Sung Tae Chung

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.

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.

Synergistic antinociception between zaprinast and morphine in the spinal cord of rats on the formalin test

Background and objective: The cyclic guanosine monophosphate level, which causes an antinociception, is increased in cells as a direct result of phosphodiesterase inhibition. This study used a nociceptive test to examine the nature of the pharmacological interaction between intrathecal zaprinast, a phosphodiesterase inhibitor, and morphine. Methods: Catheters were inserted into the intrathecal space through an incision in the atlantooccipital membrane of male Sprague‐Dawley rats. As a nociceptive model, 50 μL of a 5% formalin solution was injected into the hind paw. After observing the effect of zaprinast (37, 111, 369 nmol) and morphine (1, 4, 10, 40 nmol) alone, the interactions of their combination were examined by an isobolographic analysis. Results: Intrathecal zaprinast (P < 0.05) and morphine (P < 0.05) dose‐dependently suppressed the flinching observed during phase 1 and phase 2 in the formalin test. The ED50 values (95% confidence intervals) of zaprinast and morphine in phase 1 were 161.9 (87.9‐298.3) and 11.6 nmol (4.8‐27.9 nmol), respectively. The phase 2 ED50 values (95% confidence intervals) of zaprinast and morphine were 229.9 (142.5‐370.9) and 3.9 nmol (1.9‐7.6 nmol), respectively. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery a zaprinast‐morphine mixture in both phases. The ED50 values of (95% confidence intervals) zaprinast in the combination of zaprinast with morphine in phase 1 and phase 2 were 14.2 (4.9‐40.6) and 10.4 nmol (3‐35.9 nmol), respectively. Conclusions: Intrathecal zaprinast and morphine are effective against acute pain and facilitated pain state. Zaprinast interacts synergistically with morphine.

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.

Lack of Reciprocity between Opioid and 5-HT3 Receptors for Antinociception in Rat Spinal Cord

We examined the properties of the drug interaction between morphine and 5-HT3 receptor antagonist at the spinal level. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 µl) into the hindpaw of the rats. Intrathecal morphine and m-CPBG (5-HT3 receptor agonist) dose-dependently decreased the flinching response during phase 1 and phase 2 in the formalin test. Intrathecal 5-HT3 receptor antagonists (LY-278,584 and ondansetron) did not reverse the antinociceptive effect of intrathecal morphine. Intrathecal naloxone had little effect on attenuation of the antinociception of intrathecal m-CPBG. Taken together, no reciprocal interaction was noted between 5-HT3 receptor and opioid receptors at the spinal level. Thus, the 5-HT3 receptor antagonist may be useful to manage opioid-induced emesis at the spinal level.

Antinociceptive effect of intrathecal ginsenosides through alpha-2 adrenoceptors in the formalin test of rat of rat: 14AP3–1

could not reveal the difference between analgesic action and psychological action of acupuncture(1). Conclusion(s): These results suggest that acupuncture attenuates chronic pain independently from age groups in adults. References: 1 Madsen MV, et al: Acupuncture treatment for pain: systematic review of randomised clinical trials with acupuncture, placebo acupuncture, and no acupuncture groups. BMJ 2009;338:a3115.

Flecanide acetate reduces mortality to endotoxin induced acute lung injury in rats: 12AP5-5

Anesthesiology and Pain Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea Background and Goal of Study: To clarify the effects of flecanide acetate, an antiarrythmic drug, on mortality and interleukin-8 (IL-8) response to endotoxin induced acute lung injury in rats. Materials and Methods: Animals were randomly assigned to one of five groups: rats receiving subcutaneous (SC) infusion of saline and intraperitoneal (IP) injection saline (S-S group, n 14), those receiving SC infusion of saline and IP injection of Escherichia coliendotoxin (20 mg/kg) (S-E group, n 28), those receving SC infusion of flecanide acetate (0.2 mg/kg/hr) and IP injection of saline (F-S group, n 14), those receiving SC infusion of flecanide acetate (0.1 mg/kg/hr) and IP injection of endotoxin (F 0.1-E group, n 14), those receiving SC infusion of flecanide acetate (0.2 mg/kg/hr) and IP injection of endotoxin (F 0.2-E group, n 17) SC influsion of saline or flecanide acetate using by mini-osmotic pump was started 3 hours before IP injection of saline or endotoxin and continued until 24 hours after IP injection of saline or endotoxin when all rats were killed. The wet weight/dry weight (W/D) ratio of lung, lung injury score and number of WBC, % polymorphonuclear cells and concentration of IL-8 in bronchoalveolar lavage fluid (BALF) and mortality rate were calculated 24 hours after IP injection of saline or endotoxin. Results and Discussions: The mortality rates for F 0.1-E groups (0%) and F 0.2-E groups (17.7%) were significantly lower than that for the S-E group (43%). The increases in W/D ratio, lung injury score and the number of WBC, % polymorphonuclear cells and concentration of IL-8 in BALF were attenuated for the F-E group than the S-E group. Conclusion(s): Flecanide acetate dramatically reduced the mortality rate and attenuated IL-8 and inflammatory response to the endotoxin induced acute lung in rats. These findings suggest that flecanide acetate has a therapeutic effect to the acute lung injury to sepsis.