Development Of Painful Peripheral Neuropathy Research Articles

Paclitaxel Inhibits KCNQ Channels in Primary Sensory Neurons to Initiate the Development of Painful Peripheral Neuropathy.

Cancer patients undergoing paclitaxel infusion usually experience peripheral nerve degeneration and serious neuropathic pain termed paclitaxel-induced peripheral neuropathy (PIPN). However, alterations in the dose or treatment schedule for paclitaxel do not eliminate PIPN, and no therapies are available for PIPN, despite numerous studies to uncover the mechanisms underlying the development/maintenance of this condition. Therefore, we aimed to uncover a novel mechanism underlying the pathogenesis of PIPN. Clinical studies suggest that acute over excitation of primary sensory neurons is linked to the pathogenesis of PIPN. We found that paclitaxel-induced acute hyperexcitability of primary sensory neurons results from the paclitaxel-induced inhibition of KCNQ potassium channels (mainly KCNQ2), found abundantly in sensory neurons and axons. We found that repeated application of XE-991, a specific KCNQ channel blocker, induced PIPN-like alterations in rats, including mechanical hypersensitivity and degeneration of peripheral nerves, as detected by both morphological and behavioral assays. In contrast, genetic deletion of KCNQ2 from peripheral sensory neurons in mice significantly attenuated the development of paclitaxel-induced peripheral sensory fiber degeneration and chronic pain. These findings may lead to a better understanding of the causes of PIPN and provide an impetus for developing new classes of KCNQ activators for its therapeutic treatment.

The possible involvement of JNK activation in the spinal dorsal horn in bortezomib-induced allodynia: the role of TNF-α and IL-1β.

Bortezomib (BTZ), a widely used chemotherapeutic drug, is closely associated with the development of painful peripheral neuropathy, but the mechanism underlying the induction of this disorder by BTZ remains largely unclear. To examine this association, we have evaluated the activation of mitogen-activated protein kinase (MAPK) family members in the spinal dorsal horn and the role of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in BTZ-induced allodynia in rats. Male Sprague-Dawley rats were used as the model animals. The paw withdrawal test, in which mechanical stimuli (von Frey hairs) is applied to the plantar surface of the hindpaw, was used to determine any changes in the paw withdrawal threshold of the treated rats. A PE-10 catheter was placed intrathecally to deliver TNF-α neutralizing antibody, IL-1 receptor antagonist (IL-1ra) or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. The mRNA levels of various cytokines were measured by real-time quantitative PCR. The expression of TNF-α, IL-1β and mitogen-activated protein kinase (MAPK) family members in the spinal dorsal horn was measured by western blot analysis and immunohistochemistry. All data were expressed as the mean±standard error of the mean and analyzed using the SPSS version 13.0 software program. The BTZ treatment induced an upsurge in the mRNA and protein levels of TNF-α in the neurons and IL-1β in the astrocytes in the spinal dorsal horn. It also significantly upregulated the phosphorylation of JNK but not of extracellular signal-regulated kinases (ERK) and p38-MAPK in astrocytes of the spinal dorsal horn. Inhibition of TNF-α or IL-1β ameliorated JNK activation and mechanical allodynia induced by BTZ. Co-administration of thalidomide (TNF-α synthesis inhibitor) and IL-1ra prevented BTZ-induced mechanical allodynia. Our results suggest that the TNF-α or IL-1β/JNK pathway in the spinal dorsal horn may play a critical role in the development of painful peripheral neuropathy induced by BTZ.

JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy

Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [3H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [3H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.

Differential GABAergic disinhibition during the development of painful peripheral neuropathy

An impaired spinal GABAergic inhibitory function is known to be pivotal in neuropathic pain (NPP). At present, data concerning time-dependent alterations within the GABAergic system itself and post-synaptic GABA(A) receptor-mediated inhibitory transmission are highly controversial, likely related to the experimental NPP model used. Furthermore, it is unknown whether the severity of NPP is determined by the degree of these GABAergic disturbances. In the present study we therefore examined in one experimental animal model whether anatomical changes within the spinal GABAergic system and its GABA(A) receptor-mediated inhibitory function are gradually aggravated during the development of partial sciatic nerve injury (PSNL)-induced NPP and are related to the severity of PSNL-induced hypersensitivity. Three and 16 days after a unilateral PSNL (early and late NPP, respectively), GABA-immunoreactivity (GABA-IR) and the number of GABA-IR neuronal profiles were determined in Rexed laminae 1-3 of lumbar spinal cord cryosections. Additionally, the efficiency of dorsal horn GABA(A) receptor-induced inhibition was examined by cation chloride cotransporter 2 (KCC2) immunoblotting. NPP-induced hypersensitivity was only observed at the ipsilateral side, both at early and late time points. During early NPP, a decrease in ipsilateral dorsal horn GABA-IR was observed without alterations in the number of GABA-IR neuronal profiles or KCC2 protein levels. In contrast, bilateral increases in spinal GABA-IR accompanied by an unchanged number of GABA-IR interneurons were observed during late NPP. This was furthermore attended with decreased ipsilateral KCC2 levels. Moreover, the degree of hypersensitivity was not related to disturbances within the spinal GABAergic system at all time points examined. In conclusion, our anatomical data suggest that a dysfunctional GABA production is likely to be involved in early NPP whereas late NPP is characterized by a combined dysfunctional GABA release and decreased KCC2 levels, the latter suggesting an impaired GABA(A) receptor-mediated inhibition.

Dysfunction in Multiple Primary Afferent Fiber Subtypes Revealed By Quantitative Sensory Testing in Patients with Chronic Vincristine-Induced Pain

Vincristine is one of the frontline chemotherapy drugs for the treatment of numerous lymphoid neoplasias. The main dose-limiting complication of vincristine is the development of painful peripheral neuropathy. Although clinical reports have appeared in the literature detailing the symptoms of vincristine neuropathy, quantitative sensory testing data that might yield insight to dysfunction in subsets of primary afferents are lacking. In this report, pain descriptors and anatomical distributions of sensory abnormalities were collected in each patient. Touch detection threshold, sharpness detection threshold, the thresholds for the detection of skin warming, heat pain, skin cooling, and the perception of cooling-induced pain were measured in patients with chronic vincristine-induced pain in each area of sensory abnormality and in skin perceived as outside the affected areas. Elevated touch detection thresholds were observed both within and outside areas affected by pain and sensory abnormality. Elevated sharpness and warm detection thresholds were noted only in areas affected by pain. These data suggest that chronic vincristine-induced pain is associated with dysfunction in Aβ, Aδ, and C caliber primary afferent fibers. Deficits in Aβ fibers appear to precede and presage deficits in the other fiber types, whereas deficits in Aδ- and C-fiber function appear to be specifically associated with the generation of pain.

Propentofylline attenuates vincristine-induced peripheral neuropathy in the rat

The development of painful peripheral neuropathy is a dose-limiting side effect of numerous cancer chemotherapeutic agents. The present study utilized a rodent model of vincristine-induced neuropathy to determine whether a glial modulating agent, propentofylline, could attenuate vincristine-induced mechanical allodynia. Intravenous vincristine administered on days 1 through 5 and days 8 through 11 produced mechanical allodynia using 2 and 12 g von Frey filaments. Lumbar spinal cord from animals on day 15 expressed mild bilateral microglial and astrocytic activation as compared to saline-treated animals. Daily intraperitoneal propentofylline at 10 mg/kg attenuated mechanical allodynia induced by vincristine administration. In addition, propentofylline was found to decrease spinal microglial and astrocytic activation on day 15. These data suggest that central glial cells may play an important role in the development of painful neuropathy following vincristine administration.

Ophthalmologic Features of Thallium Poisoning

Thallium intoxication is characterized by the development of painful peripheral neuropathy, alopecia, mental disorders, and in severe cases, respiratory failure and death. Toxic optic neuropathy is also a feature. Ophthalmologic features of thallium poisoning include optic neuropathy, blepharoptosis, lens opacities, and ophthalmoplegia. A 44-year-old man with criminal sublethal thallium poisoning was examined one month after he was seen in the neurology department with classic systemic features. He was found to have diminished contrast sensitivity, a tritan defect in color vision, and a relative cecocentral scotoma before he developed optic atrophy.

Ophthalmologic Features of Thallium Poisoning

Thallium intoxication is characterized by the development of painful peripheral neuropathy, alopecia, mental disorders, and in severe cases, respiratory failure and death. Toxic optic neuropathy is also a feature. Ophthalmologic features of thallium poisoning include optic neuropathy, blepharoptosis, lens opacities, and ophthalmoplegia. A 44-year-old man with criminal sublethal thallium poisoning was examined one month after he was seen in the neurology department with classic systemic features. He was found to have diminished contrast sensitivity, a tritan defect in color vision, and a relative cecocentral scotoma before he developed optic atrophy.

Pharmacodynamics of 2′,3′-dideoxycytidine: An inhibitor of human immunodeficiency virus

The incidence of acquired immunodeficiency syndrome and the number of people infected with the human immunodeficiency virus (HIV) is likely to increase into the 1990s and perhaps beyond. Zidovudine, a 2′,3′-dideoxynucleoside approved for the treatment of acquired immunodeficiency syndrome, provides immunologic, virologic, and survival benefits. However, because its hematologic toxicity can be dose-limiting, investigations are ongoing with other 2′,3′-dideoxynucleosides. After zidovudine, the first of these agents to be tested was 2′,3′-dideoxycytidine (ddC), the most potent inhibitor of HIV reverse transcriptase among the dideoxynucleosides tested thus far. Concentrations of ddC as low as 0.5 μM provide protection against HIV in cultured T cells (and monocytes), even at high multiplicities of infection. Like the other dideoxynucleosides, activation of ddC is dependent on intracellular phosphorylation to its 5′-triphosphate form. Efforts are under way to alter enzymatically the intracellular ratio of ddC-5′-triphosphate to deoxycytidine-5′-triphosphate, its endogenous counterpart. ddC has relatively straightforward pharmacokinetics; it has a plasma half-life of about 1.2 hours and an oral bioavailability of about 87 percent. Approximately 75 percent of the drug is excreted unchanged in the urine. Patients treated with ddC have experienced both immunologic and virologic benefit, although long-term high doses are limited by the development of painful peripheral neuropathy. Significant hematologic toxicity is not evident in most patients; low-dose regimens of ddC alone, as well as alternating or in combination with zidovudine, are being tested in an effort to retain antiviral activity while minimizing treatment toxicities.