Inhibition of Cytochrome P450 Side-Chain Cleavage Attenuates the Development of Mechanical Allodynia by Reducing Spinal D-Serine Production in a Murine Model of Neuropathic Pain

Research indicates that neurosteroids are locally synthesized in the central nervous system and play an important modulatory role in nociception. While the neurosteroidogenic enzyme, cytochrome P450 side-chain cleavage enzyme (P450scc), is the initiating enzyme of steroidogenesis, P450scc has not been examined under the pathophysiological conditions associated with peripheral neuropathy. Thus, we investigated whether chronic constriction injury (CCI) of the sciatic nerve increases the expression of P450scc in the spinal cord and whether this increase modulates serine racemase (Srr) expression and D-serine production contributing to the development of neuropathic pain. CCI increased the immunoreactivity of P450scc in astrocytes of the ipsilateral lumbar spinal cord dorsal horn. Intrathecal administration of the P450scc inhibitor, aminoglutethimide, during the induction phase of neuropathic pain (days 0 to 3 post-surgery) significantly suppressed the CCI-induced development of mechanical allodynia and thermal hyperalgesia, the increased expression of astrocyte Srr in both the total and cytosol levels, and the increases in D-serine immunoreactivity at day 3 post-surgery. By contrast, intrathecal administration of aminoglutethimide during the maintenance phase of pain (days 14 to 17 post-surgery) had no effect on the developed neuropathic pain nor the expression of spinal Srr and D-serine immunoreactivity at day 17 post-surgery. Intrathecal administration of exogenous D-serine du...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research

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Publication date: Available online 7 January 2020Source: Brain, Behavior, and ImmunityAuthor(s): Shahani Noor, Joshua J. Sanchez, Melody S. Sun, Zinia Pervin, Jacob E. Sanchez, Mara A. Havard, Lauren T. Epler, Monique V. Nysus, Jeffrey P. Norenberg, Carston R. Wagner, Suzy Davies, Wagner Jennifer L, Daniel D. Savage, Lauren L. Jantzie, Nikolaos Mellios, Erin.D. MilliganAbstractPrevious reports show that moderate prenatal alcohol exposure (PAE) poses a risk factor for developing neuropathic pain following adult-onset peripheral nerve injury in male rats. Recently, evidence suggests that immune-related mechanisms underlying ...
Source: Brain, Behavior, and Immunity - Category: Neurology Source Type: research
Abstract Previous reports show that moderate prenatal alcohol exposure (PAE) poses a risk factor for developing neuropathic pain following adult-onset peripheral nerve injury in male rats. Recently, evidence suggests that immune-related mechanisms underlying neuropathic pain in females are different compared to males despite that both sexes develop neuropathy of similar magnitude and duration following chronic constriction injury (CCI) of the sciatic nerve. Data suggest that the actions of peripheral T cells play a greater role in mediating neuropathy in females. The goal of the current study is to identify specif...
Source: Brain, Behavior, and Immunity - Category: Neurology Authors: Tags: Brain Behav Immun Source Type: research
In this study we investigated whether P450c17 modulates astrocyte activation and whether this process is mediated by spinal p38 mitogen-activated protein kinase phosphorylation ultimately leading to the development of mechanical allodynia in CCI mice. Sciatic nerve injury induced a significant increase in glial fibrillary acidic protein (GFAP) expression in the superficial dorsal horn (SDH, laminae I-II) and nucleus proprius (NP, laminae III-IV) regions of the spinal cord dorsal horn. Repeated daily (from days 0–3 post-surgery) intrathecal administration of the P450c17 inhibitor, ketoconazole (10 nmol) significantl...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
This study not only provides biological evidence to support the use of duloxetine as the first standard CIPN drug but will also lead to potential new targets for CIPN drug development. Introduction A major dose-limiting complication of chemotherapy is chemotherapy-induced peripheral neuropathy (CIPN). The greatest contributors to CIPN are taxanes (e.g., paclitaxel) and platinum-based (e.g., oxaliplatin) treatments (Krukowski et al., 2015). Paclitaxel (PTX) can effectively treat several of the most common cancers including breast cancer, lung cancer, and ovarian cancer (Ewertz et al., 2015; Cetinkaya-Fisgin et al., ...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Publication date: Available online 26 March 2019Source: Neuroscience LettersAuthor(s): Sheu-Ran Choi, Ho-Jae Han, Alvin J. Beitz, Jang-Hern LeeAbstractIt has been suggested that interactions of neuronal nitric oxide synthase (nNOS) with postsynaptic density 95 (PSD95) play important roles in the development of chronic neuropathic pain. Here we examine the possible role of nNOS-PSD95 interactions in central sensitization as represented by phosphorylation of the NMDA receptor GluN1 subunit (pGluN1) in mice with chronic constriction injury (CCI) of the sciatic nerve. Intrathecal administration of the nNOS-PSD95 interactions i...
Source: Neuroscience Letters - Category: Neuroscience Source Type: research
Abstract Chronic neuropathic pain is a debilitating condition that remains challenging to treat. Glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been used to treat neuropathic pain, but the exact sites of their actions have been unclear until recently. Although conventionally postsynaptic, NMDARs are also expressed presynaptically, particularly at the central terminals of primary sensory neurons, in the spinal dorsal horn. However, presynaptic NMDARs in the spinal cord are normally quiescent and are not actively involved in physiological nociceptive transmission. In this review, we describe the em...
Source: Cellular and Molecular Life Sciences : CMLS - Category: Cytology Authors: Tags: Cell Mol Life Sci Source Type: research
CONCLUSION: Studies aimed at understanding the mechanisms underlying EAE-induced neuropathic pain and investigating the efficacy of novel pharmacological interventions at the animal level offer an exciting area of future research, and may inform future therapeutic options for MS-associated neuropathic pain. PMID: 28875858 [PubMed - as supplied by publisher]
Source: Medicinal Chemistry - Category: Chemistry Authors: Tags: Med Chem Source Type: research
The blood–spinal cord barrier (BSCB) prevents leakage of molecules, such as pronociceptive mediators, into the spinal cord, but its role in the pathophysiology of neuropathic pain is not completely understood. Rats with chronic constriction injury (CCI) develop mechanical allodynia, thermal hypersensitivity, and reduced motor performance (Rota‐Rod test) compared with sham‐injured mice—similar to mice with spared nerve injury (SNI). The BSCB becomes permeable for small and large tracers 1 day after nerve ligation. Messenger RNA (mRNA) expression of tight junction proteins (TJPs) occludin, claudin‐1, claudi...
Source: Annals of the New York Academy of Sciences - Category: Science Authors: Tags: Original Article Source Type: research
The objective of this study was to assess the relationship between euphoria and early treatment response to pregabalin using data from placebo-controlled trials in patients with chronic pain due to diabetic peripheral neuropathy, postherpetic neuralgia, spinal cord injury, fibromyalgia, chronic low back pain, or osteoarthritis.
Source: The Journal of Pain - Category: Materials Science Authors: Source Type: research
Conclusions Anti-inflammatory and anti-apoptotic processes might contribute to the anti-allodynic and anti-hyperalgesic effects of rosemary following nerve injury. Our findings support the ethnopharmacological use of rosemary as a potential candidate in treating neuropathic pain and different neurological disorders that associate with the activation of apoptosis and inflammatory pathways. Graphical abstract
Source: Journal of Ethnopharmacology - Category: Drugs & Pharmacology Source Type: research
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