Hong Beom Bae

Antinociception of intrathecal adenosine receptor subtype agonists in rat formalin test

Adenosine has shown antinociceptive action via spinal adenosine receptors. There are four types of adenosine receptors: A1, A2A, A2B, and A3. We characterized the nature of types of adenosine receptors for the control of nociception at the spinal level. For nociception, formalin solution (5%, 50 &mgr;L) was injected into the hindpaw of male Sprague-Dawley rats. The effects of intrathecal adenosine A1 (CPA), A2A (DPMA), and A3 (IB-MECA) receptor agonists were examined. CPA and IB-MECA produced limited or no effect on the early phase response of the formalin test, respectively, but the two drugs depressed the late phase response. DPMA suppressed both phase responses. CPA was the most potent drug among the three in the late phase. These results suggest that spinal adenosine A1 and A2A receptors may be involved in the modulation of the early and the late phase responses of the formalin test, whereas adenosine A3 receptor may be involved in the regulation of the late phase response.

Roles of Adenosine Receptor Subtypes in the Antinociceptive Effect of Intrathecal Adenosine in a Rat Formalin Test

The contributions of adenosine receptor subtypes to antinociception produced by adenosine were determined at the spinal level. There are 4 types of adenosine receptors, namely A₁, A_2A, A_2B and A₃. The authors investigated the properties of the subtypes of spinal adenosine receptors in terms of nociceptive modulation. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 µl) into the hind paws of male Sprague-Dawley rats. After observing the effect of intrathecal adenosine during the formalin test, the effects of intrathecal adenosine A₁(CPT), A_2A (CSC), A_2B (alloxazine) and A₃(MRS 1220) receptor antagonists on the action of adenosine were examined. Intrathecal adenosine inhibited phase 2 flinching response without affecting phase 1 response. CPT, CSC, alloxazine and MRS 1220 antagonized the antinociceptive action of adenosine during phase 2 of the formalin test. These results suggest that spinal adenosine A₁, A_2A, A_2B and A₃receptors may play an important role in the antinociception of adenosine in the formalin-induced facilitated state.

Antinociceptive effects and synergistic interaction with morphine of intrathecal metabotropic glutamate receptor 2/3 antagonist in the formalin test of rats.

Spinal metabotropic glutamate receptors (mGluRs) have been known to be involved in the modulation of nociception. While the antinociceptive effects of the mGluR1/5 have been demonstrated, the role of mGluR2/3 for nociception is less clear. This study investigated the effects of an intrathecal mGluR2/3 agonist, APDC, and a mGluR2/3 antagonist, LY341495, for inflammatory and acute pain in the formalin test and thermal stimulation test. We also examined their interaction with intrathecal morphine for the antinociceptive effect. APDC had little effect on the formalin-induced nociception. In contrast, LY341495 caused a dose-dependent suppression of the phase 2 flinching response to the formalin stimulus without affecting phase 1 flinching response. Furthermore, the suppression of pain behavior by LY341495 during phase 2 was reduced significantly by pretreatment with APDC. LY341495 and morphine also showed synergistic drug interaction for antinociception during phase 2 in the formalin test.

Antinociceptive Interactions between Intrathecal Gabapentin and MK801 or NBQX in Rat Formalin Test

Antagonists for spinal N-methyl-D-aspartate (NMDA) and amino-hydroxy-methtyl-isoxazolepropionate (AMPA) receptors are effective in attenuating acute nociception or injury-induced hyperalgesia. The antinociception of spinal gabapentin is developed in injury-induced hyperalgesia without affecting acute nociception. The authors evaluated the effects of intrathecal gabapentin, NMDA antagonist (MK801) and AMPA antagonist (NBQX) in the formalin test which shows injury-induced hyperalgesia as well as acute pain. We further assessed the interactions between gabapentin and either MK801 or NBQX. Male Sprague-Dawley rats were implanted with intrathecal catheters. To evoke pain, 50 µL of 5% formalin solution was injected into the hindpaw. The interaction was investigated by a fixed dose analysis or an isobolographic analysis. MK801 and NBQX suppressed flinching responses during phase 1 of the formalin test, while gabapentin had little effect on phase 1. All three agents decreased the phase 2 flinching response. A fixed dose analysis in phase 1 showed that gabapentin potentiated the antinociceptive effect of MK801 and NBQX. Isobolographic analysis in phase 2 revealed a synergistic interaction after coadministration of gabapentin-MK801 or gabapentin-NBQX. Correspondingly, spinal gabapentin with NMDA or AMPA antagonist may be useful in managing acute pain and injury-induced hyperalgesia.

Effect of ulinastatin on cytokine reaction during gastrectomy

Background Inflammation plays an important role in the postoperative morbidity of organs, which is related to the activation of pro-inflammatory and anti-inflammatory cytokines. Ulinastatin (Urinary trypsin inhibitor, UTI) is a serine protease inhibitor found in human urine or serum that inhibits the activation of human leukocyte elastase. This study examined the effect of UTI on the inflammation response in patients undergoing a gastrectomy. Methods Thirty patients scheduled to undergo a gastrectomy were divided into two groups as follows: Control group (untreated, n = 15) and UTI group (100,000 units of UTI were continuously injected intravenously for 2 hours, n = 15). Arterial blood was sampled before surgery (T0), 10 minutes after its onset (T1), at its end (T2), and 1 hour after surgery (T3) to measure the level of cytokines. Results Both the control and treatment groups had higher interleukin (IL)-6 levels at T2 and T3 than T0, and the level increased with time. However, the increase was smaller in the treatment group. The IL-8 levels were not activated significantly in any of the groups. Conclusions UTI inhibits the secretion of IL-6, which is an inflammatory cytokine produced after a gastrectomy. This shows that UTI can decrease the inflammation reaction caused by surgical stress.

Lack of the nitric oxide-cyclic GMP-potassium channel pathway for the antinociceptive effect of intrathecal zaprinast in a rat formalin test

Zaprinast is a phosphodiesterase inhibitor that is active in various models of pain when administered locally. In addition, the antinociception of zaprinast is involved in the nitric oxide (NO)-cGMP pathway. However, the effect of zaprinast administered spinally has not been examined. Therefore, this study examined the effect of zaprinast on the formalin-induced nociception at the spinal level. Next, the role of the NO-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. Catheters were inserted into the intrathecal space of male Sprague-Dawley (SD) rats. Pain was induced by applying 50 microl of a 5% formalin solution to the hindpaw. The change in the zaprinast-induced effect was examined after an intrathecal pretreatment with a NO synthase inhibitor (l-NMMA), a guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide). Zaprinast produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Intrathecal l-NMMA, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase of the formalin test. These results suggest that zaprinast is effective against both acute pain and the facilitated pain state at the spinal level. However, the NO-sensitive cGMP-potassium channel pathway is not contributable to the antinociceptive mechanism of zaprinast in the spinal cord.

Analysis of Interactions between Serotonin and Gabapentin or Adenosine in the Spinal Cord of Rats

We evaluated the nature of the pharmacologic interaction after concurrent administration of 5-HT–gabapentin and 5-HT–adenosine at the spinal level. Intrathecal catheters were placed in the subarachnoid space of male Sprague-Dawley rats. Nociception was induced by subcutaneous injection of formalin solution (5%, 50 µl) into the hind paw. A fixed dose analysis and an isobolographic analysis were used to determine the properties of interaction. Intrathecal 5-HT dose-dependently suppressed the flinching response during phase 1 of the formalin test, while neither gabapentin nor adenosine affected the phase-1 flinching response. All three intrathecal drugs attenuated the phase-2 flinching response in a dose-dependent manner. The intrathecal combination of 5-HT with a fixed dose of gabapentin or adenosine in phase 1 had little effect or increased the antinociception of 5-HT alone. Isobolographic analysis in phase 2 revealed an additive or a synergistic interaction after intrathecal delivery of 5-HT–gabapentin or 5-HT–adenosine mixture. Taken together, the combination of 5-HT with either gabapentin or adenosine may offer a potential remedy in the treatment of the facilitated state as well as acute pain in the spinal cord.

Evaluation of Interaction between Intrathecal Adenosine and MK801 or NBQX in a Rat Formalin Pain Model

Adenosine and excitatory amino acids have been known to be involved in modulating nociceptive transmission at the spinal level. The authors assessed the characteristics of the interaction of the adenosine-excitatory amino acid antagonist combinations in the spinal cord of rats on the formalin-induced nociception. Intrathecal NMDA antagonist ((5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a[,]d]cyclohepten-5,10-imine hydrogen maleate, MK801, 30 µg) and AMPA antagonist (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[F]quinoxaline-7-sulfonamide, NBQX, 3 µg) decreased the total number of flinches during both phases in the formalin test. Intrathecal adenosine (300 µg) had little effect on the phase 1 flinching response, but decreased the phase 2 response. The fixed dose analysis and the isobolographic analysis revealed that adenosine interacts additively with MK801 and NBQX in the spinal cord.

Spinal 5-HT1A, not the 5-HT1B or 5-HT3 receptors, mediates descending serotonergic inhibition for late-phase mechanical allodynia of carrageenan-induced peripheral inflammation.

Previous electrophysiological studies demonstrated a limited role of 5-hydroxytryptamine 3 receptor (5-HT3R), but facilitatory role of 5-HT1AR and 5-HT1BR in spinal nociceptive processing of carrageenan-induced inflammatory pain. The release of spinal 5-HT was shown to peak in early-phase and return to baseline in late-phase of carrageenan inflammation. We examined the role of the descending serotonergic projections involving 5-HT1AR, 5-HT1BR, and 5-HT3R in mechanical allodynia of early- (first 4h) and late-phase (24h after) carrageenan-induced inflammation. Intrathecal administration of 5-HT produced a significant anti-allodynic effect in late-phase, but not in early-phase. Similarly, intrathecal 5-HT1AR agonist (8-OH-DPAT) attenuated the intensity of late-phase allodynia in a dose dependent fashion which was antagonized by 5-HT1AR antagonist (WAY-100635), but produced no effect on the early-phase allodynia. However, other agonists or antagonists of 5-HT1BR (CP-93129, SB-224289) and 5-HT3R (m-CPBG, ondansetron) did not produce any anti- or pro-allodynic effect in both early- and late- phase allodynia. These results suggest that spinal 5-HT1A, but not 5-HT1B or 5-HT3 receptors mediate descending serotonergic inhibition on nociceptive processing of late-phase mechanical allodynia in carrageenan-induced inflammation.

Protective Effect of Sauchinone Against Regional Myocardial Ischemia/Reperfusion Injury: Inhibition of p38 MAPK and JNK Death Signaling Pathways

Sauchinone has been known to have anti-inflammatory and antioxidant effects. We determined whether sauchinone is beneficial in regional myocardial ischemia/reperfusion (I/R) injury. Rats were subjected to 20 min occlusion of the left anterior descending coronary artery, followed by 2 hr reperfusion. Sauchinone (10 mg/kg) was administered intraperitoneally 30 min before the onset of ischemia. The infarct size was measured 2 hr after resuming the perfusion. The expression of cell death kinases (p38 and JNK) and reperfusion injury salvage kinases (phosphatidylinositol-3-OH kinases-Akt, extra-cellular signal-regulated kinases [ERK1/2])/glycogen synthase kinase (GSK)-3β was determined 5 min after resuming the perfusion. Sauchinone significantly reduced the infarct size (29.0% ± 5.3% in the sauchinone group vs 44.4% ± 6.1% in the control, P < 0.05). Accordingly, the phosphorylation of JNK and p38 was significantly attenuated, while that of ERK1/2, Akt and GSK-3β was not affected. It is suggested that sauchinone protects against regional myocardial I/R injury through inhibition of phosphorylation of p38 and JNK death signaling pathways.