Pharmacology/Drug Development

Oxidative stress is an important driver of neuropathic painDimethyl fumarate activates nuclear factor erythroid 2-related factor 2, increasing the expression of multiple antioxidant genes WHAT THIS ARTICLE TELLS US THAT IS NEW: Using a rat model of nerve injury, both male and female animals displayed reduced mechanical and nociceptive sensitization when given dimethyl fumarateDimethyl fumarate administration increased superoxide dismutase activity while decreasing cytokine expression and improving mitochondrial bioenergetics BACKGROUND:: Available treatments for neuropathic pain have modest efficacy and significant adverse effects, including abuse potential. Because oxidative stress is a key mechanistic node for neuropathic pain, the authors focused on the master regulator of the antioxidant response-nuclear factor erythroid 2-related factor 2 (NFE2L2; Nrf2)-as an alternative target for neuropathic pain. The authors tested whether dimethyl fumarate (U.S. Food and Drug Administration-approved treatment for multiple sclerosis) would activate NFE2L2 and promote antioxidant activity to reverse neuropathic pain behaviors and oxidative stress-dependent mechanisms.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling pain condition which occurs as a consequence of cancer chemotherapy with anti-cancer agents like paclitaxel, oxaliplatin, etc. Despite immense research in the pathological pathways involved in CIPN, treatment options still remain limited. Recently, pathological involvement of Wnt signaling has been investigated in various neuropathic pain models, however there are no reports as yet on the role of Wnt signaling in CIPN. In the present study, we have investigated the neuroprotective effects of Wnt signaling inhibitors namely LGK974 (Porcupine inhibitor), NSC668036 (Disheveled inhibitor) and PNU76454 (β-catenin inhibitor) in paclitaxel-induced neuropathic pain. Paclitaxel (2 mg/kg, i. p.) was administered to male Sprague Dawley rats on four alternate days. After 21 days, paclitaxel-treated rats showed reduced behavioral pain thresholds (cold allodynia, heat & mechanical hyperalgesia) and nerve functions (nerve conduction velocity and nerve blood flow). Moreover, Wnt signaling proteins (Wnt3a, β-catenin, c-myc and Dvl1), inflammatory marker (matrix metalloproteinase 2) and endoplasmic reticulum stress marker (GRP78) were found to be upregulated in the sciatic nerves of paclitaxel-treated rats accompanied with loss of intraepidermal nerve fiber density as compared to the control rats. Intrathecal administration of Wnt inhibitors (each at dose of 10 and 30 μM) for three consecutive days to paclitaxel-treated rats, significantly improved behavioral pain thresholds and nerve functional parameters by inhibition of Wnt signaling, inflammation, endoplasmic reticulum stress and improvement of intraepidermal nerve fiber density. All these results suggested the neuroprotective potential of Wnt signaling inhibitors in CIPN.

Opioids are the most powerful analgesics available to date. However, they may also induce adverse effects including paradoxical opioid-induced hyperalgesia (OIH). A mechanism that might underlie OIH is the amplification of synaptic strength at spinal C-fibre synapses after withdrawal from systemic opioids such as remifentanil ("opioid-withdrawal-LTP").Here, we show that both, the induction as well as the maintenance of opioid-withdrawal-LTP were abolished by pharmacological blockade of spinal glial cells. In contrast, the blockade of TLR4 had no effect on the induction of opioid-withdrawal-LTP. D-serine, which may be released upon glial cell activation, was necessary for withdrawal-LTP. D-serine is the dominant co-agonist for neuronal NMDA-receptors, which are required for the amplification of synaptic strength upon remifentanil withdrawal.Unexpectedly, opioid-withdrawal-LTP was transferable via the cerebrospinal fluid between animals. This suggests that glial cell-derived mediators accumulate in the extracellular space and reach the cerebrospinal fluid at biologically active concentrations, thereby creating a soluble memory trace that is transferable to another animal ("transfer-LTP"). When we enzymatically degraded D-serine in the superfusate, LTP could no longer be transferred. Transfer-LTP was insensitive to pharmacological blockade of glial cells in the recipient animal, thus representing a rare form of glial-cell independent LTP in the spinal cord.