Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia.

BACKGROUND: Many chemotherapeutic drugs, including paclitaxel, produce neuropathic pain in patients with cancer, which is a dose-dependent adverse effect. Such chemotherapy-induced neuropathic pain (CINP) is difficult to treat with existing drugs. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidative responses and activates phosphorylated Nrf2 (pNrf2). We determined the analgesic effects of bardoxolone methyl (BM), an Nrf2 activator, and the role of pNrf2 on CINP. METHODS: CINP was induced in rats by intraperitoneally injecting paclitaxel on 4 alternate days in rats. BM was injected systemically as single or repeated injections after pain fully developed. RNA transcriptome, mechanical hyperalgesia, levels of inflammatory mediators and pNrf2, and location of pNrf2 in the dorsal root ganglia (DRG) were measured by RNA sequencing, von Frey filaments, Western blotting, and immunohistochemistry in rats and human DRG samples. In addition, the mitochondrial functions in 50B11 DRG neuronal cells were measured by fluorescence assay. RESULTS: Our RNA transcriptome of CINP rats showed a downregulated Nrf2 pathway in the pain condition. Importantly, single and repeated systemic injections of BM ameliorated CINP. Paclitaxel increased inflammatory mediators, but BM decreased them and increased pNrf2 in the DRG. In addition, paclitaxel decreased mitochondrial membrane potential and increased mitochondrial volume in 50B11 cells, but BM restored them. Furthermore, pNrf2 was expressed in neurons and satellite cells in rat and human DRG. CONCLUSIONS: Our results demonstrate the analgesic effects of BM by Nrf2 activation and the fundamental role of pNrf2 on CINP, suggesting a target for CINP and a therapeutic strategy for patients.

Neuro-Plastic Mechanisms of Pain and Addiction.

Pain plays an important role in human survival [...].

Update on cannabis and cannabinoids for cancer pain.

PURPOSE OF REVIEW: The prevalence of cancer pain will continue to rise as pain is common among the survivorship and general cancer population. As interest in cannabis and cannabinoids for medicinal use including pain management continues to rise, there is growing need to update and review the current state of evidence for their use. The literature was searched for articles in English with key words cannabis, cannabinoids, and cancer pain. The sources of articles were PubMed, Embase, and open Google search. RECENT FINDINGS: In a double-blind randomized placebo-controlled trial including a 3-week treatment period of nabiximol for advanced cancer patients with pain refractory to optimized opiate therapy, improvements in average pain were seen in the intention to treat population (P = 0.0854) and per- protocol population (P = 0.0378). SUMMARY: To date, preclinical data has demonstrated evidence to suggest promising potential for cancer pain and the urgent need to translate this into clinical practice. Unfortunately, due to limited data, for adults with advanced cancer being treated with opiate therapy, the addition of cannabis or cannabinoids is not currently supported to address cancer pain effectively.

Peripheral and central oxidative stress in chemotherapy-induced neuropathic pain.

Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse side effect of many anti-cancer chemotherapeutic treatments. CIPN often causes neuropathic pain in extremities, and oxidative stress has been shown to be a major contributing factor to this pain. In this study, we determined the site of oxidative stress associated with pain (specifically, mechanical hypersensitivity) in cisplatin- and paclitaxel-treated mouse models of CIPN and investigated the neurophysiological mechanisms accounting for the pain. C57BL/6N mice that received either cisplatin or paclitaxel (2 mg/kg, once daily on four alternate days) developed mechanical hypersensitivity to von Frey filament stimulations of their hindpaws. Cisplatin-induced mechanical hypersensitivity was inhibited by silencing of Transient Receptor Potential channels V1 (TRPV1)- or TRPA1-expressing afferents, whereas paclitaxel-induced mechanical hypersensitivity was attenuated by silencing of Aß fibers. Although systemic delivery of phenyl N-tert-butylnitrone, a reactive oxygen species scavenger, alleviated mechanical hypersensitivity in both cisplatin- and paclitaxel-treated mice, intraplantar phenyl N-tert-butylnitrone was effective only in cisplatin-treated mice, and intrathecal phenyl N-tert-butylnitrone, only in paclitaxel-treated mice. In a reactive oxygen species-dependent manner, the mechanosensitivity of Aδ/C fiber endings in the hindpaw skin was increased in cisplatin-treated mice, and the excitatory synaptic strength in the spinal dorsal horn was potentiated in paclitaxel-treated mice. Collectively, these results suggest that cisplatin-induced mechanical hypersensitivity is attributed to peripheral oxidative stress sensitizing mechanical nociceptors, whereas paclitaxel-induced mechanical hypersensitivity is due to central (spinal) oxidative stress maintaining central sensitization that abnormally produces pain in response to Aß fiber inputs.

The Analgesic Effect of Rolipram, a Phosphodiesterase 4 Inhibitor, on Chemotherapy-Induced Neuropathic Pain in Rats.

BACKGROUND: Chemotherapy-induced neuropathic pain is a significant side effect of chemotherapeutic agents. Currently, there are no effective analgesics for chemotherapy-induced neuropathic pain. Rolipram is a selective phosphodiesterase 4 inhibitor, which increases intracellular cyclic AMP in nerve and immune cells. The aim of our study was to determine the analgesic effects of rolipram on paclitaxel (PAC)-induced neuropathic pain in rats. METHODS: Chemotherapy-induced neuropathic pain was produced by intraperitoneal injection of PAC on 4 alternate days in male Sprague-Dawley rats. Mechanical allodynia was measured by using von Frey filaments. RESULTS: After the rats developed PAC-induced pain behavior (such as mechanical allodynia), a single intraperitoneal injection and continuous infusion of rolipram ameliorated PAC-induced pain behavior. In addition, systemic infusion of the drug during the early phase of developing pain behavior did not prevent the development of mechanical allodynia induced by PAC. CONCLUSIONS: These results suggest that rolipram alleviated mechanical allodynia induced by PAC in rats. Thus, phosphodiesterase 4 inhibitors may prove useful in the treatment of chemotherapy-induced neuropathic pain. However, further studies are needed to clarify their effects in clinical settings.

Reactive Oxygen Species Donors Increase the Responsiveness of Dorsal Horn Neurons and Induce Mechanical Hyperalgesia in Rats.

Our previous studies suggest that reactive oxygen species (ROS) scavengers have analgesic effect on neuropathic pain through spinal mechanisms in the rat. The studies suggest that superoxide in spinal cord is one of important mediators of persistent pain. To test the hypothesis that increase of superoxide-derived intermediates leads to central sensitization and pain, the effects of an intrathecal injection of chemical ROS donors releasing either OH(∙), OCl(-), or H2O2 were examined on pain behaviors. Following treatment with t-BOOH (OH(∙) donor), dorsal horn neuron responses to mechanical stimuli in normal rats and the changes of neuronal excitability were explored on substantia gelatinosa (SG) neurons using whole-cell patch clamping recordings. Intrathecal administration of t-BOOH or NaOCl (OCl(-) donor), but not H2O2, significantly decreased mechanical thresholds of hind paws. The responses of wide dynamic range neurons to mechanical stimuli increased after a local application of t-BOOH. The t-BOOH increased the frequency and the amplitude of excitatory postsynaptic potentials, depolarized membrane potential in SG neurons, and increased the frequency of action potentials evoked by depolarizing current pulses. These results suggest that elevated ROS, especially OH(∙), in the spinal cord sensitized dorsal horn neurons and produced hyperalgesia in normal rats.

Brief review: chemotherapy-induced painful peripheral neuropathy (CIPPN): current status and future directions.

PURPOSE: Chemotherapy-induced painful peripheral neuropathy (CIPPN) affects up to 90% of cancer patients treated with chemotherapy agents. Despite the fact that it is relatively common, the underlying pathophysiology is still unclear and its treatment remains generic. Mechanisms of CIPPN are multifactorial, dependent on the specific chemotherapeutic agent used, and include multiple patient-related factors, including genetic factors that may predispose patients to either develop or not develop CIPPN. The purpose of this article is to review mechanisms, clinical signs and symptoms, diagnosis, treatment options, and prognosis for patients who develop CIPPN. We also offer research considerations for this complex and unpredictable phenomenon. PRINCIPAL FINDINGS: Chemotherapeutic agents can damage the peripheral nervous system, including the nerve terminals, axons, cell body, and myelin sheath of sensory nerves. Herein, we describe some of the anatomical and functional changes that are thought to take place at various levels of the nervous system. On a clinical level, patients with CIPPN report multiple symptoms. It is essential to obtain an accurate history from the patient and to perform a thorough physical examination in order to obtain the patient's subjective perspective. Additionally, objective measurements may be needed in order to articulate clearly the effects of this complex syndrome and to ensure an accurate diagnosis, treatment, and prognosis. CONCLUSIONS: The management of CIPPN remains a clinical challenge for pain practitioners. As more research is being carried out to elucidate its pathophysiology and therapy, the innovative use of several non-traditional categories of drugs seems promising in the management of this complex phenomenon. Studies addressing predictability and possible genetic predisposition are necessary not only for preventive measures but also for targeted treatments.

Calcium-independent phospholipase A2 inhibitor produces an analgesic effect in a rat model of neuropathic pain by reducing central sensitization in the dorsal horn.

OBJECTIVE: Phospholipase A2 (PLA2) plays an important role in regulating the production of arachidonic acid and various eicosanoids. The aim of our study was to investigate the analgesic mechanisms of calcium-dependent cytosolic phospholipase A2 and calcium-independent PLA2 (iPLA2) inhibitors in the spinal cord in a rat model of neuropathic pain. METHODS: Lumbar 5 spinal nerve ligation was performed in male Sprague-Dawley rats to develop a peripheral neuropathic pain model. Paw withdrawal thresholds in response to von Frey filaments, brush, pressure, and pinch were measured. Lumbar wide dynamic range neuronal firing rates and iPLA2 subtype expression were measured by in vivo extracellular recording and double immunofluorescence staining, respectively. RESULTS: In our rat models, oral administration of prednisolone, a non-selective PLA2 inhibitor, and intrathecal injection of bromoenolactone, a iPLA2 inhibitor, significantly increased the ipsilateral hindpaw withdrawal thresholds in response to von Frey filament stimulation, but intrathecal injection of arachidonyl trifluoromethyl ketone, a selective cytosolic PLA2 inhibitor, did not show significant changes. In spinal dorsal horn neurons, bromoenolactone reduced neuronal firing rates in response to withdrawal stimulation and spontaneous firing rates in the ipsilateral side of the spinal dorsal horn. In addition, the expression of iPLA2 was co-localized with astrocytes and neurons on the ipsilateral side of the dorsal horn in rats that underwent spinal nerve ligation. DISCUSSION: These data suggest that selective iPLA2 inhibitor produce analgesia in neuropathic rats by reducing central sensitization in the dorsal horn.

Blockers of Wnt3a, Wnt10a, or ß-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo.

Although chemotherapy is a key cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/ß-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of ß-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated ß-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1ß in DRG. PAC also upregulated rAxin2 in mice. Furthermore, ß-catenin was expressed in neurons, including calcitonin gene-related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and ß-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP.

Phenyl N-tert-butylnitrone, a free radical scavenger, reduces mechanical allodynia in chemotherapy-induced neuropathic pain in rats.

BACKGROUND: Paclitaxel is a widely used chemotherapeutic drug for breast and ovarian cancer. Unfortunately, it induces neuropathic pain, which is a dose-limiting side effect. Free radicals have been implicated in many neurodegenerative diseases. The current study tests the hypothesis that a free radical scavenger plays an important role in reducing chemotherapy-induced neuropathic pain. METHODS: Neuropathic pain was induced by intraperitoneal injection of paclitaxel (2 mg/kg) on four alternate days (days 0, 2, 4, and 6) in male Sprague-Dawley rats. Phenyl N-tert-butylnitrone (PBN), a free radical scavenger, was administered intraperitoneally as a single dose or multiple doses before or after injury. Mechanical allodynia was measured by using von Frey filaments. RESULTS: The administration of paclitaxel induced mechanical allodynia, which began to manifest on days 7-10, peaked within 2 weeks, and plateaued for at least 2 months after the first paclitaxel injection. A single injection or multiple intraperitoneal injections of PBN ameliorated paclitaxel-induced pain behaviors in a dose-dependent manner. Further, multiple administrations of PBN starting on day 7 through day 15 after the first injection of paclitaxel completely prevented the development of mechanical allodynia. However, an intraperitoneal administration of pbn for 8 days starting with the first paclitaxel injection did not prevent the development of pain behavior. CONCLUSIONS: This study clearly shows that PBN alleviated mechanical allodynia induced by paclitaxel in rats. Furthermore, our data show that PBN given on days 7 through 15 after the first paclitaxel injection prevented the development of chemotherapy-induced neuropathic pain. This clearly has a clinical implication.

Ketamine Use for Cancer and Chronic Pain Management.

Ketamine, an N-methyl-D-aspartate receptor antagonist, is widely known as a dissociative anesthetic and phencyclidine derivative. Due to an undesirable adverse event profile when used as an anesthetic it had widely fallen out of human use in favor of more modern agents. However, it has recently been explored for several other indications such as treatment resistant depression and chronic pain. Several recent studies and case reports compiled here show that ketamine is an effective analgesic in chronic pain conditions including cancer-related neuropathic pain. Of special interest is ketamine's opioid sparing ability by counteracting the central nervous system sensitization seen in opioid induced hyperalgesia. Furthermore, at the sub-anesthetic concentrations used for analgesia ketamine's safety and adverse event profiles are much improved. In this article, we review both the basic science and clinical evidence regarding ketamine's utility in chronic pain conditions as well as potential adverse events.

Circadian regulation of chemotherapy-induced peripheral neuropathic pain and the underlying transcriptomic landscape.

Growing evidence demonstrates circadian rhythms of pain hypersensitivity in various chronic disorders. In chemotherapy-induced peripheral neuropathy (CIPN), agents such as paclitaxel are known to elicit chronic neuropathic pain in cancer patients and seriously compromise their quality of life. Here, we report that the mechanical threshold for allodynia in paclitaxel-treated rats exhibited a robust circadian oscillation, reaching the nadir during the daytime (inactive phase). Using Per2::LucSV circadian reporter mice expressing a PER2::LUC fusion protein, we isolated dorsal root ganglia (DRG), the primary sensory cell body for peripheral nerve injury generated hypersensitivity, and monitored ex vivo reporter bioluminescence. We observed strong circadian reporter rhythms in DRG neurons which are highly entrainable by external cues. Paclitaxel treatment significantly lengthened DRG circadian periods, with little effects on the amplitude of oscillation. We further observed the core protein BMAL1 and PER2 in DRG neurons and satellite cells. Using DRG and dorsal horn (DH; another key structure for CIPN pain response) tissues from vehicle and paclitaxel treated rats, we performed RNA-sequencing and identified diurnal expression of core clock genes as well as clock-controlled genes in both sites. Interestingly, 20.1% and 30.4% of diurnal differentially expressed genes (DEGs) overlapped with paclitaxel-induced DEGs in the DRG and the DH respectively. In contrast, paclitaxel-induced DEGs displayed only a modest overlap between daytime and nighttime (Zeitgeber Time 8 and 20). Furthermore, paclitaxel treatment induced de novo diurnal DEGs, suggesting reciprocal interaction of circadian rhythms and chemotherapy. Our study therefore demonstrates a circadian oscillation of CIPN and its underlying transcriptomic landscape.

Losartan, an Angiotensin II Type 1 Receptor Antagonist, Alleviates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain by Inhibiting Inflammatory Cytokines in the Dorsal Root Ganglia.

Chemotherapy-induced peripheral neuropathy (CIPN) adversely impacts quality of life and a challenge to treat with existing drugs used for neuropathic pain. Losartan, an angiotensin II type 1 receptor (AT1R) antagonist widely used to treat hypertension, has been reported to have analgesic effects in several pain models. In this study, we assessed losartan's analgesic effect on paclitaxel-induced neuropathic pain (PINP) in rats and its mechanism of action in dorsal root ganglion (DRG). Rats received intraperitoneal injections of 2 mg/kg paclitaxel on days 0, 2, 4, and 6 and received single or multiple intraperitoneal injections of losartan potassium dissolved in phosphate-buffered saline at various times. The mechanical thresholds, protein levels of inflammatory cytokines, and cellular location of AT1R and interleukin 1ß (IL-1ß) in the DRG were assessed with behavioral testing, Western blotting, and immunohistochemistry, respectively. Data were analyzed by two-way repeated-measures analysis of variance for the behavioral test or the Mann-Whitney U test for the Western blot analysis and immunohistochemistry. Single and multiple injections of losartan ameliorated PINP, and losartan delayed the development of PINP. Paclitaxel significantly increased, and losartan subsequently decreased, the expression levels of inflammatory cytokines, including IL-1ß and tumor necrosis factor α (TNF-α), in the lumbar DRG. AT1R and IL-1ß were expressed in both neurons and satellite cells and losartan decreased the intensity of IL-1ß in the DRG. Losartan ameliorates PINP by decreasing inflammatory cytokines including IL-1ß and TNF-α in the DRG. Our findings provide a new or add-on therapy for CIPN patients.

Phenyl N-t-butylnitrone, a reactive oxygen species scavenger, reduces zymosan-induced visceral pain in rats.

To examine a possible involvement of reactive oxygen species (ROS) in visceral pain, the levels of ROS in the colon and the effect of a ROS scavenger phenyl N-t-butylnitrone (PBN) on pain were examined in zymosan-induced colitis rats. Zymosan was instilled into the colon of adult rats. The electromyograms (EMGs) of abdominal muscle contractions in response to colorectal distension (CRD) were recorded as an indicator of visceral pain. After zymosan treatment, the rats showed enhanced EMG and elevated levels of H2O2 in the colon. PBN treatment (intraperitoneal, intrathecal or intracolonic) significantly reduced the enhanced EMGs induced by zymosan. The results suggest that elevated ROS in the spinal cord and the colon are involved in visceral pain.

Treatment of Chemotherapy-Induced Peripheral Neuropathy: Systematic Review and Recommendations.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a commonly encountered disease entity following chemotherapy for cancer treatment. Although only duloxetine is recommended by the American Society of Clinical Oncology (ASCO) for the treatment of CIPN in 2014, the evidence of the clinical outcome for new pharmaceutic therapies and non-pharmaceutic treatments has not been clearly determined. OBJECTIVE: To provide a comprehensive review and evidence-based recommendations on the treatment of CIPN. STUDY DESIGN: A systematic review of each treatment regimen in patients with CIPN. METHODS: The literature on the treatment of CIPN published from 1990 to 2017 was searched and reviewed. The 2011 American Academy of Neurology Clinical Practice Guidelines Process Manual was used to grade the evidence and risk of bias. We reviewed and updated the recommendations of the ASCO in 2014, and evaluated new approaches for treating CIPN. RESULTS: A total of 26 treatment options in 35 studies were identified. Among these, 7 successful RCTs, 6 failed RCTs, 18 prospective studies, and 4 retrospective studies were included. The included studies examined not only pharmacologic therapy but also other modalities, including laser therapy, scrambler therapy, magnetic field therapy and acupuncture, etc. Most of the included studies had small sample sizes, and short follow-up periods. Primary outcome measures were highly variable across the included studies. No studies were prematurely closed owing to its adverse effects. LIMITATIONS: The limitations of this systematic review included relatively poor homogeneous, with variations in timing of treatment, primary outcomes, and chemotherapeutic agents used. CONCLUSION: The evidence is considered of moderate benefit for duloxetine. Photobiomodulation, known as low level laser therapy, is considered of moderate benefit based on the evidence review. Evidence did not support the use of lamotrigine and topical KA (4% ketamine and 2% amitriptyline). The evidence for tricyclic antidepressants was inconclusive as amitriptyline showed no benefit but nortriptyline had insufficient evidence. Further research on CIPN treatment is needed with larger sample sizes, long-term follow-up, standardized outcome measurements, and standardized treatment timing. KEY WORDS: Chemotherapy-induced neuropathy, peripheral neuropathy, chemotherapy-tumor, neuropathic pain, chronic pain, toxicology, treatment, reduction of pain, level of evidence.

Proteomics study of neuropathic and nonneuropathic dorsal root ganglia: altered protein regulation following segmental spinal nerve ligation injury.

Peripheral nerve injury is often followed by the development of severe neuropathic pain. Nerve degeneration accompanied by inflammatory mediators is thought to play a role in generation of neuropathic pain. Neuronal cell death follows axonal degeneration, devastating a vast number of molecules in injured neurons and the neighboring cells. Because we have little understanding of the cellular and molecular mechanisms underlying neuronal cell death triggered by nerve injury, we conducted a proteomics study of rat 4th and 5th lumbar (L4 and L5) dorsal root ganglion (DRG) after L5 spinal nerve ligation. DRG proteins were displayed on two-dimensional gels and analyzed through quantitative densitometry, statistical validation of the quantitative data, and peptide mass fingerprinting for protein identification. Among approximately 1,300 protein spots detected on each gel, we discovered 67 proteins that were tightly regulated by nerve ligation. We find that the injury to primary sensory neurons turned on multiple cellular mechanisms critical for the structural and functional integrity of neurons and for the defense against oxidative damage. Our data indicate that the regulation of metabolic enzymes was carefully orchestrated to meet the altered energy requirement of the DRG cells. Our data also demonstrate that ligation of the L5 spinal nerve led to the upregulation in the L4 DRG of the proteins that are highly expressed in embryonic sensory neurons. To understand the molecular mechanisms underlying neuropathic pain, we need to comprehend such dynamic aspect of protein modulations that follow nerve injury.

Rolipram, a Selective Phosphodiesterase 4 Inhibitor, Ameliorates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain through Inhibition of Inflammatory Cytokines in the Dorsal Root Ganglion.

Chemotherapy-induced neuropathic pain is a significant side effect of chemotherapeutic agents and is the most common reason for stopping chemotherapy. The aim of the present study was to find the major site and mechanisms of action by which rolipram, a selective phosphodiesterase-4 inhibitor, alleviates paclitaxel-induced neuropathic pain. Chemotherapy-induced neuropathic pain was induced in adult male Sprague-Dawley rats by intraperitoneal injection of paclitaxel on four alternate days. Rolipram was administered systemically or locally into the lumbar spinal cord, L5 dorsal root ganglion, sciatic nerve, or skin nerve terminal. The mechanical threshold, the protein level of several inflammatory cytokines, and the cellular locations of phosphodiesterase-4 and interleukin-1ß in the dorsal root ganglion were measured by using behavioral testing, Western blotting, and immunohistochemistry, respectively. The local administration (0.03-mg) of rolipram in the L5 dorsal root ganglion ameliorated paclitaxel-induced pain behavior more effectively than did local administration in the other sites. Paclitaxel significantly increased the expression of inflammatory cytokines including tumor necrosis factor-α (2.2 times) and interleukin-1ß (2.7 times) in the lumbar dorsal root ganglion, and rolipram significantly decreased it. In addition, phosphodiesterase-4 and interleukin-1ß were expressed in the dorsal root ganglion neurons and satellite cells and paclitaxel significantly increased the intensity of interleukin-1ß (2 times) and rolipram significantly decreased it. These results suggest that the major site of action of rolipram on paclitaxel-induced neuropathic pain in rats was the dorsal root ganglion. Rolipram decreased the expression of inflammatory cytokines in the dorsal root ganglion. Thus, phosphodiesterase-4 inhibitors may ameliorate chemotherapy-induced neuropathic pain by decreasing expression of inflammatory cytokines in the dorsal root ganglion.

Moxibustion at ST36 alleviates pain in complete Freund's adjuvant-induced arthritic rats.

This study was to investigate the antinociceptive effects of moxibustion in a complete Freund's adjuvant (CFA)-induced arthritic rat model, and the effects of moxibustion on immunohistochemical changes at the spinal cord level. Moxibustion was applied to the ipsilateral (right) Zusanli (ST36) acupoint to the lesion side for 9 days to CFA-induced arthritic rats. The stepping force was measured as a behavioral test, c-Fos immunohistochemistry, NO production and nNOS Western blots were examined to evaluate antinociceptive effects. Moxibustion at ST36 significantly improved the stepping force in the affected hind limb in CFA-induced arthritis. Moreover, moxibustion at ST36 suppressed the production of NO and the protein expression of c-Fos and nNOS induced by arthritis. These results suggest that moxibustion at ST36 has a potent antinociceptive effect in an arthritic rat model, and modulates neuronal excitability and endogenous NO production by suppressing c-Fos and nNOS protein expression.

Tempol Ameliorates and Prevents Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain.

Chemotherapy-induced neuropathic pain is difficult to treat and prevent. Tempol decreases cellular superoxide radical levels and oxidative stress. The aims of our study were to investigate the analgesic and preventive effects of tempol on paclitaxel-induced neuropathic pain in rats and to identify the associated mechanisms of action. Neuropathic pain was induced with intraperitoneally injected paclitaxel on four alternate days in male Sprague-Dawley rats. Tempol was administered systemically as a single injection and a continuous infusion before or after the injection of paclitaxel. The mechanical threshold for allodynia, protein levels, and free radical levels were measured using von Frey filaments, Western blotting, and live cell imaging, respectively. After the rats developed neuropathic pain behavior, a single intraperitoneal injection and continuous infusion of tempol ameliorated paclitaxel-induced mechanical allodynia. Systemic infusion of tempol in the early phase of the development of pain behavior prevented the development of paclitaxel-induced pain behavior. Paclitaxel increased the levels of phosphorylated protein kinase C, phosphorylated nuclear factor κB, phosphodiesterase 4D (PDE4D), IL-1ß, and monocyte chemoattractant protein-1 in the lumbar dorsal root ganglia; however, tempol decreased these levels. Paclitaxel also increased superoxide levels in a culture of primary dorsal root ganglion cells and tempol decreased these levels. In conclusion, tempol alleviates and prevents chemotherapy-induced neuropathic pain in rats by reducing the levels of inflammatory cytokines and free radicals in dorsal root ganglia.

Pentoxifylline Ameliorates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain.

BACKGROUND: Chemotherapy-induced neuropathic pain is difficult to treat. Pentoxifylline inhibits the production of inflammatory cytokines including tumor necrosis factor α(TNF- α) and interleukin 1ß (IL-1ß). OBJECTIVE: The aims of our study were to investigate the analgesic and preventive effects of pentoxifylline on paclitaxel-induced neuropathic pain in rats and to identify its mechanisms of action. STUDY DESIGN: Controlled animal study. METHODS: Neuropathic pain was induced with intraperitoneally injected paclitaxel on 4 alternate days in male Sprague-Dawley rats. Pentoxifylline was administered systemically as a single injection and a continuous infusion before or after the injection of paclitaxel. The mechanical threshold for allodynia was measured by using von Frey filaments. Protein levels and localization of inflammatory cytokines were performed by using Western blotting and immunohistochemistry, respectively. RESULTS: After the rats developed neuropathic pain behavior, a single intraperitoneal injection and continuous infusion of pentoxifylline ameliorated paclitaxel-induced mechanical allodynia. In addition, systemic infusion of pentoxifylline in the early phase of the development of pain behavior delayed the onset of paclitaxel-induced pain behavior. Paclitaxel increased the levels of the catalytic subunit α of protein kinase A, phosphorylated nuclear factor ;κB, TNF- α, and IL-1κ in the lumbar dorsal root ganglia. Pentoxifylline decreased the paclitaxel-induced TNF- α and IL-1ß levels. In addition, IL-1ß was expressed in neurons and satellite cells in the lumbar dorsal root ganglia after paclitaxel. LIMITATIONS: Although this study was performed in the animal model by well-designed manner, clinical study will be needed to confirm the analgesic effect of pentoxifylline. CONCLUSION: Pentoxifylline alleviated chemotherapy-induced neuropathic pain in rats by reducing the levels of inflammatory cytokines in dorsal root ganglia and may be effective chemotherapy-induced neuropathic pain in patients.