Persistent Pain Is Dependent on Spinal Mitochondrial Antioxidant Levels

Abstract

Reactive oxygen species (ROS) scavengers have been shown to relieve persistent pain; however, the mechanism is not clearly understood. Superoxide produced from mitochondrial oxidative phosphorylation is considered the major source of ROS in neurons during excitation where mitochondrial superoxide levels are normally controlled by superoxide dismutase (SOD-2). The present study hypothesizes that capsaicin-induced secondary hyperalgesia is a consequence of superoxide build-up in spinal dorsal horn neurons and SOD-2 is a major determinant. To test this hypothesis, the spinal levels of SOD-2 activity, inactivated SOD-2 proteins, and mitochondrial superoxide were measured and correlated to the levels of capsaicin-induced secondary hyperalgesia in mice with and without SOD-2 manipulations. The data suggest that superoxide accumulation is a culprit in the abnormal sensory processing in the spinal cord in capsaicin-induced secondary hyperalgesia. Our studies also support the notion that SOD-2 nitration is a critical mechanism that maintains elevated superoxide levels in the spinal cord after capsaicin treatment. Finally, our findings suggest a therapeutic potential for the manipulation of spinal SOD-2 activity in pain conditions.

Mitochondrial Ca2+ uptake is essential for synaptic plasticity in pain

“…These results indicate that mitochondrial superoxide generation is an essential step connecting MCU to spinal synaptic plasticity. The present data are in line with several previous findings that superoxide scavengers reduce persistent pain (Kim et al, 2004;Schwartz et al, 2009), dorsal horn neuron hyperexcitability (Lee et al, 2007) and spinal LTP induction (Lee et al, 2010). In contrast, an artificial elevation of spinal superoxide produces pain behaviors in normal animals (Kim et al, 2008).…”

“…Capsaicin injection evokes an acute nociceptive pain behavior and subsequent long-lasting secondary hyperalgesia in the adjacent region, mainly through a central mechanism of postsynaptic NMDA receptor activation (Sakurada et al, 1998;Zou et al, 2000). To investigate spinal dorsal horn neuron plasticity, the long-lasting mechanical hyperalgesia (up to 120 min) was measured in the region of secondary hyperalgesia, away from the injection site as described before (Schwartz et al, 2008;Schwartz et al, 2009). Blocking mitochondrial Ca 2+ uptake by an intrathecal pre-treatment with either Ru360 (50 µM) or FCCP (50 µM) significantly reduced the longlasting mechanical hyperalgesia after capsaicin treatment (P<0.05; Fig.…”

Wingless-type Mammary Tumor Virus Integration Site Family, Member 5A (Wnt5a) Regulates Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Glycoprotein 120 (gp120)-induced Expression of Pro-Inflammatory Cytokines via the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) and c-Jun N-terminal Kinase (JNK) Signaling Pathways

“…)-For direct transcutaneous intrathecal injection of drugs, a modified version (45,46) of the original method (47) was used. Mice were anesthetized with isoflurane (2% during the induction phase and 1.5% during the maintenance phase) with a flow of O 2 , placed in the prone position, and hair on the caudal back was clipped.…”

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

“…This hypothesis was validated further in the capsaicin test. Intraplantar injection of capsaicin elicited primary and secondary mechanical allodynia in WT mice, but only the secondary mechanical allodynia, which is mediated by central sensitization (33,34), was attenuated in Casp6 -/-mice (Supplemental Figure 2, A and B). …”