Chemotherapy-induced Peripheral Neuropathic Pain Research Articles

Regulating tumor innervation by nanodrugs potentiates cancer immunochemotherapy and relieve chemotherapy-induced neuropathic pain

Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic-co-glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with anti-PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer.

Pilot Study of the Effectiveness of Repetitive Transcranial Magnetic Stimulation on Pain and Quality of Life in Patients with Chemotherapy-Induced Peripheral Neuropathic Pain

Background. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that acts on the activity of the cerebral cortex employing electrical currents. Aim. The objective of this project is to evaluate the effectiveness of rTMS on pain and quality of life in patients with chemotherapy-induced peripheral neuropathic pain. Method. Ten patients with chemotherapy-induced peripheral neuropathic pain received 20 sessions of rTMS, consisting of 15 minutes of treatment repeated 5 times per week for four weeks (10 Hz, 20s, 30 trains with 81% intensity). Patients were evaluated using the Brief pain inventory (BPI) and the Functional Assessment of Cancer Therapy and neurotoxicity (FACT-GOG-NTX 13). Results. There were significant differences in BPI mean severity, interference score and FACT-GOG-NTX 13 (p<0,05). Conclusion. The pilot study results suggest that rTMS is potentially beneficial for the treatment of chemotherapy-induced peripheral neuropathy. rTMS over the M1 had an important reduction in pain severity, interference with daily activities, and quality of life scores. However, results should be taken with caution due to the small sample size, absence of a control group and short period of follow-up.

Targeting TRPV1 for Cancer Pain Relief: Can It Work?

Chronic intractable pain affects a large proportion of cancer patients, especially those with metastatic bone disease. Blocking sensory afferents for cancer pain relief represents an attractive alternative to opioids and other drugs acting in the CNS in that sensory nerve blockers are not addictive and do not affect the mental state of the patient. A distinct subpopulation of sensory afferents expresses the capsaicin receptor TRPV1. Intrathecal resiniferatoxin, an ultrapotent capsaicin analog, ablates TRPV1-expressing nerve endings exposed to the cerebrospinal fluid, resulting in permanent analgesia in women with cervical cancer metastasis to the pelvic bone. High-dose capsaicin patches are effective pain killers in patients with chemotherapy-induced peripheral neuropathic pain. However, large gaps remain in our knowledge since the mechanisms by which cancer activates TRPV1 are essentially unknown. Most important, it is not clear whether or not sensory denervation mediated by TRPV1 agonists affects cancer progression. In a murine model of breast cancer, capsaicin desensitization was reported to accelerate progression. By contrast, desensitization mediated by resiniferatoxin was found to block melanoma growth. These observations imply that TRPV1 blockade for pain relief may be indicated for some cancers and contraindicated for others. In this review, we explore the current state of this field and compare the analgesic potential of TRPV1 antagonism and sensory afferent desensitization in cancer patients.

G Protein-Coupled Receptors and Ion Channels Involvement in Cisplatin-Induced Peripheral Neuropathy: A Review of Preclinical Studies

Cisplatin is a platinum-based chemotherapy drug widely used to treat various solid tumours. Although it is effective in anti-cancer therapy, many patients develop peripheral neuropathy during and after cisplatin treatment. Peripheral neuropathy results from lesions or diseases in the peripheral somatosensory nervous system and is a significant cause of debilitation and suffering in patients. In recent years, preclinical studies have been conducted to elucidate the mechanisms involved in chemotherapy-induced peripheral neuropathic pain, as well as to promote new therapeutic targets since current treatments are ineffective and are associated with adverse effects. G-protein coupled receptors and ion channels play a significant role in pain processing and may represent promising targets for improving the management of cisplatin-induced neuropathic pain. This review describes the role of G protein-coupled receptors and ion channels in cisplatin-induced pain, analysing preclinical experimental studies that investigated the role of each receptor subtype in the modulation of cisplatin-induced pain.

Ropivacaine-loaded hydrogels for prolonged relief of chemotherapy-induced peripheral neuropathic pain and potentiated chemotherapy

Chemotherapy can cause severe pain for patients, but there are currently no satisfactory methods of pain relief. Enhancing the efficacy of chemotherapy to reduce the side effects of high-dose chemotherapeutic drugs remains a major challenge. Moreover, the treatment of chemotherapy-induced peripheral neuropathic pain (CIPNP) is separate from chemotherapy in the clinical setting, causing inconvenience to cancer patients. In view of the many obstacles mentioned above, we developed a strategy to incorporate local anesthetic (LA) into a cisplatin-loaded PF127 hydrogel for painless potentiated chemotherapy. We found that multiple administrations of cisplatin-loaded PF127 hydrogels (PFC) evoked severe CIPNP, which correlated with increased pERK-positive neurons in the dorsal root ganglion (DRG). However, incorporating ropivacaine into the PFC relieved PFC-induced CIPNP for more than ten hours and decreased the number of pERK-positive neurons in the DRG. Moreover, incorporating ropivacaine into the PFC for chemotherapy is found to upregulate major histocompatibility complex class I (MHC-I) expression in tumor cells and promote the infiltration of cytotoxic T lymphocytes (CD8+ T cells) in tumors, thereby potentiating chemotherapy efficacy. This study proposes that LA can be used as an immunemodulator to enhance the effectiveness of chemotherapy, providing new ideas for painless cancer treatment.

Penile Cellulitis Related to Mpox Genital Lesions.

Penile Cellulitis Related to Mpox Genital Lesions.

TRPM3 as a novel target to alleviate acute oxaliplatin-induced peripheral neuropathic pain.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is an adverse effect observed in up to 80% of patients of cancer on treatment with cytostatic drugs including paclitaxel and oxaliplatin. Chemotherapy-induced peripheral neuropathic pain can be so severe that it limits dose and choice of chemotherapy and has significant negative consequences on the quality of life of survivors. Current treatment options for CIPNP are limited and unsatisfactory. TRPM3 is a calcium-permeable ion channel functionally expressed in peripheral sensory neurons involved in the detection of thermal stimuli. Here, we focus on the possible involvement of TRPM3 in acute oxaliplatin-induced mechanical allodynia and cold hypersensitivity. In vitro calcium microfluorimetry and whole-cell patch-clamp experiments showed that TRPM3 is functionally upregulated in both heterologous and homologous expression systems after acute (24 hours) oxaliplatin treatment, whereas the direct application of oxaliplatin was without effect. In vivo behavioral studies using an acute oxaliplatin model for CIPNP showed the development of cold and mechano hypersensitivity in control mice, which was lacking in TRPM3 deficient mice. In addition, the levels of protein ERK, a marker for neuronal activity, were significantly reduced in dorsal root ganglion neurons derived from TRPM3 deficient mice compared with control after oxaliplatin administration. Moreover, intraperitoneal injection of a TRPM3 antagonist, isosakuranetin, effectively reduced the oxaliplatin-induced pain behavior in response to cold and mechanical stimulation in mice with an acute form of oxaliplatin-induced peripheral neuropathy. In summary, TRPM3 represents a potential new target for the treatment of neuropathic pain in patients undergoing chemotherapy.

Mannose-coated nanozyme for relief from chemotherapy-induced peripheral neuropathic pain.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a progressive and disturbing peripheral neuropathy with currently no effective treatment. Aberrant production of reactive oxygen species (ROS) in macrophages near peripheral nerves plays a dominant role in CIPNP; however, traditional ROS scavengers have difficulty maintaining viability to target macrophages invivo. Mannose-coated superparamagnetic iron oxide nanoparticles (mSPIONs) were synthesized to treat CIPNP. The anti-ROS and anti-inflammatory effects of mSPIONs were assessed in J774A.1 cells and sciatic nerves in a nociception mouse model induced with vincristine (VCR). We found that the mSPIONs significantly reduced ROS levels invitro and invivo. Furthermore, mSPIONs administration specifically reduced IL-6 and TNF-α levels in macrophages near the sciatic nerve and relieved VCR-induced peripheral neuropathic pain. Inhibition of the VCR-upregulated HIF1α/NF-κB signaling pathway may be involved in the alleviation of inflammation. These results provide a new approach for relieving CIPNP using a nanozyme.

Chemotherapy-Induced Peripheral Neuropathic Pain in Cancer Patients/Survivors

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Neuropathic pain caused by the toxic effect of chemotherapy in patients with malignant neoplasms

This article discusses chemotherapy-induced peripheral neuropathic pain (CIPNP) and its associated neuropathic pain syndrome that occurs in patients with malignant neoplasms (MN) during cytostatic therapy. The overall prevalence of CIPNP in patients with malignant neoplasms associated with chemotherapy with neurotoxic drugs is estimated, according to various sources, to be about 70%. The pathophysiological mechanisms of CIPNP have not been fully studied, but it is known that they are based on: impaired axonal transport, oxidative stress, induction of apoptosis, DNA damage, dysfunction of voltage-gated ion channels, and central mechanisms. It is important to recognize CIPNP in the clinical symptoms of patients with cancer treated with cytostatics, since these disorders can lead to serious restrictions in the motor, sensory and autonomic functions of the upper and lower extremities, as well as reduce the quality of life and daily functioning of such patients, forcing them to adjust the dose of chemotherapy drugs, transfer the next cycles and even interrupt the treatment of cancer carried out according to vital needs. In addition to the clinical examination, scales and questionnaires have been developed to identify symptoms of CIPNP, but it is most important for neurological and oncological specialists to know and be able to recognize such symptoms in patients. The mandatory research methods for identifying the symptoms of polyneuropathy include electroneuromyography (ENMG), which allows you to assess muscle activity, functional characteristics and the state of the function of peripheral nerves. The methods used to reduce symptoms are screening patients for the development of CIPNP and identifying patients at high risk of CIPNP and, if necessary, reducing the dose or changing cytostatics. Methods for correcting this disorder using different classes of drugs require more detailed study and further research.

Changes in the expression of endocannabinoid system components in an experimental model of chemotherapy-induced peripheral neuropathic pain: Evaluation of sex-related differences

Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism.Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits.Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes.Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain.

Transcriptome analysis of microRNAs, circRNAs, and mRNAs in the dorsal root ganglia of paclitaxel-induced mice with neuropathic pain.

The microtubule-stabilizing drug paclitaxel (PTX) is a chemotherapeutic agent widely prescribed for the treatment of various tumor types. The main adverse effect of PTX-mediated therapy is chemotherapy-induced peripheral neuropathy (CIPN) and neuropathic pain, which are similar to the adverse effects associated with other chemotherapeutic agents. Dorsal root ganglia (DRG) contain primary sensory neurons; any damage to these neurons or their axons may lead to neuropathic pain. To gain molecular and neurobiological insights into the peripheral sensory system under conditions of PTX-induced neuropathic pain, we used transcriptomic analysis to profile mRNA and non-coding RNA expression in the DRGs of adult male C57BL/6 mice treated using PTX. RNA sequencing and in-depth gene expression analysis were used to analyze the expression levels of 67,228 genes. We identified 372 differentially expressed genes (DEGs) in the DRGs of vehicle- and PTX-treated mice. Among the 372 DEGs, there were 8 mRNAs, 3 long non-coding RNAs (lncRNAs), 16 circular RNAs (circRNAs), and 345 microRNAs (miRNAs). Moreover, the changes in the expression levels of several miRNAs and circRNAs induced by PTX have been confirmed using the quantitative polymerase chain reaction method. In addition, we compared the expression levels of differentially expressed miRNAs and mRNA in the DRGs of mice with PTX-induced neuropathic pain against those evaluated in other models of neuropathic pain induced by other chemotherapeutic agents, nerve injury, or diabetes. There are dozens of shared differentially expressed miRNAs between PTX and diabetes, but only a few shared miRNAs between PTX and nerve injury. Meanwhile, there is no shared differentially expressed mRNA between PTX and nerve injury. In conclusion, herein, we show that treatment with PTX induced numerous changes in miRNA expression in DRGs. Comparison with other neuropathic pain models indicates that DEGs in DRGs vary greatly among different models of neuropathic pain.

Synergistic Antinociceptive Effects of Indomethacin-Pregabalin and Meloxicam-Pregabalin in Paclitaxel-Induced Neuropathic Pain.

Neuropathic pain is often closely associated with nerve injury or inflammation, and the role of traditional nonsteroidal anti-inflammatory drugs as adjuvants for treating chemotherapy-induced peripheral neuropathic pain remains unclear. In this study, the potential synergistic antinociceptive effects of indomethacin–pregabalin and meloxicam–pregabalin were evaluated in paclitaxel-induced neuropathic pain and carrageenan-induced inflammatory pain in rodents. Although indomethacin and meloxicam alone only slightly relieved mechanical allodynia in the above two models, isobolographic analysis showed that the combination of indomethacin or meloxicam with pregabalin produced significant synergistic antinociceptive effects for paclitaxel-induced neuropathic pain (IN-PGB, experimental ED25 = [4.41 (3.13–5.82)] mg/kg, theoretical ED25 = [8.50 (6.62–10.32)] mg/kg; MEL-PGB, experimental ED25 = [3.96 (2.62–5.46)] mg/kg, theoretical ED25 = [7.52 (5.73–9.39)] mg/kg). In addition, MEL-PGB dosed via intraplantar injection into the left paw, intragastric injection, or intraperitoneal injection reversed paclitaxel-induced allodynia, indicating that they may act at multiple sites in the neuroaxis and periphery. However, indomethacin–pregabalin and meloxicam–pregabalin exerted antagonistic antiallodynic interactions in carrageenan-induced inflammatory pain in rats. Taken together, coadministration of indomethacin or meloxicam with pregabalin may possess potential therapeutic advantages for treating chemotherapy-induced neuropathic pain.

Participation of transient receptor potential vanilloid 1 in the analgesic effect of duloxetine for paclitaxel induced peripheral neuropathic pain

Painful peripheral neuropathy is a common dose-limiting side effect of chemotherapeutic paclitaxel (PTX) treatment. The American Society of Clinical Oncology (ASCO) recommends duloxetine (DUL) as a promising treatment alternative for chemotherapy-induced peripheral neuropathic pain. However, this recommendation lacks a robust theoretical basis and supporting data. To elucidate the involvement of transient receptor potential vanilloid 1 (TRPV1) in the analgesic effect of DUL for PTX-induced neuropathic pain, TRPV1 expression in the lumbar dorsal root ganglion (DRG) and spinal cord was evaluated following intraperitoneal administration of PTX (2 mg/kg/day) for four alternate days in rats. Western blot and immunohistochemistry suggested that a cumulative dosage of PTX (8 mg/kg) upregulated TRPV1 expression in the lumbar DRG and spinal dorsal horn (SDH) at day 14 post treatment. TRPV1 upregulation in the DRG was mainly expressed in calcitonin gene-related peptide (CGRP) and IB-4 positive small-size sensory neurons. Additionally, PTX increased CGRP and substance P (SP) expression in the DRG and SDH, induced SDH microglia and astrocyte activation, and upregulated spinal tumor necrosis factor-α (TNF-α) but not IL-1β or IL-10 expression. Behavioral detection showed that PTX-related mechanical and thermal hyperalgesia was significantly inhibited by consecutive administration of DUL 20 mg/kg/day greater than 10 mg/kg/day for 5 days starting at day 10 post PTX injection. Furthermore, DUL (20 mg/kg/day) for 5 days markedly ameliorated PTX-induced TRPV1, CGRP, and SP upregulation in the DRG and SDH, and mitigated PTX-induced spinal cord glia activation and TNF-α expression. Moreover, the pharmacological blockade of TRPV1 resulted in an analgesic effect on PTX-induced hyperalgesia. Collectively, these results suggest that DUL alleviates PTX-induced peripheral neuropathic pain by suppressing TRPV1 upregulation in the lumbar DRG and SDH, which is followed by a reduction in CGRP and SP release, as well as spinal glia activation and TNF-α expression.

A review of the neurological complications of breast cancer.

Conducting broad assessments of the main burden of breast cancer is the core factor for improving overdiagnosis and overtreatment of breast cancer patients as well as their survival rates. Breast cancer patients may experience neurological complications that cause devastating effects on them. Chemotherapy-induced peripheral neuropathy (CIPN) and neuropathic pain are two of the most reported complications. Objective: This study aims to review the neurological complications of breast cancer and the ways to control and treat them. Comprehensive searches were carried out about the keywords of Breast Cancer, Neurological Complications, and Breast Cancer Consequences. These keywords were searched through the most well-known databases of MEDLINE, PUBMED, Cochrane Library, Best Evidence, CancerLit, HealthSTAR, and LegalTrac. In this regard, 83 articles were chosen to be included in this study from 2010 to 2021. The identification and treatment process of neurologic syndromes are not easy. The main neurologic syndromes which the breast cancer patients face are opsoclonus myoclonus syndrome (OMS), encephalitis, sensorimotor neuropathy, retinopathy, cerebellar degeneration, and stiff-person's syndrome. CIPN and neuropathic pain are among the most prevalent side effects which are categorized as neurological complications and mainly seen 1 year after the management of breast cancer. Aiming to minimize the burden following the treatment of breast cancer, these complications should be diagnosed and treated accurately.

The molecular mechanism of oxaliplatin-induced peripheral neuropathic pain

Objective: To investigate the molecular mechanism of oxaliplatin-induced chemotherapy-induced peripheral neuropathic pain (CIPNP). Methods: A total of 16 male Sprague-Dawley rats of specific pathogen-free grade were randomly divided into two groups: oxaliplatin experimental group (2.4 mg/kg oxaliplatin dissolved in 5.0% glucose solution, n=8) and control group (equal volume 5% glucose solution, n=8). The rat model of CIPNP was established by continuous administration with oxaliplatin. In addition, mechanical allodynia, thermal hyperalgesia and cold hyperalgesia were measured and compared between the two groups. To explore the molecular mechanism of oxaliplatin-induced CIPNP, the gene expression of dorsal root ganglia (DRG) from the rat model of CIPNP was analyzed using RNA sequencing (RNA-Seq). Results: Mechanical and thermal hypersensitivity was exhibited on day 7 and a stronger hypersensitivity was observed on day 14. A total of 20 152 genes were quantified by RNA-Seq, and 379 differentially expressed genes (DEGs) were obtained with absolute fold change cut-offs ≥ 2 and P value<0.05. There were 7 genes (Npy, Car3, Cdkn1a, Nts, Prc1, Ms4a7 and Ecel1) that were involved in peripheral nerve injury-related neuropathic pain. Gene ontology (GO) functional enrichment analyses indicated that the DEGs induced by oxaliplatin were involved in oxygen transport, cell division, intermediate, centromere, oxygen transporter activity, oxygen binding. Moreover, the result of Kyoto Encyclopedia of genes and genomes (KEGG) analyses highlighted that the DEGs induced by oxaliplatin were involved in malaria, African trypanosomiasis, primary immunodeficiency, peroxisome proliferator activated receptor (PPAR) signaling pathway. Conclusion: Oxaliplatin induces CIPNP via pain-related genes and signaling pathways.

A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABAA Receptor.

Metastatic bone pain and chemotherapy-induced peripheral neuropathic pain are the most common clinical symptoms in cancer patients. The current clinical management of these two disorders is ineffective and/or produces severe side effects. The present study employed a dual-target compound named as ZL006-05 and examined the effect of systemic administration of ZL006-05 on RM-1-induced bone cancer pain and paclitaxel-induced neuropathic pain. Intravenous injection of ZL006-05 dose-dependently alleviated RM-1-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and spontaneously ongoing nociceptive responses during both induction and maintenance periods, without analgesic tolerance, affecting basal/acute pain and locomotor function. Similar behavioral results were observed in paclitaxel-induced neuropathic pain. This injection also decreased neuronal and astrocyte hyperactivities in the lumbar dorsal horn after RM-1 tibial inoculation or paclitaxel intraperitoneal injection. Mechanistically, intravenous injection of ZL006-05 potentiated the GABAA receptor agonist-evoked currents in the neurons of the dorsal horn and anterior cingulate cortex and also blocked the paclitaxel-induced increase in postsynaptic density-95-neuronal nitric oxide synthase interaction in dorsal horn. Our findings strongly suggest that ZL006-05 may be a new candidate for the management of cancer pain and chemotherapy-induced peripheral neuropathic pain.

Latent Pain Sensitization unmasks µ-δ opioid heteromer in neuropathic and inflammatory pain

Rodent models of latent pain sensitization can be used to study the episodic nature that chronic pain can exhibit. At pain remission, central sensitization is countered by the activity of endogenous opioid receptors. In animal models, latent pain sensitization can be unmasked by antagonizing opioid receptors resulting in pain relapse. Due to previous studies have focused predominantly on inflammatory pain, the presence of latent pain sensitization in animal model of chemotherapy-induced peripheral neuropathic pain and in female mice is unknown. This study investigates whether μ- and δ-OR suppress latent pain sensitization in model of chemotherapy-induced neuropathic pain in both sexes. We first targeted μ- and δ-OR separately in a model of chemotherapy induced neuropathy after remission to investigate whether antagonizing the receptors reinstated pain hypersensitivity. We then were able to specifically target the μ-δ OR heteromer using a novel peptide to prevent its heteromerization. We used this peptide to investigate whether disruption of the μ-δOR heteromer, after remission, reinstates pain hypersensitivity. At remission from cisplatin-induced neuropathic pain, antagonism of µOR and δOR reinstates pain hypersensitivity in both sexes. Disruption of the μ-δOR heteromer reinstates pain hypersensitivity in both sexes after remission from cisplatin-induced neuropathic and postsurgical pain. Taken together our findings suggest that the μ-δOR heteromer plays a crucial role in remission in various pain models and may represent a novel therapeutic target to prevent the relapse to pain and the transition to chronic pain. American Pain Society and the Rita Allen Foundation.

Preventing oxaliplatin-induced neuropathic pain: Using berberine to inhibit the activation of NF-κB and release of pro-inflammatory cytokines in dorsal root ganglions in rats.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a serious, undesirable effect of cancer treatment which is particularly difficult to prevent. Berberine and its derivatives have been reported to display robust antioxidant and analgesic effects in rat models of diabetic neuropathic pain and peripheral nerve injury. However, the analgesic role of berberine on oxaliplatin-induced CIPNP remains unknown. The present study aimed to explore the analgesic effect of berberine on CIPNP. Sprague Dawley rats were used to create the CIPNP animal model by oxaliplatin administration. Behavioral tests were performed by von Frey test, acetone drop test, hot plate test, and motor coordination. The protein expression levels of NF-κB p65 and phosphorylated p65 in dorsal root ganglions (DGRs) were detected by western blot analysis. Finally, TNF-α and IL-6 levels in DRGs were measured using specific ELISA kits. The results from the behavioral analysis demonstrated that a single injection of berberine ameliorated the mechanical and cold allodynia and thermal hyperalgesia in the model rats in a dose-dependent manner. Cumulative administration of berberine prevented the mechanical and cold allodynia and thermal hyperalgesia in the development of CIPNP induced by oxaliplatin. This prophylactic effect of berberine was associated with reduced phosphorylation of p65 and with decreased levels of pro-inflammatory cytokines IL-6 and TNF-α. The present study indicated that berberine may have a role in preventing the development of CIPNP and may serve as a therapeutic compound for the treatment of CIPNP.

Escin alleviates chemotherapy-induced peripheral neuropathic pain by inducing autophagy in the spinal cord of rats

To investigate the effect of escin in relieving chemotherapy-induced peripheral neuropathic pain in rats and explore and the underlying mechanism. Eighteen SD rats were randomly divided into 3 groups (n=6), including an escin preconditioning group (treated with 4 mg/kg escin on days 1-7 and then with 2 mg/kg taxol on days 8, 10, 12, and 14), an escin postconditioning group (treated with 2 mg/kg taxol on days 1, 3, 5, and 7 and then with 4 mg/mg escin on days 8-14) and control group (treated with 2 mg/kg taxol on days 1, 3, 5, and 7 and then with saline on days 8-14). Mechanical allodynia and thermal hyperalgesia of the mice were tested on days 4, 7, 10 and 14, and the expression levels of LC3II and p62 in the spinal cord of the rats were detected using Western blotting. The rats in both the escin preconditioning group and escin postconditioning group showed obviously increased thresholds of mechanical allodynia and thermal hyperalgesia as compared with those in the control group (P < 0.01). Western blotting showed that the expression level of LC3II was significantly increased while p62 expression was lowered in escin preconditioning group as compared with those in the control group (P < 0.05). The escin postconditioning group also showed significantly higher LC3II expression and lower p62 expression levels than the control group (P < 0.05). Escin can alleviate chemotherapy-induced peripheral neuropathic pain in rats possibly by upregulating the expressions of autophagy-related proteins in the spinal cord.