involvement of spinal muscarinic and serotonergic receptors in the anti-allodynic effect of electroacupuncture in rats with oxaliplatin-induced neuropathic pain.

This study was performed to investigate whether the spinal cholinergic and serotonergic analgesic systems mediate the relieving effect of electroacupuncture (EA) on oxaliplatin-induced neuropathic cold allodynia in rats. The cold allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) was evaluated by immersing the rat's tail into cold water (4℃) and measuring the withdrawal latency. EA stimulation (2 Hz, 0.3-ms pulse duration, 0.2~0.3 mA) at the acupoint ST36, GV3, or LI11 all showed a significant anti-allodynic effect, which was stronger at ST36. The analgesic effect of EA at ST36 was blocked by intraperitoneal injection of muscarinic acetylcholine receptor antagonist (atropine, 1 mg/kg), but not by nicotinic (mecamylamine, 2 mg/kg) receptor antagonist. Furthermore, intrathecal administration of M2 (methoctramine, 10 µg) and M3 (4-DAMP, 10 µg) receptor antagonist, but not M1 (pirenzepine, 10 µg) receptor antagonist, blocked the effect. Also, spinal administration of 5-HT3 (MDL-72222, 12 µg) receptor antagonist, but not 5-HT1A (NAN-190, 15 µg) or 5-HT2A (ketanserin, 30 µg) receptor antagonist, prevented the anti-allodynic effect of EA. These results suggest that EA may have a signifi cant analgesic action against oxaliplatin-induced neuropathic pain, which is mediated by spinal cholinergic (M2, M3) and serotonergic (5-HT3) receptors.

Analgesic Effects of Bee Venom Derived Phospholipase A(2) in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain.

A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A2 (bvPLA2) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA2, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA2-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA2 treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system.

Low-level laser therapy improves chemotherapy-induced cold allodynia in rats

Low-level laser therapy improves chemotherapy-induced cold allodynia in rats

Nicotinic Acetylcholine Receptors Mediate the Suppressive Effect of an Injection of Diluted Bee Venom into the GV3 Acupoint on Oxaliplatin-Induced Neuropathic Cold Allodynia in Rats.

Oxaliplatin, a platinum-based chemotherapy drug, often induces acute neuropathic pain, especially cold allodynia, even after a single administration. Subcutaneous injection of diluted bee venom (BV) into acupoints has been used to treat various pain symptoms in traditional oriental medicine. Although we previously demonstrated the suppressive effect of BV injection on oxaliplatin-induced cold allodynia in rats, its neurochemical mechanism remained unclear. This study investigates whether and how the cholinergic system mediates the relieving effect of BV injection on cold allodynia in oxaliplatin-administered rats. The behavioral signs of cold allodynia induced by an oxaliplatin administration (6 mg/kg, intraperitoneally (i.p.)) were evaluated by a tail immersion test in cold water (4°C). BV (0.25 mg/kg, subcutaneously (s.c.)) injection into the Yaoyangguan acupoint, located between the spinous processes of the fourth and fifth lumbar vertebrae, significantly alleviated the cold allodynia. This relieving effect of BV injection on oxaliplatin-induced cold allodynia was blocked by a pretreatment with mecamylamine (a non-selective nicotinic receptor antagonist, 2 mg/kg, i.p.), but not by atropine (a non-selective muscarinic receptor antagonist, 1 mg/kg, i.p.). Further, dihydro-β-erythroidinehydrobromide (DHβE, an α4β2 nicotinic antagonist, 5 mg/kg, i.p.) prevented the anti-allodynic effect of BV, whereas methyllycaconitine (an α7 nicotinic antagonist, 6 mg/kg, i.p.) did not. Finally, intrathecal administration of DHβE (10 nM) blocked the BV-induced anti-allodynic effect. These results suggest that nicotinic acetylcholine receptors, especially spinal α4β2 receptors, but not muscarinic receptors, mediate the suppressive effect of BV injection on oxaliplatin-induced acute cold allodynia in rats.

Protective effect of Rubia cordifolia in paclitaxel-induced neuropathic pain in experimental animals

Background: Neuropathic pain is a pain initiated or caused by a primary lesion or dysfunction of the nervous system. Material and Methods: In this study, we evaluated the effect of alcoholic extract of roots and rhizomes of Rubia cordifolia on the development and expression of neuropathic pain induced by paclitaxel in sciatic nerve ligated rats. A peripheral mononeuropathy was produced in adult Wistar rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia, and spontaneous pain were produced. Treatment with paclitaxel (2 mg/kg i.p. on 7 th , 10 th , and 21 st day) produced long-lasting (2-3 weeks) heat hyperalgesia and cold allodynia in rats. Conclusion: Co-administration of R. cordifolia extract for 21 days significantly decreased pain indicating its usefulness in neuropathic pain.

Serotonergic mechanism of the relieving effect of bee venom acupuncture on oxaliplatin-induced neuropathic cold allodynia in rats.

BackgroundOxaliplatin, an important chemotherapy drug for advanced colorectal cancer, often induces peripheral neuropathy, especially cold allodynia. Our previous study showed that bee venom acupuncture (BVA), which has been traditionally used in Korea to treat various pain symptoms, potently relieves oxaliplatin-induced cold allodynia in rats. However, the mechanism for this anti-allodynic effect of BVA remains poorly understood. We investigated whether and how the central serotonergic system, a well-known pathway for acupuncture analgesia, mediates the relieving effect of BVA on cold allodynia in oxaliplatin-injected rats.MethodsThe behavioral signs of cold allodynia in Sprague–Dawley (SD) rats were induced by a single injection of oxaliplatin (6 mg/kg, i.p.). Before and after BVA treatment, the cold allodynia signs were evaluated by immersing the rat’s tail into cold water (4°C) and measuring the withdrawal latency. For BVA treatment, a diluted BV (0.25 mg/kg) was subcutaneously administered into Yaoyangguan (GV3) acupoint, which is located between the spinous processes of the fourth and the fifth lumbar vertebra. Serotonin was depleted by a daily injection of DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for 3 days. The amount of serotonin in the spinal cord was measured by ELISA. Serotonergic receptor antagonists were administered intraperitoneally or intrathecally before BVA treatment.ResultsThe serotonin levels in the spinal cord were significantly increased by BVA treatment and such increase was significantly reduced by PCPA. This PCPA pretreatment abolished the relieving effect of BVA on oxaliplatin-induced cold allodynia. Either of methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 1 mg/kg, i.p.) or MDL-72222 (5-HT3 receptor antagonist, 1 mg/kg, i.p) blocked the anti-allodynic effect of BVA. Further, an intrathecal injection of MDL-72222 (12 μg) completely blocked the BVA-induced anti-allodynic action, whereas NAN-190 (5-HT1A receptor antagonist, 15 μg, i.t.) or ketanserin (5-HT2A receptor antagonist, 30 μg, i.t.) did not.ConclusionsThese results suggest that BVA treatment alleviates oxaliplatin-induced acute cold allodynia in rats via activation of the serotonergic system, especially spinal 5-HT3 receptors. Thus, our findings may provide a clinically useful evidence for the application of BVA as an alternative therapeutic option for the management of peripheral neuropathy, a dose-limiting side effect that occurs after an administration of oxaliplatin.

Role of nerve growth factor-tyrosine kinase receptor A signaling in paclitaxel-induced peripheral neuropathy in rats

The mechanisms underlying paclitaxel-induced peripheral neuropathy remain unknown. Nerve growth factor (NGF) is a representative neurotrophic factor that maintains neuronal function, promotes survival, and mediates neuropathic pain. We investigated expression levels of NGF and its receptors in the dorsal root ganglia (DRG) and spinal dorsal horn (DH) following paclitaxel treatment. Intraperitoneal (I.P.) administration of paclitaxel induced significant mechanical hypersensitivity and cold allodynia in rats, significantly increased the expression of NGF and its receptor tyrosine kinase receptor A (trkA) in the DRG, and increased NGF expression in the DH. In contrast, paclitaxel treatment did not alter the mRNA levels of NGF or its receptors in the DRG, DH, sciatic nerve, or hindpaw skin. Moreover, expression of NEDD4-2, a negative regulator of trkA, was significantly increased in the DRG of paclitaxel-treated rats. Intrathecal (I.T.) administration of the tyrosine kinase receptor inhibitor k252a significantly alleviated mechanical hypersensitivity in paclitaxel-treated rats. Our results suggest that NGF–trkA signaling is involved in mechanical allodynia in paclitaxel-induced neuropathy.

Analgesic effect of sinomenine in rodents after inflammation and nerve injury

Sinomenine is an alkaloid originally isolated from the root of the plant Sinomenium acutum. It is used in traditional medicine in China to treat rheumatic arthritis. In the present study, we evaluated the potential antinociceptive effects of sinomenine in rodents with nociceptive, inflammatory and neuropathic pain. In normal rats and mice, systemic sinomenine produced moderate antinociceptive effect in the hot plate and tail flick tests. Sinomenine also exerted analgesic effects on mechanical and heat hypersensitivity in mice after carrageenan induced inflammation. Finally, sinomenine effectively alleviated mechanical and cold allodynia in rats and mice after injury to peripheral nerve or spinal cord. The analgesic effect of sinomenine is not associated with side effects and is not reversed by the opioid receptor antagonist naloxone. Our results showed that sinomenine has a wide spectrum analgesic effect in rodent models of nociceptive, inflammatory and neuropathic pain.

Ventral posterolateral deep brain stimulation treatment for neuropathic pain shortens pain response after cold stimuli

Neuropathic pain is often severe. Deep brain stimulation (DBS) is a treatment method for neuropathic pain, but its mechanism of action remains unclear. Patients with neuropathic pain are affected by various stimulations, such as mechanical and cold stimuli, but studies of cold allodynia showed the associated pain to be less than that caused by mechanical stimuli. This study focused on the effects of DBS on cold allodynia in rats. To observe the effects of DBS, we established three groups: a normal group (normal), a neuropathic pain group (pain), and a DBS with neuropathic pain group (DBS). The stimulation target was the ventral posterolateral nucleus (VPL). We observed differences in the degree of cold allodynia elicited between a conventional method that measured the number of pain responses and our altered novel method that measured the duration of pain responses. Cold allodynia after DBS did not differ when conventional analysis was applied, but the pain response duration was decreased. We suggest that VPL DBS was partially effective in cold allodynia, implicating complex pathways of pain signaling.

Activation of TRPM8 cold receptor triggers allodynia-like behavior in spinally injured rats

AimsPain in response to innocuous cold stimulation (cold allodynia) is a common symptom in patients with neuropathic pain. Cold allodynia is difficult to treat and its mechanisms are poorly understood. Several transient receptor potential (TRP) channels have been shown to be the molecular sensors for cold stimulation in a temperature-dependent manner, but the contribution of various TRP channels in mediating cold allodynia in neuropathic pain is unclear. We have previously shown that spinally injured rats developed neuropathic pain-like behaviors, including marked cold allodynia. We now assessed the role of TRP channels in mediating cold allodynia in rats after ischemic spinal cord injury. MethodsSpinal cord injury was produced using a photochemical method. The mechanical allodynia was assessed by examining the vocalization thresholds to graded mechanical touch/pressure applied with von Frey hairs. Temperature controlled cold stimulation was produced by a Peltier thermode (active surface 25mm×50mm) connected to a MSA Thermal Simulator (Somedic, Sweden) with baseline temperature of 32°C. The rate of temperature change was 0.5°C/s. The temperature required to elicit cold allodynia was examined. The responses of the rats to topical application of icilin or menthol, agonists of transient receptor potential melastain 8 (TRPM8), were also studied. ResultsNormal rats did not exhibit nociceptive responses to cooling stimulation to the trunk and back area (minimal temperature +6°C) and they also did not react aversively to topical application of icilin or menthol. After spinal cord injury, the rats developed mechanical allodynia at the trunk and back just rostral to the dermatome of the injured spinal segments. In the same area, rats exhibited significant nociceptive responses to cooling from day 1 after injury, lasting for at least 70 days which is the longest time of observation. For the first two weeks after injury, the majority of spinally injured rats had a nociceptive response to cooling above 17°C. At day 70, about 50% of rats responded to cooling above 17°C. Topical application of 400μM icilin or 4mM menthol also elicited pain-like responses in spinally injured rats and these two cold mimetics also significantly exacerbated existing mechanical allodynia. ConclusionsOur results showed that activation of the TRPM8 channel by menthol or icilin triggers allodynia in spinally injured rats and increases, rather than decreases, mechanical allodynia. TRPM8 channels which respond to cooling above 17°C may be involved at least in part in mediating cold allodynia in the rat model of neuropathic spinal cord injury pain. ImplicationsThe work introduced a method of quantitative testings of responses of rats to cold stimulation and may contribute to the understanding of mechanisms of cold allodynia after injury to the nervous system.