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Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy.

Many of the most effective anti-cancer drugs induce a dose-limiting peripheral neuropathy that compromises therapy. Evidence from animal models of chemotherapy-induced painful peripheral neuropathy produced by the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin, indicate that they produce neuropathy via a common mechanism-a toxic effect on the mitochondria in primary afferent sensory neurons. Bortezomib is from the proteasome-inhibitor class of chemotherapeutics. It also produces a dose-limiting peripheral neuropathy, but its effects on neuronal mitochondria are unknown.

Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression.

The development of chronic pain after surgery is not rare. Nerve injury from complete or partial nerve section during surgery leads to macrophage recruitment and release of pro-inflammatory cytokines, leading in turn to sensitization. Macrophages also express alpha2-adrenoceptors, and we previously demonstrated a prolonged reduction in hypersensitivity following peri-neural injection of the alpha2-adrenoceptor agonist, clonidine, in rats with chronic nerve injury. The current study tested whether peri-neural clonidine at the time of injury could also prevent development of hypersensitivity. Ra

Pharmacological Treatments and Therapeutic Drug Monitoring in Patients with Chronic Pain.

Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient's life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use of opioids may be considered with caution. These drugs, in fact, do not always induce optimal analgesia in patients, and several problems are associated with their use. The purpose of this narrative review is to describe the pharmacological approaches currently used for the management of chronic pain. We rev

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… According to a 2016 study, hyperalgesia occurs in both short-term and long-term treatments, regardless of whether addiction and withdrawal phenomena appear or not [ 191 ]. Several mechanisms are associated with opioid-induced hyperalgesia. … However, there are many similarities between the mechanisms of tolerance and hyperalgesia; for example, CCK acts on descending pathways that modulate pain, thus contributing to both opioid-induced tolerance and hyperalgesia [ 190 ]. …

Mesenchymal stem cells therapy enhances the efficacy of pregabalin and prevents its motor impairment in paclitaxel-induced neuropathy in rats: Role of Notch1 receptor and JAK/STAT signaling pathway.

Peripheral neuropathy is a common adverse effect observed during the use of paclitaxel (PTX) as chemotherapy. The present investigation was directed to estimate the modulatory effect of bone marrow derived mesenchymal stem cells (BM-MSCs) on pregabalin (PGB) treatment in PTX-induced peripheral neuropathy. Neuropathic pain was induced in rats by injecting PTX (2 mg/kg, i.p) 4 times every other day. Rats were then treated with PGB (30 mg/kg/day, p.o.) for 21 days with or without a single intravenous administration of BM-MSCs. At the end of experiment, behavioral and motor abnormalities were asse

β-arrestin-2 regulates NMDA receptor function in spinal lamina II neurons and duration of persistent pain.

Mechanisms of acute pain transition to chronic pain are not fully understood. Here we demonstrate an active role of β-arrestin 2 (Arrb2) in regulating spinal cord NMDA receptor (NMDAR) function and the duration of pain. Intrathecal injection of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin produces paradoxical behavioural responses: early-phase analgesia and late-phase mechanical allodynia which requires NMDAR; both phases are prolonged in Arrb2 knockout (KO) mice. Spinal administration of NMDA induces GluN2B-dependent mechanical allodynia, which is prolonged in A

Attenuation of reserpine-induced pain/depression dyad by gentiopicroside through downregulation of GluN2B receptors in the amygdala of mice.

Epidemiological studies demonstrate that pain frequently occurs comorbid with depression. Gentiopicroside (Gent) is a secoiridoid compound isolated from Gentiana lutea that exhibits analgesic properties and inhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the anterior cingulate cortex of mice. However, the effects of Gent on the reserpine-induced pain/depression dyad and its underlying mechanisms are unclear. Reserpine administration (1 mg/kg subcutaneous daily for 3 days) caused a significant decrease in the nociceptive threshold as evidenced by the reduce

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain.

Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na(v)s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Navs, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na(v)1.7-specific inhibitor, ProTxII, allowed

Ca(2+)/calmodulin-dependent protein kinase II is associated with pelvic pain of neurogenic cystitis.

Interstitial cystitis/painful bladder syndrome is a chronic bladder inflammatory disease of unknown etiology that is often regarded as a neurogenic cystitis. Interstitial cystitis is associated with urothelial lesions, voiding dysfunction, and pain in the pelvic/perineal area. In this study, we used a murine neurogenic cystitis model to identify genes participating in the development of pelvic pain. Neurogenic cystitis was induced by the injection of Bartha's strain of pseudorabies virus (PRV) into the abductor caudalis dorsalis (tail base) muscle of female C57BL/6J mice. Mice infected with PR

Determination of changes in mRNA expression in a rat model of neuropathic pain by Taqman quantitative RT-PCR.

The aim of this study was to develop a rapid and accurate high throughput method of screening multiple genes across a single sample set to detect changes in gene expression in the dorsal root ganglion (DRG) following partial sciatic nerve ligation in the rat. Using Taqman quantitative RT-PCR, we show that expression of a number of genes, including galanin, vasointestinal peptide and neuropeptide Y are rapidly increased 24 h post-operation in the DRGs on the ligated side only. Other genes tested, including vanilloid receptor-1, substance P, galanin receptor-2 and housekeeping genes did not alte

High mobility group box 1 induces bone pain associated with bone invasion in a mouse model of advanced head and neck cancer.

Advanced head and neck cancer (HNC) can invade facial bone and cause bone pain, thus posing a significant challenge to the quality of life of patients presenting with advanced HNC. The present study was designed to investigate HNC bone pain (HNC‑BP) in an intratibial mouse xenograft model that utilized an HNC cell line (SAS cells). These mice develop HNC‑BP that is associated with an expression of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in dorsal root ganglia (DRG) sensory neurons. Our experiments demonstrated that the inhibition of high mobility gr

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… To evaluate the role of HMGB1 in SAS-induced HNC-BP, we investigated SAS injection-induced mechanical hyperalgesia in the mouse bone marrow after the injection of SAS cells. … Treatment with the RAGE antagonist FPS-ZM1 or TLR4 antagonist TAK-242 both significantly reduced hyperalgesia compared to the SAS cell-injected mice ( Fig. 4A ). …

Mechanisms of spinal glial activation in chemotherapy-induced peripheral neuropathy: Focus on microglia and astrocytes.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication in patients with malignant tumors during chemotherapy. The pathological mechanisms of CIPN remain unclear, and effective preventive and therapeutic strategies are still lacking, posing a major challenge in clinical practice. Aberrant activation of spinal glial cells, particularly microglia and astrocytes, is a key pathological hallmark of CIPN. Evidence from multiple animal models supports a causal link between glial activation and CIPN, suggesting that glial cells may serve as potential therapeutic targets. However, ow

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… Astrocyte Paclitaxel can induce marked and persistent hyperalgesia. … Inhibition of inflammatory pathways and oxidative stress can alleviate oxaliplatin‐induced hyperalgesia. …

Danshenol B alleviates central post-stroke pain by regulating the PIK3CG/NLRP3 signaling pathway.

BACKGROUND: Central post-stroke pain (CPSP) is a debilitating neuropathic condition that significantly impairs quality of life and is challenging to manage. Salvia miltiorrhiza (Danshen), a traditional Chinese herb, has demonstrated efficacy against neuropathic pain, but its active analgesic components and underlying mechanisms remain unclear. This study investigated the therapeutic potential of Danshenol B, an active component of Danshen, in a CPSP mouse model, focusing on its mechanism of action via the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG)/N

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… Thermal hyperalgesia test Thermal hyperalgesia was measured by recording the paw withdrawal latency (PWL) in response to a heat source. The mice were placed on a raised glass platform, and a radiant heat source was directed onto the plantar surface of the hind paw through the glass plate. … We established a CPSP model by injecting collagenase IV into the right VPL/VPM of mice, which led to significant mechanical allodynia and cold hyperalgesia, but not heat hyperalgesia. This finding suggests that the VPL/VPM nuclei may not be critical in transmitting heat pain. …

Role of TRP Channels in Cancer-Induced Bone Pain.

The burden of cancer is growing in almost every country. Bone metastases significantly affect the prognosis and lead to an increase in mortality and morbidity. The management of cancer-induced bone pain (CIBP) still shows various unmet needs. Opioid use is burdened by a number of possible side effects. Moreover, recent progresses in cancer treatment significantly increased the life expectancy of cancer patients, even those with metastatic disease. In this narrative review, we reported the main findings regarding TRP channel function in cancer pain models. TRP cation channels play a key role in

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… Opioid-induced constipation (OIC) [ 7 , 8 ], analgesic tolerance, and opioid-induced hyperalgesia (OIH) [ 9 ] may limit their use. … In this scenario, IGF-1 is thought to contribute to pain pathogenesis in cancer; the stimulation of IGF-1-receptor produces mechanical allodynia and thermal hyperalgesia. …

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating t

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… These functional and structural mechanisms might highly contribute to acute and chronic cold allodynia and hyperalgesia induced by oxaliplatin, as observed in clinical practice. … Gheraldin et al. [ 80 ] showed that blocking this channel attenuates hyperalgesia in rats. 4.6. …

Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN).

Chemotherapy induced peripheral neuropathy (CIPN) is a type of neuropathic pain that is a major dose-limiting side-effect of potentially curative cancer chemotherapy treatment regimens that develops in a "stocking and glove" distribution. When pain is severe, a change to less effective chemotherapy agents may be required, or patients may choose to discontinue treatment. Medications used to alleviate CIPN often lack efficacy and/or have unacceptable side-effects. Hence the unmet medical need for novel analgesics for relief of this painful condition has driven establishment of rodent models of C

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… Sensory symptoms that are commonly reported include paresthesia, dysesthesia, allodynia, hyperalgesia, hypoalgesia or pain that is burning, shooting or electric-shock-like (Boland et al., 2010 ). … NGF and GDNF differentially regulate TRPV1 expression that contributes to development of inflammatory thermal hyperalgesia . Eur. J. Neurosci . 20 , 2303 – 2310 10.1111/j.1460-9568.2004.03701.x 15525272 Anand P. ( 2004 ). …

Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain.

The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-sp

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… Analgesic ED 50 values for oral administration of NIBR14 or FTY720 in bortezomib-induced neuropathic pain (day 25) Treatment | Pain behavior | ED 50 | 95% CI | n | | μmol/kg | | NIBR14 | Allodynia | 2 | 1–3 | 6 Hyperalgesia | 2 | 1–3 | 6 FTY720 | Allodynia | 0.09 | 0.06–0.2 | 3–11 Hyperalgesia | … S2 shows the effects of i.th. or oral administration S1PR1-targeted agents on bortezomib-induced mechano-hyperalgesia. Fig. S3 shows the effects of S1PR1-targeted agents on the reversal of established bortezomib-induced mechano-hyperalgesia. …

Unraveling the role of Epac1-SOCS3 signaling in the development of neonatal-CRD-induced visceral hypersensitivity in rats.

AIMS: Visceral hypersensitivity in irritable bowel syndrome (IBS) is widespread, but effective therapies for it remain elusive. As a canonical anti-inflammatory protein, suppressor of cytokine signaling 3 (SOCS3) reportedly relays exchange protein 1 directly activated by cAMP (Epac1) signaling and inhibits the intracellular response to inflammatory cytokines. Despite the inhibitory effect of SOCS3 on the pro-inflammatory response and neuroinflammation in PVN, the systematic investigation of Epac1-SOCS3 signaling involved in visceral hypersensitivity remains unknown. This study aimed to explore

TRPM8: A Therapeutic Target for Neuroinflammatory Symptoms Induced by Severe Dry Eye Disease.

Dry eye disease (DED) is commonly associated with ocular surface inflammation and pain. In this study, we evaluated the effectiveness of repeated instillations of transient receptor potential melastatin 8 (TRPM8) ion channel antagonist M8-B on a mouse model of severe DED induced by the excision of extra-orbital lacrimal and Harderian glands. M8-B was topically administered twice a day from day 7 until day 21 after surgery. Cold and mechanical corneal sensitivities and spontaneous ocular pain were monitored at day 21. Ongoing and cold-evoked ciliary nerve activities were next evaluated by elect

Pharmacological evaluation of NSAID-induced gastropathy as a "Translatable" model of referred visceral hypersensitivity.

AIM: To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity. METHODS: Gastric ulcer pain was induced by the oral administration of indomethacin to male, CD1 mice (n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential (TRP), sodium and acid-sensing ion channels (ASICs) as well as opioid

Spinal RyR2 pathway regulated by the RNA-binding protein HuD induces pain hypersensitivity in antiretroviral neuropathy.

The antiretroviral toxic neuropathy, a distal sensory polyneuropathy associated with antiretroviral treatment, is a frequently occurring neurological complication during treatment of patients with AIDS and often leads to discontinuation of antiretroviral therapy. The mechanisms by which antiretroviral drugs contribute to the development of neuropathic pain are not known. Using drugs that reduce intracellular calcium ions (Ca(2+)), we investigated the hypothesis that altered cytosolic Ca(2+) concentration contributes to the 2',3'-dideoxycytidine (ddC)-evoked painful neuropathy. Administration o