M. H. Yoon

Antinociception of intrathecal cholinesterase inhibitors and cholinergic receptors in rats

Background:  Intrathecal cholinesterase inhibitors have been shown to have an antinociceptive effect which is mediated through the spinal cholinergic receptors, mainly muscarinic receptor. Spinal nicotinic receptor also has been involved in the control of nociception. Authors characterized the respective role of muscarinic or nicotinic receptor for the antinociception of cholinesterase inhibitors and further determined the antinociceptive potency of them.

Different role of spinal 5-HT(hydroxytryptamine)7 receptors and descending serotonergic modulation in inflammatory pain induced in formalin and carrageenan rat models

BACKGROUND Spinal serotonin (5-HT) receptors 3 (5-HT3R) and 7 (5-HT7R) are differentially involved in facilitatory or inhibitory descending modulation, respectively. Electrophysiological studies of the spinal cord have demonstrated that 5-HT3R is involved in nociception induced by intraplantar injection of formalin, but not carrageenan. In addition, depletion of spinal serotonin has been shown to attenuate pain behaviour in the formalin test, but there have been no such reports regarding the carrageenan model. This study compared the role of 5-HT7R and the influence of descending serotonergic modulation between formalin- and carrageenan-induced inflammatory pain. METHODS Effects of intrathecal (i.t.) AS-19 (5-HT7R agonist) and SB-269970 (5-HT3R antagonist) on flinching response in the formalin test and mechanical allodynia in the carrageenan model were evaluated in male Sprague-Dawley rats. The effect of serotonin depletion by i.t. 5,7-dihydroxytryptamine was also examined in the two models. RESULTS Intrathecal AS-19 significantly reduced the flinching responses in the formalin test (P<0.01), which was reversed by i.t. SB269970. However, neither AS-19 nor SB269970 produced a significant change in mechanical allodynia in the carrageenan model. Depletion of spinal serotonin attenuated the flinching response in phase 2 of the formalin test (P<0.01), but increased mechanical allodynia in the carrageenan model compared with controls (P<0.01). CONCLUSIONS Spinal 5-HT7R plays a significant inhibitory role in descending serotonergic modulation in pain induced by formalin but not carrageenan. Descending serotonergic modulation is differentially involved in inflammatory pain induced by formalin and carrageenan, with facilitatory and inhibitory effects, respectively.

Antinociceptive effect of intrathecal ginsenosides through α-2 adrenoceptors in the formalin test of rats

BACKGROUND We defined the nature of the pharmacological interaction after intrathecal co-administration of ginsenosides with clonidine, and clarified the contribution of the α-2 adrenoceptors on the effect of ginsenosides. METHODS Pain was evoked by injection of a formalin solution (5%, 50 μl) into the hindpaw of male Sprague-Dawley rats. Isobolographic analysis was performed to characterize the drug interaction between ginsenosides and clonidine. The antagonism of ginsenosides-mediated antinociception was determined with α-2A (BRL 44408), α-2B (ARC 239), and α-2C (JP 1302) adrenoceptor antagonists. The expression of α-2 adrenoceptor subtypes was examined by reverse transcriptase-polymerase chain reaction. RESULTS Intrathecal ginsenosides (n=29) and clonidine (n=31) displayed an antinociceptive effect. The ED(50) values (95% confidence intervals) of ginsenosides and clonidine for phases 1 and 2 were 109.5 (63-190.3) and 110.9 (57.1-215.5), and 11.8 (3.7-37.1) and 4.9 (3.1-6.7) μg, respectively. With an isobolographic study (n=48), the ED(50) values (95% confidence intervals) of ginsenosides in the combination of ginsenosides and clonidine for phases 1 and 2 were 58.2 (38.9-87.3) and 57.2 (46.5-70.3) μg, respectively. Intrathecal BRL 44408 (n=6), ARC 239 (n=5), and JP 1302 (n=5) reversed the antinociception of ginsenosides in both phases (P<0.01, <0.001). The injection of formalin increased the expression of α-2C adrenoceptor in the spinal cord (P<0.05). CONCLUSIONS Intrathecal ginsenosides additively interacted with clonidine in the formalin test. Furthermore, α-2A, -B, and -C adrenoceptors contributed to the antinociception of intrathecal ginsenosides.

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.

Increase of paradoxical excitement response during propofol-induced sedation in hazardous and harmful alcohol drinkers

BACKGROUND Paradoxical excitement response during sedation consists of loss of affective control and abnormal movements. Chronic alcohol abuse has been proposed as a predisposing factor despite lack of supporting evidence. Because alcohol and propofol have a common site of action, we postulated that paradoxical excitement responses during propofol-induced sedation occur more frequently in hazardous and harmful alcohol drinkers than in social or non-drinkers. METHODS One hundred and ninety patients undergoing orthopaedic knee joint surgery were enrolled in this prospective and observational study. Subjects were divided into Group HD (hazardous and harmful drinkers) or Group NHD (no hazardous drinkers) according to the alcohol use disorder identification test (AUDIT). In study 1, propofol infusion was adjusted to achieve the bispectral index at 70-80 using target-controlled infusion. In study 2, the target concentration of propofol was fixed at 0.8 (study 2/Low) or 1.4 μg ml(-1) (study 2/High). Paradoxical excitement responses were categorized by intensity into mild, moderate, or severe. RESULTS The overall incidence of paradoxical excitement response was higher in Group HD than in Group NHD in study 1 (71.4% vs 43.8%; P=0.022) and study 2/High (70.0% vs 34.5%; P=0.006) but not in study 2/Low. The incidence of moderate-to-severe response was significantly higher in Group HD of study 1 (28.6% vs 3.1%; P=0.0005) and study 2/High (23.3% vs 3.4%; P=0.029) with no difference in study 2/Low. Severe excitement response occurred only in Group HD of study 1 and study 2/High. CONCLUSIONS Paradoxical excitement occurred more frequently and severely in hazardous and harmful alcohol drinkers than in social drinkers during propofol-induced moderate-to-deep sedation, but not during light sedation.

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.

The effect of inducing morphine tolerance on anti-allodynic action of gabapentin in spinal nerve-ligated rat

BACKGROUND Morphine is more effective in inflammatory or acute pain than neuropathic pain. Recently, some reports demonstrated that the development and maintenance of opioid tolerance and neuropathic pain have similar aspects. Here, we evaluated whether morphine tolerance affects the anti-allodynic effect of gabapentin in spinal-nerve ligated rat. METHODS Male Sprague-Dawley rats weighing 100-120 g received L5,6 spinal nerve ligation to induce neuropathic pain. Rats showing allodynia were implanted with intrathecal (i.t.) catheter to administer the experimental drugs into the subarachnoid space. To induce olerance to morphine, 15 microgram of morphine was injected via i.t. catheter twice a day for 7 days, and the effect of i.t. gabapentin on the paw withdrawal threshold was examined using the von Frey test before and after the development of morphine tolerance. RESULTS Ligation of spinal nerves decreased the paw withdrawal threshold. Intrathecal morphine initially increased the paw withdrawal threshold, but this effect decreased gradually over time. However, morphine tolerance did not influence the effect of gabapentin on withdrawal threshold. CONCLUSIONS Morphine tolerance did not affect gabapentin efficacay in a neuropathic pain model.