Abstract
Oxidative stress resulting from reactive oxygen species (ROS) is known to play a key role in numerous neurological disorders, including neuropathic pain. Morphine is one of the commonly used opioids for pain management. However, long-term administration of morphine results in morphine antinociceptive tolerance (MAT) through elevation of ROS and suppression of natural antioxidant defense mechanisms. Recently, mesoporous polydopamine (MPDA) nanoparticles (NPS) have been known to possess strong antioxidant properties. We speculated that morphine delivery through an antioxidant nanocarrier might be a reasonable strategy to alleviate MAT. MPDAs showed a high drug loading efficiency of ∼50%, which was much higher than conventional NPS. Spectral and in vitro studies suggest a superior ROS scavenging ability of NPS. Results from a rat neuropathic pain model demonstrate that MPDA-loaded morphine (MPDA@Mor) is efficient in minimizing MAT with prolonged analgesic effect and suppression of pro-inflammatory cytokines. Additionally, serum levels of liver enzymes and levels of endogenous antioxidants were measured in the liver. Treatment with free morphine resulted in elevated levels of liver enzymes and significantly lowered the activities of endogenous antioxidant enzymes in comparison with the control and MPDA@Mor-treated group. Histopathological examination of the liver revealed that MPDA@Mor can significantly reduce the hepatotoxic effects of morphine. Taken together, our current work will provide an important insight into the development of safe and effective nano-antioxidant platforms for neuropathic pain management.
Highlights
Using a partial sciatic nerve transection (PSNT) model of neuropathic pain in rats, we demonstrated that delivery of morphine with mesoporous polydopamine (MPDA) significantly delayed morphine antinociceptive tolerance (MAT) by maintaining redox balance through the restoration of endogenous antioxidant enzymes in the liver along with the suppression of microglial cell activity in the spinal dorsal horn
The morphine loaded mesoporous polydopamine (MPDA-)NPS were collected by centrifugation, and washed several times with water and phosphate buffered saline (PBS) to remove free morphine and the obtained MPDA-loaded morphine (MPDA@Mor) NPS were stored in 99.9% ethanol for further use
MPDA-NPS were synthesized by emulsion-induced interface assembly using F127 and trimetyl benzene (TMB) (Figure 1) according to the procedure described by Chen et al [31]
Summary
Though natural antioxidants have phenomenal ROS scavenging ability, clinical trials have shown limited success in preventing ROS related diseases with toxicity at high doses [12,13]. PDA-NPS alone have shown excellent antioxidant properties in vivo by scavenging ROS, preventing the brain injury from ischemia, as well as healing acute lung injury and alleviating periodontal inflammation without side effects [22,23,24]. MPDA-NPS were developed for the delivery of opioid analgesic morphine to treat neuropathic pain. Using a partial sciatic nerve transection (PSNT) model of neuropathic pain in rats, we demonstrated that delivery of morphine with MPDA significantly delayed MAT by maintaining redox balance through the restoration of endogenous antioxidant enzymes in the liver along with the suppression of microglial cell activity in the spinal dorsal horn. Our current work provides a promising platform for designing efficient biocompatible nano-antioxidants for applications in the field of biomedicine
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