Pharmacological interactions between intrathecal pregabalin plus tianeptine or clopidogrel in a rat model of neuropathic pain

Background@#There is still unmet need in treating neuropathic pain and increasing awareness regarding the use of drug combinations to increase the effectiveness of treatment and reduce adverse effects in patients with neuropathic pain. @*Methods@#This study was performed to determine the individual and combined effects of pregabalin, tianeptine, and clopidogrel in a rat model of neuropathic pain.The model was created by ligation of the L5-L6 spinal nerve in male Sprague–Dawley rats; mechanical allodynia was confirmed using von Frey filaments. Drugs were administered to the intrathecal space and mechanical allodynia was assessed; drug interactions were estimated by isobolographic or fixed-dose analyses. @*Results@#Intrathecal pregabalin and tianeptine increased the mechanical withdrawal threshold in a dose-dependent manner, but intrathecal clopidogrel had little effect on the mechanical withdrawal threshold. An additive effect was noted between pregabalin and tianeptine, but not between pregabalin and clopidogrel. @*Conclusions@#These findings suggest that intrathecal coadministration of pregabalin and tianeptine effectively attenuated mechanical allodynia in the rat model of neuropathic pain. Thus, pregabalin plus tianeptine may be a valid option to enhance the efficacy of neuropathic pain treatment.

Antinociceptive role of neurotensin receptor 1 in rats with chemotherapy-induced peripheral neuropathy

Background@#Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of anti-cancer drugs. Neurotensin receptors (NTSRs) are widely distributed within the pain circuits in the central nervous system. The purpose of this study was to determine the role of NTSR1 by examining the effects of an NTSR1 agonist in rats with CIPN and investigate the contribution of spinal serotonin receptors to the antinociceptive effect. @*Methods@#Sprague–Dawley rats (weight 150–180 g) were used in this study. CIPN was induced by injecting cisplatin (2 mg/kg) once a day for 4 days. Intrathecal catheters were placed into the subarachnoid space of the CIPN rats. The antiallodynic effects of intrathecally or intraperitoneally administered PD 149163, an NTSR1 agonist, were evaluated. Furthermore, the levels of serotonin in the spinal cord were measured by high-performance liquid chromatography. @*Results@#Intrathecal or intraperitoneal PD 149163 increased the paw withdrawal threshold in CIPN rats. Intrathecal administration of the NTSR1 antagonist SR 48692 suppressed the antinociceptive effect of PD 149163 given via the intrathecal route, but not the antinociceptive effect of intraperitoneally administered PD 149163. Intrathecal administration of dihydroergocristine, a serotonin receptor antagonist, suppressed the antinociceptive effect of intrathecally administered, but not intraperitoneally administered, PD 149163. Injecting cisplatin diminished the serotonin level in the spinal cord, but intrathecal or intraperitoneal administration of PD 149163 did not affect this reduction. @*Conclusions@#NTSR1 played a critical role in modulating CIPN-related pain. Therefore, NTSR1 agonists may be useful therapeutic agents to treat CIPN. In addition, spinal serotonin receptors may be indirectly involved in the effect of NTSR1 agonist.

Effects of a Group Coaching Program on Depression, Anxiety and Hope in Women with Breast Cancer Undergoing Chemotherapy

PURPOSE: The purpose of this study was to examine the effect of a group coaching program (GCP) on depression, anxiety, and hope in women breast cancer patients undergoing chemotherapy. METHODS: A total of 152 patients were enrolled and randomly assigned to an experimental group receiving the GCP (N=76) and an untreated control group (N=76). Data collection consisted of three measurements of depression, anxiety, and hope (pre, post, and 3weeks later). The intervention was a one-time GCP consisting of 5 subparts for 30~40 minutes for a group of 3~4 people, conducted by a single nurse. RESULTS: The scores of depression, anxiety, and hope changed significantly over time (p<.001, p<.001, p<.001). Depression, anxiety, and hope changes were significantly different between the experimental and control groups (p<.001, p<.001, p<.001). There was a difference in depression, anxiety, and hope among the groups according to the implementation of the GCP (p<.001, p<.001, p<.001). In the experimental group, depression, anxiety, and hope level were significantly different between the pre- and post-test (p<.001), pre- and 3weeks later-test (p<.001), but not in the control group. CONCLUSION: The GCP for women breast cancer patients receiving chemotherapy was effective in reducing depression and anxiety, and increasing hope.

Effects of Sequential Application of Superficial Cold and Heat on Pain, Patient Satisfaction with Pain Control, Comfort Level and Subjective Response after Spine Surgery / 기본간호학회지

PURPOSE: The aims of the current study were to evaluate the effects of superficial cold and heat after spine surgery on pain, satisfaction with pain control and comfort level, and to identify subjective responses and adverse effects. METHODS: A prospective, single-blind, randomized controlled trial was utilized. The intervention group (n=36) received superficial cooling until the wound drain was removed and thereafter followed by superficial heating until discharge, while the control group (n=34) received only superficial cooling until wound drain was removed. Data were collected from August 4 to November 11 2014. RESULTS: There was significant difference in pain according to time within groups (F=71.87, p<.001). However, we found no difference in pain between groups. The intervention group reported higher patient satisfaction with pain control (4 vs 3, z=-2.83, p=.005) and higher comfort level (5 vs 4, z=-4.12, p<.001) than the control group. CONCLUSION: Results indicate that sequential application of superficial cold and heat is a useful method in clinical practice for management of pain after spine surgery.

Antiallodynic effect of intrathecal epigallocatechin-3-gallate due to suppression of reactive oxygen species / 대한마취과학회지

BACKGROUND: Green tea modulates neuropathic pain. Reactive oxygen species (ROS) are suggested as a key molecule in the underlying mechanism of neuropathic pain in the spinal cord. We examined the effect of epigallocatechin-3-gallate (EGCG), the major catechin in green tea, in neuropathic pain and clarified the involvement of ROS on the activity of EGCG. METHODS: Neuropathic pain was induced in male Sprague-Dawley rats by spinal nerve ligation (SNL). A polyethylene tube was intrathecally located. Nociceptive degree was estimated by a von Frey filament and expressed as a paw withdrawal threshold (PWT). To determine the role of ROS on the effect of EGCG, a free radical donor (tert-BuOOH) was pretreated before administration of EGCG. ROS activity was assayed by xanthine oxidase (XO) and malondialdehyde (MDA). RESULTS: SNL decreased the PWT compared to sham rats. The decrease remained during the entire observation period. Intrathecal EGCG increased the PWT at the SNL site. Intrathecal tert-BuOOH significantly decreased the effect of EGCG. The levels of both XO and MDA in the spinal cord were increased in SNL rats compared to sham. Intrathecal EGCG decreased the level of XO and MDA. CONCLUSIONS: EGCG may reduce neuropathic pain by SNL due to the suppression of ROS in the spinal cord.

Antinociceptive Effects of Amiloride and Benzamil in Neuropathic Pain Model Rats

Amiloride and benzamil showed antinocicepitve effects in several pain models through the inhibition of acid sensing ion channels (ASICs). However, their role in neuropathic pain has not been investigated. In this study, we investigated the effect of the intrathecal amiloride and benzamil in neuropathic pain model, and also examined the role of ASICs on modulation of neuropathic pain. Neuropathic pain was induced by L4-5 spinal nerve ligation in male Sprague-Dawley rats weighing 100-120 g, and intrathecal catheterization was performed for drug administration. The effects of amiloride and benzamil were measured by the paw-withdrawal threshold to a mechanical stimulus using the up and down method. The expression of ASICs in the spinal cord dorsal horn was also analyzed by RT-PCR. Intrathecal amiloride and benzamil significantly increased the paw withdrawal threshold in spinal nerve-ligated rats (87%+/-12% and 76%+/-14%, P=0.007 and 0.012 vs vehicle, respectively). Spinal nerve ligation increased the expression of ASIC3 in the spinal cord dorsal horn (P=0.01), and this increase was inhibited by both amiloride and benzamil (P<0.001 in both). In conclusion, intrathecal amiloride and benzamil display antinociceptive effects in the rat spinal nerve ligation model suggesting they may present an alternative pharmacological tool in the management of neuropathic pain at the spinal level.

Clinical Validity Comparison Study of Patients Severity Triage System in the Emergency Department: Modified Emergency Severity Index (mESI) and modified Canadian Triage Acuity System (mCTAS)

PURPOSE: This study was conducted to identify better methods of determining the severity of triage by comparing triage results and clinical outcome of patients categorized by the modified Canadian Triage Acuity Scale (mCTAS) and modified Emergency Severity Index (mESI). METHODS: Subjects enrolled in this study consisted of 1,000 adult patients (age 16 years or older) who visited the emergency room of a university affiliated hospital between September 15, 2011 and September 30, 2011 and were categorized into five levels by mCTAS and mESI. RESULTS: 1) Good confidence was verified based on weighted kappa values of 0.70 between the physicians group and nurses group. 2) Upon evaluation of triage by mESI, the majority of patients were at level 3 among 5, followed by level 4, 2, 1 and 5 in order. The same level orders were shown upon evaluation of triage by mCTAS beside differences in patient numbers. 3) Comparing clinical outcome according to the mCTAS and the mESI revealed similar results in both triage tools, with a higher triage level being associated with a higher admission rate and lower triage level and the discharge rate became higher. CONCLUSION: Triage by mESI showed good agreement among asserters and high agreement between physicians and nurses. Clinical results based on mCTAS and mESI triage showed similar rates of admission to the ward or intensive care unit and rates of discharge. Although these two triage protocols are similar in many aspects, the use of mESI is perceived as a better because mCTAS requires knowledge of various diseases and mESI has a short training period.

Analgesic Effect of Intrathecal Ginsenosides in a Murine Bone Cancer Pain

BACKGROUND: Bone cancer pain has a disruptive effect on the cancer patient's quality of life. Although ginsenosides have been used as traditional medicine in Eastern Medicine, the effect on bone cancer pain has not been thoroughly studied. The aim of this study was to determine whether ginsenosides may alter the bone cancer pain at the spinal level. METHODS: NCTC 2472 tumor cells (2.5 x 10(5)) were injected into the femur of adult male C3H/HeJ mice to evoke bone tumor and bone cancer pain. To develop bone tumor, radiologic pictures were obtained. To assess pain, the withdrawal threshold was measured by applying a von Frey filament to the tumor cells inoculation site. The effect of intrathecal ginsenosides was investigated. Effect of ginsenosides (150, 500, 1,000 microgram) was examined at 15, 30, 60, 90, 120 min after intrathecal delivery. RESULTS: The intrafemoral injection of NCTC 2472 tumor cells induced a radiological bone tumor. The withdrawal threshold with tumor development was significantly decreased compared to the sham animals. Intrathecal ginsenosides effectively increased the withdrawal threshold in the bone cancer site. CONCLUSIONS: NCTC 2472 tumor cells injection into the mice femur caused bone tumor and bone cancer pain. Intrathecal ginsenosides attenuated the bone cancer-related pain behavior. Therefore, spinal ginsenosides may be an alternative analgesic for treating bone cancer pain.

Effect of ginsenosides in a mouse model of bone cancer pain

BACKGROUND: Ginsenosides have been used for a long time as an oriental folk medicine. Although ginsenosides modulate the nociceptive transmission, the effect of ginsenosides on a bone cancer pain has not been elucidated. The authors examined the effect of ginsenosides in a mouse model of bone cancer pain. METHODS: Bone cancer was induced by intramedullary injection of osteolytic sarcoma cells in to the femur in male C3H/HeJ mice. Mice showing mechanical allodynia after 14 days after cancer cells inoculation were included in this study. Mechanical allodynia was evaluated by measuring the withdrawal threshold to von Frey filament applying on the femoral cancer site. Effect of ginsenosides (30, 100, 300 mg/kg) was examined at 15, 30, 60, 90, 120 min after intraperitoneal administration of ginsenosides. RESULTS: After cancer cells injection into the femur, bone cancer was developed in simple X-ray. A paw withdrawal threshold in a cancer site was significantly decreased. Intraperitoneal ginsenosides did not effectively alter the withdrawal threshold in the cancer site. CONCLUSIONS: Taken together, ginsenosides may not be effective to attenuate the bone cancer pain.

Effect of Sildenafil on Neuropathic Pain and Hemodynamics in Rats

PURPOSE: The inhibition of phosphodiesterase 5 produces an antinociception through the increase of cyclic guanosine monophosphate (cGMP), and increasing cGMP levels enhance the release of gamma-aminobutyric acid (GABA). Furthermore, this phosphodiesterase 5 plays a pivotal role in the regulation of the vasodilatation associated to cGMP. In this work, we examined the contribution of GABA receptors to the effect of sildenafil, a phosphodiesterase 5 inhibitor, in a neuropathic pain rat, and assessed the hemodynamic effect of sildenafil in normal rats. MATERIALS AND METHODS: Neuropathic pain was induced by ligation of L5/6 spinal nerves in Sprague-Dawley male rats. After observing the effect of intravenous sildenafil on neuropathic pain, GABAA receptor antagonist (bicuculline) and GABAB receptor antagonist (saclofen) were administered prior to delivery of sildenafil to determine the role of GABA receptors in the activity of sildenafil. For hemodynamic measurements, catheters were inserted into the tail artery. Mean arterial pressure (MAP) and heart rate (HR) were measured over 60 min following administration of sildenafil. RESULTS: Intravenous sildenafil dose-dependently increased the withdrawal threshold to the von Frey filament application in the ligated paw. Intravenous bicuculline and saclofen reversed the antinociception of sildenafil. Intravenous sildenafil increased the magnitude of MAP reduction at the maximal dosage, but it did not affect HR response. CONCLUSION: These results suggest that sildenafil is active in causing neuropathic pain. Both GABAA and GABAB receptors are involved in the antinociceptive effect of sildenafil. Additionally, intravenous sildenafil reduces MAP without affecting HR.

Effect of Intrathecal Ginsenosides on Mechanical Allodynia in a Neuropathic Rat Model

BACKGROUND: Traditionally, ginseng has been widely used to manage various types of diseases. In particular, the analgesic effect of ginsenosides has been reported for inflammatory pain. However, the effect of ginsenosides on neuropathic pain has not been determined. The aim of this study was to examine the effect of ginsenosides on neuropathic pain in the spinal cord. METHODS: Neuropathic pain was induced by ligation of the lumbar 5, 6 spinal nerves in male Sprague-Dawley rats. Intrathecal catheters were placed into the subarachnoid space of rats that presented with mechanical allodynia. Mechanical allodynia was evaluated by measuring the withdrawal threshold to a von Frey filament applied to the plantar surface of rats. The analgesic effect of intrathecal ginsenosides was observed at 15, 30, 60, 90, 120, 150 and 180 min after delivery of the ginsenosides. RESULTS: After nerve ligation, the paw withdrawal threshold was significantly decreased at the ligated site. At the doses used in this study, intrathecal ginsenosides did not alter the withdrawal threshold in the ligated paw during the entire observation period. However, a dose of intrathecal ginsenosides greater than 1,500microg caused motor impairment. CONCLUSIONS: These results suggest that ginsenosides may not have a direct modulatory role in the transmission of neuropathic pain at the spinal level.

The Role of Adrenergic and Cholinergic Receptors on the Antinociception of Korean Red Ginseng in the Spinal Cord of Rats / 대한통증학회지

BACKGROUND: Experimental evidence indicates that ginseng modulate the nociceptive transmission. Authors examined the role of adrenergic and cholinergic receptors on the antinociceptive action of Korean red ginseng against the formalin-induced pain at the spinal level. METHODS: Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. Fifty microl of 5% formalin solution was injected to the hindpaw for induction of pain and formalin-induced pain (flinching response) was observed. The role of spinal adrenergic and cholinergic receptors on the effect of Korean red ginseng was assessed by antagonists (prazosin, yohimbine, atropine and mecamylamine). RESULTS: Intrathecal Korean red ginseng produced a dose-dependent suppression of the flinching response in the rat formalin test. All of prazosin, yohimbine, atropine and mecamylamine antagonized the antinociception of Korean red ginseng. CONCLUSIONS: Spinal Korean red ginseng is effective against acute pain and facilitated pain state evoked by formalin injection. All of alpha 1, alpha 2, muscarinic and nicotinic receptors may play an important role in the antinociceptive action of Korean red ginseng at the spinal level.

Additive Antinociception between Intrathecal Sildenafil and Morphine in the Rat Formalin Test

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 microliter of 5% formalin solution was applied to the hindpaw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.

The Role of Adrenergic and Cholinergic Receptors on the Antinociception of Intrathecal Zaprinast in the Formalin Test of Rats / 대한마취과학회지

BACKGROUND: Spinal zaprinast, phospodiesterase inhibitor, has been shown to have an antinociception through an increase of cGMP. The aim of this study was to examine the role of spinal adrenergic and cholinergic receptors on the antinociceptive action of intrathecal zaprinast. METHODS: Rats were implanted with lumbar intrathecal catheters. After formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. After observing the effect of intrathecal zaprinast, antagonism of intrathecal prazosin, yohimbine, atropine and mecamylamine for the effect of zaprinast were evaluated. RESULTS: Intrathecal zaprinast produced a dose-dependent suppression of formalin-induced flinches in both phases of the formalin test. Intrathecal prazosin reversed the antinociception of zaprinast in phase 2, but not phase 1. Intrathecal yohimbine reversed the antinociception of zaprinast in both phases. Neither atropine nor mecamylamine reversed the antinocicetive action of zaprinast. CONCLUSIONS: Intrathecal zaprinast is against the nociceptive state evoked by formalin stimulus. Alpha 2 or alpha 1 adrenergic receptor, but not cholinergic receptors, may be related to the action of zaprinast in the spinal cord.

The Effect of Treatment with Intrathecal Ginsenosides in a Rat Model of Postoperative Pain / 대한통증학회지

BACKGROUND: Ginseng has been used to manage various types of pain in folk medicine. This study characterized the effect of treatment with intrathecal ginsenosides, the active components of ginseng in a postoperative pain model. METHODS: Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters. An incision was made in the plantar surface of the hindpaw. Withdrawal thresholds following the application of a von Frey filament to the wound site were measured. To determine the role of the opioid or GABA receptors following treatment with the ginsenosides, naloxone, bicuculline (a GABAA receptor antagonist), and saclofen (a GABAB receptor antagonist) were administered intrathecally 10 min before the delivery of the ginsenosides and the changes of the withdrawal thresholds after application of the von Frey filament were observed. RESULTS: Treatment with the intrathecal ginsenosides increased the withdrawal threshold in a dose dependent manner. Pre-treatment with intrathecal naloxone reversed the antinociceptive effect of the ginsenosides. However, pre-treatment with intrathecal bicuculline and saclofen failed to have an effect on the activity of the ginsenosides. CONCLUSIONS: These results suggest that ginsenosides are effective to alleviate the postoperative pain evoked by paw incision. The opioid receptor, but not GABA receptors, may be involved in the antinociceptive action of the ginsenosides at the spinal level.

GABAB Receptor Modulation on the Antinociception of Intrathecal Sildenafil in the Rat Formalin Test / 대한통증학회지

BACKGROUND: A phosphodiesterase 5 inhibitor, sildenafil, has been effective against nociception. Several lines of evidence have demonstrated the role of the GABAergic pathway in the modulation of nociception. The impact of the GABA receptors on sildenafil was studied using the formalin test at the spinal level. METHODS: Male SD rats were prepared for intrathecal catheterization. The formalin test was induced by subcutaneous injection of formalin solution. The change in the activity of sildenafil was examined after pretreatment with GABA receptor antagonists (GABAA receptor antagonist, bicuculline; GABAB receptor antagonist, saclofen). RESULTS: Intrathecal sildenafil dose-dependently attenuated the flinching observed during phase 1 and 2 in the formalin test. The antinociceptive effect of sildenafil was reversed by the GABAB receptor antagonist (saclofen) but not by the GABAA receptor antagonist (bicuculline) in both phases. CONCLUSIONS: Intrathecal sildenafil suppressed acute pain and the facilitated pain state. The antinociception of sildenafil is mediated via the GABAB receptor, but not the GABAA receptor, at the spinal level.

The Role of Opioid Receptor on the Analgesic Action of Intrathecal Sildenafil in Rats / 대한통증학회지

BACKGROUND: Intrathecal sildenafil has produced antinociception by increasing the cGMP through inhibition of phosphodiesterase 5. Spinal opioid receptor has been reported to be involved in the modulation of nociceptive transmission. The aim of this study was to examine the role of opioid receptor in the effect of sildenafil on the nociception evoked by formalin injection. METHODS: Rats were implanted with lumbar intrathecal catheters. Formalin testing was used as a nociceptive model. Formalin-induced nociceptive behavior (flinching response) was observed. To clarify the role of the opioid receptor for the analgesic action of sildenafil, naloxone was administered intrathecally 10 min before sildenafil delivery, and formalin was then injected 10 min later. RESULTS: Intrathecal sildenafil produced dose-dependent suppression of flinches in both phases during the formalin test. Intrathecal naloxone reversed the analgesic effect of sildenafil in both phases. CONCLUSIONS: Sildenafil is active against the nociceptive state that's evoked by a formalin stimulus, and the opioid receptor is involved in the analgesic action of sildenafil at thespinal level.

Antinociceptive Effects of Intrathecal 5-Hydroxytryptamine and Its Subtype Agonists in the Formalin Test / 대한마취과학회지

BACKGROUND: Although 5-hydroxytryptamine (5-HT) is involved in the modulation of nociceptive transmission in the spinal cord, the effect of it is not clear. Previous studies have revealed the presence of many types of 5-HT receptors in the spinal cord. The aim of this study was to determine the role of spinal serotonergic receptors by examination of the effects of intrathecal 5-HT and its subtype agonists on the stimulus evoked by formalin injection. METHODS: Rats were implanted with lumbar intrathecal catheters. Intrathecal 5-HT and its subtype agonists were administered 10 min before the formalin injection. After the formalin injection, a formalin-induced nociceptive behavior (flinching response) was observed for 60 min. RESULTS: Intrathecal administration of 5-HT, 5-HT(1A) agonist (dipropyl-5CT), 5-HT(1B) agonist (CGS- 12066A), 5-HT(2) agonist (alpha-methyl-5-HT), 5-HT(2B) agonist (BW723C86), 5-HT(2C) agonist (MK 212), 5-HT(3) agonist (m-CPBG) and 5-HT(4) agonist (BZTZ) produced a dose-dependent suppression of flinches in both phases. However, neither 5-HT(1D) agonist (GR 46611) nor 5-HT(1E),F agonist (BRL 54443) reduced the flinches in either phase. CONCLUSIONS: Spinal 5-HT(1A), 5-HT(1B), 5-HT(2), 5-HT(2B), 5-HT(2C), 5-HT(3) and 5-HT(4) receptors may be involved in the regulation of a nociceptive state evoked by a formalin stimulus, whereas spinal 5-HT(1D), 5-HT(1E) and 5-HT(1F) receptors may not be involved.