endomorphin-1 and Spinal-Cord-Injuries

Burn injury is one of the main causes of mortality worldwide and frequently associated with severe and long-lasting pain that compromises the quality of patient life. Several studies have shown that the mu-opioid system plays an important role in burn pain relief. In this study, we investigated the spinal antinociception induced by the endogenous mu-opioid receptor (MOR) agonists endomorphins and explored their mechanisms of actions in burn injury-induced pain model. Our results showed that intrathecal injection of endomorphin-1 and -2 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia via the mu-opioid receptor in mice on day 3 after burn injury, which was consistent with the data obtained from the mu-opioid receptor knockout mice. Western blot showed that the phosphorylation levels of extracellular signal-regulated kinase1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in ipsilateral spinal cord tissues were significantly up-regulated after burn injury. Intrathecal injection of endomorphins selectively inhibited the activation of p38 MAPK on day 3 after burn injury via the mu-opioid receptor. Further studies found that repeated application of the specific p38 MAPK inhibitor SB203580 dose-dependently inhibited burn-injury pain, as well as the activation of spinal p38 MAPK. Taken together, our present study demonstrates that intrathecal injection of endomorphins attenuates burn-injury pain in male mice by affecting the spinal activation of p38 MAPK via the mu-opioid receptor.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Burns; Disease Models, Animal; Enzyme Inhibitors; Hyperalgesia; Imidazoles; Injections, Spinal; Male; Mice; Mice, Knockout; Narcotic Antagonists; Oligopeptides; p38 Mitogen-Activated Protein Kinases; Pain; Pyridines; Receptors, Opioid, mu; Signal Transduction; Spinal Cord Injuries

Due to side effects of medications used for chronic pain, combination therapy seems to be an appropriate solution for alleviation of chronic pain and reducing the side effects. The role of inhibitory GABA system is well proven in reducing neuropathic pain. Also, special attention has been focused on endogenous morphine (endomorphins) in reducing chronic pain originates from damage to the nervous system. The purpose of this study is to investigate the analgesic effect of simultaneous administration of GABA agonist and endomorphin-1 on neuropathic pain in rat model of spinal cord injury (SCI). The role of oxidative stress, NR1 subunits of NMDA receptors, and α. Spinal cord at level of T6-T8 was compressed. Three weeks after spinal cord injury, muscimol and endomorphin-1 were injected (intrathecally once a day for 7 days) individually or in combination. Mechanical and cold allodynia, thermal and mechanical hyperalgesia were evaluated before injection and 15 and 60 min after injection. At the end of behavioral experiments, histological and biochemical evaluations were done on prepared spinal cord samples.. Isobologram results showed that combination therapy significantly increased the pain threshold comparing to injection of endomorphin-1 (EM) or muscimol alone. Histological studies indicated the increased expression of α2 subunits of GABA receptors, and NR1 subunits of NMDA receptors in the spinal cord. The combination therapy also increased the glutathione (GSH) and superoxide dismutase (SOD) level and decreased the malondialdehyde (MDA) levels in the spinal cord.. Simultaneous administration of muscimol and endomorphine-1 could be a new candidate for alleviation of pain resulting from spinal cord injury.

Topics: Animals; Hyperalgesia; Injections, Spinal; Muscimol; Neuralgia; Oligopeptides; Rats; Spinal Cord; Spinal Cord Injuries