The sigma-1 receptor has recently been implicated in a myriad of cellular functions and biological processes. Previous studies have demonstrated that the spinal sigma-1 receptor plays a pro-nociceptive role in acute pain and that the direct activation of sigma-1 receptor enhances the nociceptive response to peripheral stimuli, which is closely associated with calcium-dependent second messenger cascades including protein kinase C (PKC). In addition, the activation of sigma-1 receptor increases PKC- and protein kinase alpha (PKA)-dependent phosphorylation of the N-Methyl- D-aspartate (NMDA) receptor in the spinal cord, which results in the potentiation of intrathecal NMDA-evoked spontaneous pain behavior. Moreover, the blockade of spinal sigma-1 receptor suppresses the development of neuropathic pain and blocks the increase of phosphorylation of extracellular signal-regulated kinase (ERK) as well as pNR1 in the spinal cord. Recently, it was also reported that spinal neurosteroids such as pregnenolone and dehydroepiandrosterone sulfate, which are recognized as endogenous ligands for sigma-1 receptor, could produce mechanical hypersensitivity via sigma-1 receptor-mediated increase of pNR1. Collectively, these findings demonstrate that the activation of spinal sigma-1 receptor or the increase of neurosteroids is closely associated with the acute pain sensation or the development of chronic pain, and imply that sigma-1 receptor can be a new potential target for the development of analgesics.
Acute Pain ; Analgesics ; Biological Processes ; Central Nervous System Sensitization ; Chronic Pain ; D-Aspartic Acid ; Dehydroepiandrosterone Sulfate ; Hypersensitivity ; Ligands ; Neuralgia ; Neurotransmitter Agents ; Phosphorylation ; Phosphotransferases ; Pregnenolone ; Protein Kinase C ; Protein Kinases ; Receptors, sigma ; Second Messenger Systems ; Sensation ; Spinal Cord

Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1), also known as growth differentiation factor-15 (GDF-15), is associated with cancer, diabetes, and inflammation, while there is limited understanding of the role of NAG-1 in nociception. Here, we examined the nociceptive behaviors of NAG-1 transgenic (TG) mice and wild-type (WT) littermates. Mechanical sensitivity was evaluated by using the von Frey filament test, and thermal sensitivity was assessed by the hot-plate, Hargreaves, and acetone tests. c-Fos, glial fibrillary acidic protein (GFAP), and ionized calcium binding adaptor molecule-1 (Iba-1) immunoreactivity was examined in the spinal cord following observation of the formalin-induced nociceptive behaviors. There was no difference in mechanical or thermal sensitivity for NAG-1 TG and WT mice. Intraplantar formalin injection induced nociceptive behaviors in both male and female NAG-1 TG and WT mice. The peak period in the second phase was delayed in NAG-1 TG female mice compared with that of WT female mice, while there was no difference in the cumulative time of nociceptive behaviors between the two groups of mice. Formalin increased spinal c-Fos immunoreactivity in both TG and WT female mice. Neither GFAP nor Iba-1 immunoreactivity was increased in the spinal cord of TG and WT female mice. These findings indicate that NAG-1 TG mice have comparable baseline sensitivity to mechanical and thermal stimulation as WT mice and that NAG-1 in female mice may have an inhibitory effect on the second phase of inflammatory pain. Therefore, it could be a novel target to inhibit central nervous system response in pain.

In this study, we aimed to determine the antinociceptive and/or anti-inflammatory effect of Bang-Poong (BP, Radix Ledebouriellae) on Freund's adjuvant-induced arthritis in rats. Traditionally, BP has been used to treat several inflammatory diseases such as arthritis. Whole BP is extracted into two fractions that were ethylacetate and hexane-soluble fractions. Adult Sprague-Dawley rats (n=30, 130-150 g) were subcutaneously administered by the Freund's complete adjuvant (FCA) into the plantar surface of right hindpaw. Twelve days after the injection of FCA, the rats initially showed typical inflammatory edema and arthritis-related symptoms on the contralateral side (i.e. left hindpaw). Both antinociceptive (evaluation of mechanical, thermal pain threshold and analysis of spinal Fos expression) and anti- inflammatory (evaluation of paw edema, serum interleukin-6 level and x-ray analysis) effect of BP extracts were examined. The ethylacetate fraction of BP (BPE) significantly suppressed the FCA-induced paw edema as well as the serum level of interleukin-6 and it alleviated the radiological changes. Moreover, both mechanical and thermal hyperalgesia were attenuated by the treatment of BPE. In addition, spinal Fos expression that was increased by FCA- injection was suppressed in BPE group. Therefore, this study showed that BPE produced significant both antinociceptive and anti-inflammatory effects on FCA- induced arthritis in rats, while hexane fraction of BP did not show these effects. In conclusion, it is suggested that the ethylacetate fraction of BP is recommended to alleviate the arthritis-related symptoms in human according to the results of this study.
Analgesics/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Arthritis, Experimental/*drug therapy/radiography ; Drugs, Chinese Herbal/*pharmacology ; Edema/veterinary ; Hindlimb/radiography ; Hyperalgesia/veterinary ; Interleukin-6/blood ; Male ; Pain Measurement/veterinary ; *Phytotherapy ; Plant Extracts/pharmacology ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/metabolism

This study was designed to investigate the optimal poloxamer concentration in the mixed solution of recombinant human epidermal growth factor and poloxamer which can be effective in the wound healing process. Two full-thickness excisions were made on the back of the experimental animals. Recombinant human epidermal growth factors(RhEGF) containing different poloxamer concentrations were applied twice a day and the rates of wound closure were measured every day for 14 days. On the 7th and 14th postoperative day, the histological analysis for epithelization and granulation were performed using computerized imaging analysis system after Masson's trichrome stains. The healing times 50% were significantly reduced in the RhEGF containing 0, 3 and 6% poloxamer treated groups as compared with both the non treated control and vehicle control group(p < 0.05). However, there were no statistical differences in the healing times 50% in the RhEGF containing 10, 15 and 20% poloxamer treated groups as compared with both the non treated control and vehicle control group. Histological examinations revealed that epithelization and granulation were increased significantly in the RhEGF containing 0, 3 and 6% poloxamer treated groups as compared with control group and vehicle control group at the 7th day after operation(p < 0.05). In conclusion, these findings suggest that RhEGF may enhance the epithelial wound healing process through stimulating cell proliferation. The concentration of 0, 3 and 6% of poloxamers can be applied to stabilize and enhance the wound healing effect of RhEGF for clinical application.
Animals ; Cell Proliferation ; Coloring Agents ; Epidermal Growth Factor* ; Humans* ; Poloxamer* ; Rats* ; Wound Healing* ; Wounds and Injuries*

The wound healing effect of topical application of the recombinant human epidermal growth factor(rhEGF) on full-thickness dermal injury was investigated. Two full-thickness excisions were made on the back of the experimental animals. The rhEGF was applied twice a day and the rate of wound closure was measured every day for 14 days. On the seventh postoperative day, the histological findings of epithelization and granulation were examined by Massons tichrome stain, and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and alpha-smooth muscle actin(alpha-SMA). The wound size was a significant reduction in the rhEGF treated groups as compared with the control group (p<0.05). However, there was no statistical difference in the wound size among the concentrations of the rhEGF treated group. Histological examination revealed that epithelization and granulation was increased significantly in the rhEGF group compared to control group (p < 0.01, 0.05). PCNA and alpha-SMA immunoreactive cells were observed at the margin of wound and the rhEGF treatments significantly increased the number of PCNA and alpha-SMA immunoreactive cells as compared to those of control group (p < 0.01, 0.05). Taken together, these findings suggest that rhEGF enhance the epithelial wound healing by the stimulate of cell proliferation. The wound contraction might be also affected by rhEGF application.
Animals ; Cell Proliferation ; Epidermal Growth Factor* ; Humans* ; Proliferating Cell Nuclear Antigen ; Rats* ; Skin* ; Wound Healing ; Wounds and Injuries*

Background: Scalding burn injuries can occur in everyday life but occur more frequently in young children. Therefore, it is important to develop more effective burn treatments. Objectives: This study examined the effects of bee venom (BV) stimulation on scalding burn injury-induced nociception in mice as a new treatment for burn pain. Methods: To develop a burn injury model, the right hind paw was immersed temporarily in hot water (65°C, 3 seconds). Immediately after the burn, BV (0.01, 0.02, or 0.1 mg/kg) was injected subcutaneously into the ipsilateral knee area once daily for 14 days. A von Frey test was performed to assess the nociceptive response, and the altered walking parameters were evaluated using an automated gait analysis system. In addition, the peripheral and central expression changes in substance P (Sub P) were measured in the dorsal root ganglion and spinal cord by immunofluorescence. Results: Repeated BV treatment at the 2 higher doses used in this study (0.02 and 0.1 mg/kg) alleviated the pain responses remarkably and recovered the gait performances to the level of acetaminophen (200 mg/kg, intraperitoneal, once daily), which used as the positive control group. Moreover, BV stimulation had an inhibitory effect on the increased expression of Sub P in the peripheral and central nervous systems by a burn injury. Conclusions These results suggest that a peripheral BV treatment may have positive potency in treating burn-induced pain.

In this study, we examined the antinociceptive effect of Cyperi rhizoma (CR) and Corydalis tuber (CT) extracts using a chronic constriction injury-induced neuropathic pain rat model. After the ligation of sciatic nerve, neuropathic pain behavior such as mechanical allodynia and thermal hyperalgesia were rapidly induced and maintained for 1 month. Repeated treatment of CR or CT (per oral, 10 or 30 mg/kg, twice a day) was performed either in induction (day 0~5) or maintenance (day 14~19) period of neuropathic pain state. Treatment of CR or CT at doses of 30 mg/kg in the induction and maintenance periods significantly decreased the nerve injury-induced mechanical allodynia. In addition, CR and CT at doses of 10 or 30 mg/kg alleviated thermal heat hyperalgesia when they were treated in the maintenance period. Finally, CR or CT (30 mg/kg) treated during the induction period remarkably reduced the nerve injury-induced phosphorylation of NMDA receptor NR1 subunit (pNR1) in the spinal dorsal horn. Results of this study suggest that extracts from CR and CT may be useful to alleviate neuropathic pain.
Animals ; Constriction ; Corydalis ; Horns ; Hot Temperature ; Hyperalgesia ; Ligation ; N-Methylaspartate ; Neuralgia ; Phosphorylation ; Rats ; Sciatic Nerve

We have previously demonstrated that the neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces functional potentiation of N-methyl-D-aspartate (NMDA) receptors via increases in phosphorylation of NMDA receptor GluN1 subunit (pGluN1). However, the modulatory mechanisms responsible for the expression of the DHEA-synthesizing enzyme, cytochrome P450c17 following peripheral nerve injury have yet to be examined. Here we determined whether oxidative stress induced by the spinal activation of nitric oxide synthase type II (NOS-II) modulates the expression of P450c17 and whether this process contributes to the development of neuropathic pain in rats. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of NOS-II in microglial cells and NO levels in the lumbar spinal cord dorsal horn at postoperative day 5. Intrathecal administration of the NOS-II inhibitor, L-NIL during the induction phase of neuropathic pain (postoperative days 0~5) significantly reduced the CCI-induced development of mechanical allodynia and thermal hyperalgesia. Sciatic nerve injury increased the expression of PKC- and PKA-dependent pGluN1 as well as the mRNA and protein levels of P450c17 in the spinal cord at postoperative day 5, and these increases were suppressed by repeated administration of L-NIL. Co-administration of DHEAS together with L-NIL restored the development of neuropathic pain and pGluN1 that were originally inhibited by L-NIL administration alone. Collectively these results provide strong support for the hypothesis that activation of NOS-II increases the mRNA and protein levels of P450c17 in the spinal cord, ultimately leading to the development of central sensitization and neuropathic pain induced by peripheral nerve injury.
Animals ; Central Nervous System Sensitization ; Constriction ; Cytochromes ; Dehydroepiandrosterone ; Dehydroepiandrosterone Sulfate ; Hyperalgesia ; N-Methylaspartate ; Neuralgia ; Nitric Oxide Synthase Type II ; Nitric Oxide Synthase ; Nitric Oxide ; Oxidative Stress ; Peripheral Nerve Injuries ; Phosphorylation ; Rats ; RNA, Messenger ; Rodentia ; Sciatic Nerve ; Spinal Cord ; Spinal Cord Dorsal Horn

PURPOSE: To provide epidemiologic data of the burn injuries in stroke patients and to determine the most effective prevention and education methods. METHODS: We retrospectively reviewed the medical records of patients who had been admitted to the burn center at the Hangang Sacred Heart Hospital between January 2002 and June 2008. Burn cause, size, depth, duration of hospital stay, rate of operation performed, outcomes and time from stroke onset to burn were reviewed and compared. RESULTS: We reviewed the charts of total 87 patients (57 men and 30 women with a mean age of 61.95+/-14.48 years). Places of burn were divided into two groups (at home: n=52, outside: n=25) and patients injured at home were more than twice than who were outside. According to etiology of infarction, patients group was divided into ischemic (n=49) and hemorrhagic (n=38) group. Most of the patients were injured from flame burn. The rate of operation for ischemic group was significantly higher than hemorrhagic group. The etiology of infarction and cause of burn were not significant to prognosis. Chronic group (defined as burn occurred 6 months after the onset of stroke) had the higher incidence of burn injuries. But, there was no significant relationship between the time from stroke onset to burn and burn cause, prognosis, rate of operation, total body surface area burned. Non-survivor group had a higher operation rate than survivor group, although there was no difference in total burn surface area. CONCLUSION: Functional recovery of stroke was not associated with burn injury in our study. Flame burn took the highest percentage of burn causes. We believe that studies pooling different center's results are need to improve significance of conclusion drawn from these data.
Body Surface Area ; Burn Units ; Burns ; Female ; Heart ; Humans ; Incidence ; Infarction ; Length of Stay ; Male ; Medical Records ; Prognosis ; Retrospective Studies ; Stroke ; Survivors

Recently, the antinociceptive and anti-inflammatory efficacy of bee venom (BV, Apis mellifera) has been confirmed in rodent models of inflammation and arthritis. Interestingly, the antinociceptive and anti-inflammatory effect of whole BV can be reproduced by two water-soluble fractions of BV (>20 kDa:BVAF1 and<10 kDa: BVAF3). Based on these scientific findings, BV and its effective water-soluble fractions have been proposed as potential anti-inflammatory and antinociceptive pharmaceuticals. While BV's anti-inflammatory and antinociceptive properties have been well documented, there have been no careful studies of potential, side effects of BV and its fractions when administered in the therapeutic range (BV, 5 microgram/kg; BVAF1, 0.2 microgram/kg: BVAF3, 3 microgram/kg; subcutaneous or intradermal). Such information is critical for future clinical use of BV in humans. Because of this paucity of information, the present study was designed to determine the general pharmacological/physiological effects of BV and its fractions administration on the rodent central nervous, cardiovascular, respiratory and gastrointestinal system. Subcutaneous BV and its fractions treatment did not produce any significant effects on general physiological functions at the highest dose tested (200-fold and 100-fold doses higher than that used clinically, respectively) except writhing test. These results demonstrate that doses of BV or BV subfractions in the therapeutic range or higher can be used as safe antinociceptive and anti-inflammatory agents.
Analgesics/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Bee Venoms/*pharmacology ; Cardiovascular System/*drug effects ; Central Nervous System/*drug effects ; Digestive System/*drug effects ; Male ; Mice ; Mice, Inbred ICR ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Respiratory System/*drug effects