Reduction of bone cancer pain by activation of spinal cannabinoid receptor 1 and its expression in the superficial dorsal horn of the spinal cord in a murine model of bone cancer pain.

BACKGROUND: Bone cancer pain has a strong impact on the quality of life of patients, but it is difficult to treat. Therefore, development of a novel strategy for the treatment of bone cancer pain is needed for improvement of patient quality of life. This study examined whether selective spinal cannabinoid receptor 1 (CB1) activation alleviates bone cancer pain and also examined the spinal expression of CB1. METHODS: A bone cancer pain model was made by implantation of sarcoma cells into the intramedullary space of the mouse femur. In behavioral experiments, the authors examined the effects of activation of spinal CB1 and inhibition of metabolism of endocannabinoid on bone cancer-related pain behaviors. Immunohistochemical experiments examined the distribution and localization of CB1 in the superficial dorsal horn of the spinal cord using specific antibodies. RESULTS: Spinal CB1 activation by exogenous administration of a CB1 agonist arachidonyl-2-chloroethylamide reduced bone cancer-related pain behaviors, including behaviors related to spontaneous pain and movement-evoked pain. In immunohistochemical experiments, although mu-opioid receptor 1 expression was reduced in the superficial dorsal horn ipsilateral to the site of implantation of sarcoma cells, CB1 expression was preserved. In addition, CB1 was mainly expressed in the axon terminals, but not in the dendritic process in the superficial dorsal horn. CONCLUSION: Spinal CB1 activation reduced bone cancer-related pain behavior. Presynaptic inhibition may contribute to the analgesic effects of spinal CB1 activation. These findings may lead to novel strategies for the treatment of bone cancer pain.

Involvement of transient receptor potential vanilloid subfamily 1 in endothelin-1-induced pain-like behavior.

Although local administration of endothelin-1 (ET-1) is known to evoke spontaneous pain, the mechanism of ET-1-induced pain has not been elucidated. We investigated the involvement of protein kinase C (PKC) and transient receptor potential vanilloid subfamily 1 (TRPV1) in ET-1-induced pain-like behavior. Intraplantar ET-1 evoked pain-like behaviors, including licking, flinching, and biting, in a dose-dependent manner in wild-type mice. ET-1-induced pain-like behavior was attenuated by an endothelin type A receptor antagonist but not by PKC inhibitors and was also attenuated in TRPV1-deficient (KO) mice. In addition, we found a significant reduction of spinal Fos expression caused by the same dose of ET-1 in KO mice compared with that in wild-type mice. This study showed that endothelin type A receptor and TRPV1 are involved in ET-1-induced pain-like behaviors but failed to reveal the contribution of PKC.

[Two cases of epidural anesthesia using ultrasound imaging].

We report two cases of epidural anesthesia in an 11-year-old obese girl (BMI 34.5) using ultrasound imaging by an inexperienced resident. It was useful for performing epidural anesthesia in these difficult cases to observe anatomical structure around epidural space and to measure the angle and distance from the skin to the epidural space. The distances in ultrasound imaging and actual puncture in case 1 were 171 mm and 250 mm, and in case 2 these were 439 mm and 480 mm, respectively. In both cases, epidural puncture was performed smoothly at the first attempt and there was no adverse effect. We conclude that using ultrasound imaging before epidural puncture in obese children is safer and more educational for residents.

[Anesthetic management of endovascular repair for aortic abdominal aneurysm in a patient with severe chronic obstructive pulmonary disease].

A 66-year-old man with severe chronic obstructive pulmonary disease (COPD) was scheduled for elective endovascular repair of an aortic abdominal aneurysm and femoral-femoral artery bypass. Because spirometry revealed marked reduction of percent forced expiratory volume in 1 second (%FEV1.0), postoperative respiratory failure was anticipated. Spinal anesthesia and no use of tracheal intubation were planned. When the patient entered the operating room, his oxygen saturation (SpO2) was 92%. Four ml of isobaric 0.5% bupivacaine was injected intrathecally at the L3-4 inter-space using a 25-gauge spinal needle. After the final analgesic level of the spinal anesthesia had been ensured at T6, 1.0% lidocaine 5 ml was injected intradermally in the right elbow for insertion of a catheter sheath. Additional analgesia was acquired with a total of 0.1 mg of fentanyl IV. The endovascular repair was completed uneventfully. In conclusion, spinal anesthesia combined with local anesthesia in the elbow is useful for management of endovascular repair of an aortic abdominal aneurysm in patients with severe COPD for whom postoperative respiratory failure is anticipated.

[Neuromuscular blocking effects of Org 9426 (rocuronium bromide); a comparative study with vecuronium bromide in Japanese patients].

BACKGROUND: Efficacy and safety of Org 9426 were compared with those of vecuronium bromide in Japanese patients. METHODS: We studied 88 Japanese patients undergoing surgery requiring general anesthesia. Patients were allocated randomly to receive intubation dose of 0.6 mg x kg(-1), 0.9 mg x kg(-1) of Org 9426 or 0.1mg x kg(-1) of vecuronium. Following an intubation dose, patients received maintenance doses of 0.1, 0.15 or 0.2 mg x kg(-1) of Org 9426 or 0.025 mg x kg(-1) of vecuronium. The neuromuscular block was monitored with acceleromyography using TOF stimuli. Sevoflurane was administered to all treatment groups after intubation. RESULTS: The onset times of the 0.6 and 0.9 mg x kg(-1) of Org 9426 groups were 84.6 and 77.1 sec respectively, which showed statistical difference between the onset time of 0.1 mg x kg(-1) of vecuronium, 125.7 sec. The intubation condition was similar among three treatment groups. The clinical durations of 0.6 and 0.9 mg x kg(-1) of Org 9426 and 0.1 mg x kg(-1) of vecuronium were 53.4, 73.4 and 59.9 min, respectively. Clinical duration and spontaneous recovery time of maintenance dose of 0.15 mg x kg(-1) of Org 9426 were similar to those of 0.025 mg x kg(-1) of vecuronium. CONCLUSIONS: Org 9426 showed more rapid onset time than that of vecuronium and similar clinical duration and recovery times to those of vecuronium in Japanese patients.

A selective beta2-adrenergic agonist, terbutaline, improves sepsis-induced diaphragmatic dysfunction in the rat.

BACKGROUND: Sepsis causes diaphragmatic dysfunction, which can lead to the development of respiratory failure. We previously reported that isoproterenol, non-selective beta-adrenergic agonist, improved contractility of the diaphragm in a septic rat model. Since beta(2)-adrenoceptor agonists are widely used in the treatment of chronic respiratory disease, we investigated the effect of terbutaline, a selective beta(2)-adrenergic agonist, on contractility of the septic rat diaphragm and the contribution of intracellular Ca(2+) to the effect of terbutaline in vitro. METHODS: Forty-eight rats were divided into a sham group (in which sham laparotomy was performed) and a CLP group (in which peritonitis was induced by cecal ligation and perforation). The left hemidiaphragm was removed at 16 h after the operation. The effect of terbutaline (10(-)(6) M) on contractility of the diaphragm was assessed by twitch characteristics (twitch tension, contraction time and contraction velocity) and force-frequency relationship. In addition, to investigate the role of calcium ions in the effect of terbutaline on contractility of the diaphragm, contractility of the diaphragm was assessed after the pre-incubation of the diaphragm with methoxy-verapamil (10(-)(5) M), Ca(2+)-free Krebs-Ringer's solution buffered with 2 mM of ethylene glycol tetra-acetic acid (EGTA), and ryanodine (10(-)(6) M). RESULTS: Terbutaline significantly improved twitch characteristics and force-frequency relationship of the diaphragm in the CLP group (P<0.01). Incubation with methoxy-verapamil or calcium-free solution with EGTA did not show any changes in the inotropic effect of terbutaline in the CLP group. However, incubation with ryanodine completely abolished the inotropic effect of terbutaline in the CLP group. CONCLUSIONS: The present study demonstrated that terbutaline increased contractility of the diaphragm in the septic rats. Since this inotropic effect was abolished by ryanodine administration, calcium release from the sarcoplasmic reticulum may contribute to the terbutaline-induced improvement in dysfunction of the septic diaphragm.

[Anesthetic management in a patient with Goldenhar's syndrome using a perilaryngeal airway and a videolaryngoscope].

A 5-year-old girl with Goldenhar's syndrome was scheduled for reconstruction of her left thumb. Because her preanesthetic X-p had revealed airway abnormality, difficult intubation was anticipated. After induction of anesthesia with thiamylal, the lungs were ventilated easily via a facemask. A perilaryngeal airway (PLA) was inserted after obtaining adequate depth of anesthesia with sevoflurane. Anesthesia was maintained with sevoflurane (2%) plus nitrous oxide (66%) under spontaneous ventilation. The operation was finished uneventfully. However, a re-operation was scheduled for postoperative hemorrhage on that day. In consideration of potential regurgitation of gastric content, endotracheal intubation was scheduled. Her vocal cord was confirmed with a videolaryngoscope, and she was intubated successfully. In conclusion, a PLA and a videolaryngoscope are useful for airway management of patients with Goldenhar's syndrome for whom difficulty in intubation is anticipated.

Pain management after lumbar spinal fusion surgery using continuous subcutaneous infusion of buprenorphine.

PURPOSE: The continuous subcutaneous infusion (CSI) technique is a simple, inexpensive method for managing postoperative pain. We examined the analgesic effects of CSI of buprenorphine in patients undergoing lumbar spinal fusion surgery. METHODS: The patients were randomly assigned to one of three groups for postoperative pain management: control group (n = 17), high-dose buprenorphine group (BH group, n = 17), and low-dose buprenorphine group (BL group, n = 16). Infusion solutions containing buprenorphine at concentrations of 25.0 and 16.7 microg x ml(-1) combined with droperidol at a concentration of 52.0 microg x ml(-1) were used in the BH and BL groups, respectively; and an infusion solution containing droperidol at a concentration 52.0 microg x ml(-1) was used in the control group. CSI of each solution was started at a rate of 1 ml x h(-1) and was continued for 48 h. RESULTS: The BH and BL groups showed significantly lower scores than the control group on the Visual Analogue Scale. There were significantly fewer administrations of flurbiprofen as a supplemental analgesic in the BL and BH groups than in the control group. The incidences of sedation and nausea were comparable in the three groups. The median number of administrations of flurbiprofen was significantly less in the BH group than in the control group on the day of the operation and on the first postoperative day, whereas the number in the BL group was less than that in the C group only on the day of the operation. CONCLUSION: CSI of buprenorphine effectively reduces pain after lumbar spinal fusion surgery without apparent side effects. This technique is simple and useful for postoperative pain management.

The addition of epidural morphine to ropivacaine improves epidural analgesia after lower abdominal surgery.

PURPOSE: To assess the analgesic and side effects of the continuous epidural infusion of 0.2% ropivacaine combined with morphine compared to both drugs alone. METHODS: In this study, both observers and patients were blinded to patient group assignment. Sixty patients scheduled to undergo lower abdominal surgery were enrolled. Patients were randomized to one of three postoperative treatment groups: 1) combination group (a combination of 0.2% ropivacaine and 0.003% morphine); 2) morphine group (0.003% morphine); or 3) ropivacaine group (0.2% ropivacaine). Postoperatively, all solutions were administered epidurally at a rate of 6 mL.hr(-1) for 24 hr. Patients were given iv flurbiprofen as a supplemental analgesic on demand. RESULTS: The combination group showed lower visual analogue scale scores than those of patients receiving either drug alone, both at rest and on coughing. The combination group showed a slight motor block at two hours after the continuous epidural infusion, while the ropivacaine and morphine groups did not show any motor block. The incidence of itching was significantly increased in the morphine and combination groups, compared to the ropivacaine group. There was no significant difference between the numbers of patients with nausea in the three groups. No hypotension or respiratory complications were observed in the three groups. CONCLUSION: The combination of epidural 0.2% ropivacaine and 0.003% morphine has more effective analgesic effects than either of the drugs alone for postoperative pain relief after lower abdominal surgery.

Contribution of interaction between nitric oxide and cyclooxygenases to the production of prostaglandins in carrageenan-induced inflammation.

BACKGROUND: Nitric oxide (NO) and prostaglandins (PGs) are crucial mediators contributing to generation of inflammatory responses and pain. This study was designed to investigate the effects of peripherally released NO on cyclooxygenase (COX) expression/activation and production of PGs in carrageenan-induced inflammation. METHODS: A microdialysis probe was implanted subcutaneously into the skin of hind paws of rats. The concentrations of NO metabolites, PGE2, and 6-keto-PGF1alpha (metabolite of PGI2) in the dialysate were measured. Carrageenan was injected into the plantar surface of the hind paw during perfusion of the dialysis catheter with modified Ringer's solution or N-monomethyl-L-arginine acetate. In addition, the effects of the selective COX-1 inhibitor SC-560 and the selective COX-2 inhibitor NS-398 on the production of NO, PGE2, and 6-keto-PGF1alpha were examined. Western blotting was performed to evaluate the expression of COX-1 and COX-2 in the skin at the site of the inflammation. RESULTS: Carrageenan injection resulted in increases in the concentrations of NO, PGE2, and PGI2, and these increases were completely suppressed by N-monomethyl-L-arginine acetate. SC-560 effectively inhibited the increase in PGE2 and PGI2 concentrations for the first 2 h, and NS-398 inhibited 3-6 h after carrageenan. Western blot analysis showed that the concentrations of both COX-1 and COX-2 in the skin increased after carrageenan. The up-regulation of COX-1 in the skin was observed 3 and 6 h after carrageenan and was not suppressed in the rats treated with N-monomethyl-L-arginine acetate. The up-regulation of COX-2 in the skin was also observed 3 and 6 h after carrageenan and was completely suppressed in the rats treated with N-monomethyl-L-arginine acetate. CONCLUSION: The results of the current study suggest that NO activates COX-1 in the early phase of carrageenan and up-regulates COX-2 expression in the late phase in the skin, resulting in production of PGE2 and PGI2 at the site of inflammation, which would contribute to exacerbation of the inflammatory process.

Role of prostaglandin receptor subtype EP1 in prostaglandin E2-induced nociceptive transmission in the rat spinal dorsal horn.

It has been indicated that prostaglandin E2 (PGE2) and the receptor for PGE2 (EP receptor) are key factors contributing to the facilitated generation of nociception. This study was designed to investigate the roles of PGE2 and EP1 receptors in the spinal cord in the nociceptive transmission, using behavioral and intracellular calcium ion concentration ([Ca2+]i) assays and in situ hybridization. Experiments were conducted on Sprague-Dawley rats. In behavioral assays, withdrawal thresholds to mechanical stimuli were evaluated using von Frey filament. The effect of an intrathecally administered selective EP1 antagonist, 6-[(2S,3S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)-bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid (ONO-8711), on the intrathecal PGE2-induced hyperalgesia was examined. In [Ca2+]i assays, we measured [Ca2+]i in the dorsal horn of spinal cord slices and examined the effects of PGE2 and ONO-8711 perfusion on the [Ca2+]i changes. In situ hybridization using EP1 digoxigenin probe was performed on the slice sections of the lumbar spinal cord and bilateral L4 and L5 dorsal root ganglions (DRGs). Mechanical hyperalgesia was observed after intrathecal PGE2 administration. Intrathecal administration of ONO-8711 attenuated the PGE2-induced mechanical hyperalgesia in a dose- and time-dependent manner. Perfusion of ONO-8711 markedly suppressed PGE2-induced [Ca2+]i increment in laminae II-VI in dorsal horn of the spinal cord slice. Moreover, in situ hybridization revealed EP1 hybridization signals in the DRG neurons, but not in the spinal cord. The results of this study suggested that spinal PGE2 activates the EP1 receptors existing on the central terminals of primary afferents, subsequently increasing in [Ca2+]i in the spinal dorsal horn, which are involved in the mechanisms of spinal PGE2-induced nociceptive transmission.

Endoscopic thoracic sympathectomy suppresses baroreflex control of heart rate in patients with essential hyperhidrosis.

UNLABELLED: Endoscopic thoracic (T2-3 or T3-4) sympathectomy (ETS) is a highly effective treatment for palmar hyperhidrosis. Because the T2-3 or T3-4 sympathetic ganglia are involved in direct sympathetic innervation of the heart, sympathectomy at this level may alter baroreflex control of heart rate. The purpose of our study was to examine the influence of ETS on baroreflex responses to pressor and depressor stimuli under small-dose sevoflurane anesthesia. We studied 40 patients with palmar or axillary hyperhidrosis who were scheduled to receive ETS. In the ETS procedure, the sympathetic trunk was identified by using thoracic endoscopy and was transected. Before and after ETS, the pressor or depressor test was performed by using an IV infusion of phenylephrine or nitroglycerin, respectively, under small-dose general anesthesia. Baroreflex sensitivity was calculated from R-R intervals and systolic blood pressure. ETS did not change heart rate and systemic blood pressure at rest, although ETS significantly altered baroreflex in both pressor and depressor tests in all patients. Baroreflex was completely suppressed in 1 of 19 patients in the pressor test and in 9 of 21 patients in the depressor test. We conclude that baroreflex responses are suppressed in patients who receive ETS. IMPLICATIONS: Endoscopic thoracic sympathectomy suppressed the baroreflex control of heart rate during pressor and depressor tests in patients with palmar or axillary hyperhidrosis.

[Pneumothorax during laparoscopic adrenal surgery: a case report].

A 55-year-old female patient was scheduled for laparoscopic adrenal surgery. In the operating room, anesthesia was induced with propofol and maintained with nitrous oxide/sevoflurane and epidural anesthesia. The operation was completed uneventfully. After tracheal extubation, Spo2 decreased suddenly from 98 to 92% and chest auscultation revealed weaker breathing sound on the left side. Left pneumothorax and pneumomediastinum were noticed on a chest X-ray. The pneumothorax in this case was thought to have been caused by passage of insufflation gas through the retroperitoneum to the mediastinum and thoracic cavity or by a minor injury of diaphragm. Although pneumothorax complication in laparoscopic surgery is rare, the frequency of its occurrence in laparoscopic adrenal surgery appears to be higher than other laparoscopic operations and may be due to the organ's location in the retroperitoneum near the diaphragm. Attention should be paid to the possibility of pneumothorax occurring during laparoscopic adrenal surgery even if there is no apparent surgical injury.

The activation of 5-HT(3) receptors evokes GABA release in the spinal cord.

We carried out experiments using a microdialysis method to determine whether activation of 5-HT(3) receptors increases the concentration of GABA in the dorsal horn of the spinal cord. Intrathecal perfusion of a selective 5-HT(3) receptor agonist, 1-phenylbiguanide (0.3, 1.0, and 3.0 mM) dose-dependently, increased GABA concentration, while concentrations of glutamate and glycine were not changed. The concentration of aspartate was increased only by 3.0 mM of 1-phenylbiguanide. Our results have provided direct evidence that activation of 5-HT(3) receptors evokes GABA release in the spinal dorsal horn, possibly producing analgesia.

Antihyperalgesic and side effects of intrathecal clonidine and tizanidine in a rat model of neuropathic pain.

BACKGROUND: Although intrathecal clonidine produces pronounced analgesia, antinociceptive doses of intrathecal clonidine produce several side effects, including hypotension, bradycardia, and sedation. Intrathecal tizanidine, another alpha(2)-adrenergic agonist, has provided antinociception without producing pronounced hemodynamic changes in animal studies. However, it has been unclear whether antihyperalgesic doses of intrathecal clonidine and tizanidine produce hypotension and bradycardia in a neuropathic pain state. This study was designed to evaluate the antihyperalgesic effects and side effects of intrathecal clonidine and tizanidine in a rat model of neuropathic pain. METHODS: Male Sprague-Dawley rats were chronically implanted with lumbar intrathecal catheters, and the sciatic nerve was loosely ligated. After 21-28 days after surgery, the rats received intrathecal clonidine (0.3, 1.0, and 3.0 microg) and tizanidine (1.0, 2.0, and 5.0 microg), and the antihyperalgesic effects of thermal and mechanical stimuli were examined. In addition, the changes in blood pressure and heart rate, sedation level, and other side effects after intrathecal administration of drugs were recorded. RESULTS: The administration of 3.0 microg intrathecal clonidine or 5.0 microg tizanidine significantly reversed both thermal and mechanical hyperalgesia. The administration of 3.0 microg intrathecal clonidine, but not 5.0 microg tizanidine, significantly decreased mean blood pressure and heart rate and produced urinary voiding. A greater sedative effect was produced by 3.0 microg intrathecal clonidine than by 5.0 microg tizanidine. CONCLUSION: The antihyperalgesic dose of intrathecal clonidine and the antinociceptive doses produced several side effects. Intrathecal tizanidine at the dose that reversed hyperalgesia would be preferable for neuropathic pain management because of absence of hypotension and bradycardia and lower incidence of sedation.

[Inhibitory action of sensory transmission by inhalational anesthetics in the spinal cord].

This review article focuses on the suppression of sensory transmission by inhalational anesthetics at the spinal cord level. Volatile anesthetics (e.g. halothane and isoflurane) suppress neuronal responses evoked by both noxious and non-noxious stimuli. This suppression is mediated largely by activation of GABAA and glycine receptors systems in the spinal dorsal horn. Depression of spinal glutamate receptor systems is also probably involved. The analgesic action of nitrous oxide is produced by activation of supra-spinal descending inhibitory systems, not by direct action on the spinal cord. Activation of the descending inhibitory systems by nitrous oxide causes release of noradrenaline in the spinal dorsal horn, and activates alpha 2 adrenergic receptor systems, resulting in depression of neuronal responses evoked by noxious stimuli. GABAA and glycine receptor systems in the spinal dorsal horn are also important components of nitrous oxide anesthesia in depressing neuronal responses evoked by non-noxious stimuli. Although excitation or inhibition of GABAA, glycine, alpha 2 adrenergic and glutamate receptors systems is an important action of inhalational anesthetics, influence of inhalational anesthetics on interactions among these receptor systems has yet to be studied.

A comparison of hyperbaric 1% and 3% solutions of small-dose lidocaine in spinal anesthesia.

UNLABELLED: We examined whether the concentration of hyperbaric lidocaine affected the regression of motor block when the dose of lidocaine was kept constant at 30 mg. We also examined the spread, duration, and regression of sensory block. Sixty-five patients (ASA physical status I or II), scheduled for elective perineum or lower limb surgery, were enrolled in this study. Patients received spinal anesthesia with 1 mL of 3% lidocaine or 3 mL of 1% lidocaine. Adequate level of block was obtained for surgery in 63 of 65 patients. Whereas the administration of 3 mL of hyperbaric 1% lidocaine solution produced a level of sensory block similar to that produced by the administration of 1 mL of hyperbaric 3% lidocaine solution in spinal anesthesia, the administration of 3 mL of hyperbaric 1% lidocaine solution resulted in shorter times to full motor recovery and to urination and produced less motor block compared with 1 mL of hyperbaric 3% lidocaine solution. Two patients receiving 1% lidocaine and four patients receiving 3% lidocaine required IV ephedrine because of hypotension. Our results showed the clinical advantages of hyperbaric 1% lidocaine spinal anesthesia compared with hyperbaric 3% lidocaine spinal anesthesia for surgery of short duration. IMPLICATIONS: When the dose of lidocaine was kept constant at 30 mg, hyperbaric 1% lidocaine solution resulted in shorter times for recovery from motor block and to urination than did hyperbaric 3% lidocaine solution. Levels of sensory block were similar. Therefore, the more dilute lidocaine for spinal anesthesia may be suitable for day-care surgery and short duration surgery.

Role of prostaglandin receptor EP1 in the spinal dorsal horn in carrageenan-induced inflammatory pain.

BACKGROUND: Prostaglandin E2 (PGE2) and the receptor for PGE2 (EP receptor) are key factors contributing to the generation of hyperalgesia caused by inflammation. The current study was designed to investigate the roles of PGE2 and EP1 receptors in the spinal cord in the development and maintenance of inflammatory pain, using behavioral, microdialysis, and intracellular calcium ion concentration ([Ca2+]i) assays. METHODS: Inflammation was induced by an injection of carrageenan into the plantar surface of the rat hind paw. The effects of inflammation were evaluated at the time points of 3 h (early phase) and 15 h (late phase) after carrageenan injection. In behavioral assays, withdrawal thresholds to mechanical stimuli were evaluated. The effect of an intrathecally administered selective EP1 antagonist, ONO-8711, on the carrageenan-induced hyperalgesia was examined. Using a spinal microdialysis method, PGE2 concentration in the spinal dorsal horn was measured. In [Ca2+]i assays, we measured [Ca2+]i in the spinal dorsal horn in transverse spinal slices and examined the effects of pretreatment with ONO-8711. Sensitivities of the changes in [Ca2+]i to PGE2 perfusion were also assessed. RESULTS: Mechanical hyperalgesia and paw edema were observed in both the early and late phases. The hyperalgesia was inhibited by intrathecal ONO-8711 in the late, but not early, phase. The concentration of PGE2 in the spinal dorsal horn increased in the late phase. The [Ca2+]i in the dorsal horn increased on the ipsilateral side to the inflammation in the late, but not early phase. This increase was suppressed by the pretreatment with ONO-8711. Magnitude of the increase in [Ca2+]i on the ipsilateral side in response to PGE2 perfusion was greater in the late phase than in the early phase. CONCLUSION: The results suggested that activation of spinal EP1 receptors was crucial in the carrageenan-induced mechanical hyperalgesia in the late phase. It seems that some of the mechanisms underlying inflammation-induced plastic changes are mediated by time-dependent increase in PGE2 concentration, activation of EP1 receptors, and increase in [Ca2+]i in the spinal dorsal horn.

The effects of intrathecal administration of an antagonist for prostaglandin E receptor subtype EP(1) on mechanical and thermal hyperalgesia in a rat model of postoperative pain.

UNLABELLED: Despite substantial advances in understanding acute pain mechanisms and in the treatment of pain, postoperative pain, especially mechanically evoked pain (incident pain), is generally not effectively treated. Tissue injury and inflammation increase the release of prostaglandin E(2) in the spinal cord, contributing to the development of hyperalgesia. We designed the present study to determine whether the intrathecal administration of an antagonist for prostaglandin E(2) receptor subtype EP(1), ONO-8711, has an analgesic effect on incision-induced mechanical and thermal hyperalgesia. A 1-cm longitudinal skin incision was made in the plantar aspect of the rat foot. The withdrawal threshold to mechanical stimulation and the withdrawal latency to thermal stimulation applied adjacent to the wound of the hindpaw were investigated. Both mechanical and thermal hyperalgesia were observed at 2 h and 24 h after the incision had been made. ONO-8711 (50, 80, 100 micro g) or saline was administered intrathecally. ONO-8711 significantly increased the withdrawal thresholds to mechanical stimulation, but not to thermal stimulation, in a dose- and time-dependent manner. We conclude that EP(1) receptor-mediated sensitization of the spinal dorsal horn may contribute to the generation of mechanical, but not thermal, hyperalgesia and that an EP(1) receptor antagonist administered intrathecally is a potential analgesic for postoperative pain, especially mechanically evoked pain (incident pain). IMPLICATIONS: We examined the effects of an intrathecally administered selective EP(1) receptor antagonist on mechanical and thermal hyperalgesia in a postoperative pain model. The intrathecal EP(1) receptor antagonist inhibited the mechanical, but not thermal, hyperalgesia, indicating the potential for an EP(1) receptor antagonist to be used as an analgesic for postoperative pain, especially incident pain.