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 [mu]g) and tizanidine (1.0, 2.0, and 5.0 [mu]g), 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 [mu]g intrathecal clonidine or 5.0 [mu]g tizanidine significantly reversed both thermal and mechanical hyperalgesia. The administration of 3.0 [mu]g intrathecal clonidine, but not 5.0 [mu]g tizanidine, significantly decreased mean blood pressure and heart rate and produced urinary voiding. A greater sedative effect was produced by 3.0 [mu]g intrathecal clonidine than by 5.0 [mu]g tizanidine.     

Intrathecal Adenosine: Interactions with Spinal Clonidine and Neostigmine in Rat Models of Acute Nociception and Postoperative Hypersensitivity

Background: Spinal adenosine receptor agonists exert antinociception in animal models of acute and chronic pain, but adenosine itself has not been examined. The authors tested the antinociceptive and antihypersensitivity interactions of intrathecal adenosine and its interactions with intrathecal clonidine and neostigmine in rat models of acute thermal nociception and postoperative hypersensitivity.

Methods: Rats were prepared with lumbar intrathecal catheters. Responses to acute noxious stimulation were evaluated by latency to paw withdrawal from a radiant heat source focused on the hind paw. Postoperative hypersensitivity was measured after an incision in the rat hind paw by application of von Frey filaments to the heel adjacent to the wound. An isobolographic design was used to distinguish between additive and synergistic drug interactions.

Results: Spinal administration of clonidine and neostigmine, but not adenosine, produced dose-dependent antinociception to noxious thermal stimulation. Addition of adenosine enhanced the antinociceptive effect of clonidine but not neostigmine. In contrast, each of these three agents alone reversed postoperative hypersensitivity. Pretreatment with the [Greek small letter alpha]-adrenergic antagonist phentolamine completely reversed adenosine's antihypersensitivity action. Adenosine interacted synergistically with neostigmine and additively with clonidine in reducing postoperative hypersensitivity.     

Analysis of Drug Interaction between Intrathecal Clonidine and MK-801 in Peripheral Neuropathic Pain Rat Model

Background: Spinally delivered alpha2 -adrenoceptor agonists and N-methyl-D-aspartate antagonists each have been shown to have actions attenuating the hyperesthesia in rat models of nerve injury pain. Using a fixed-dose analysis and an isobolographic paradigm, the spinal interaction between the alpha2 -adrenoceptor agonist clonidine and the N-methyl-D-aspartate antagonist MK-801 is characterized in a rat model of nerve injury-induced tactile hyperesthesia.

Methods: Male Sprague Dawley rats were anesthetized with halothane, and the left L5 and L6 spinal nerves were ligated (Chung model). After 7-10 days' recovery, a Polyethylene tubing catheter was implanted into the lumbar intrathecal space. After recovery from catheter implantations (5-7 days), intrathecal dose-response curves were established for the antihyperesthesia effects of clonidine (3, 6, 10, and 20 micro gram) and MK-801 (1, 3, 10, and 20 micro gram) alone to obtain the ED50 for each agent. In separate studies, three doses of clonidine (l, 3, and 10 micro gram) were injected mixed with one dose of MK-801 (1 micro gram) for fixed-dose analysis, and three doses of the two agents (2, 6, and 20 micro gram) were injected jointly in a fraction of the dose ratio 1:1 for isobolographic analysis. Thresholds for left hind paw withdrawal to von Frey hair application were assessed.

Results: Rats with nerve ligation showed a reliable tactile hyperesthesia (mechanical threshold 1-3 g vs. normal > 15 g). Intrathecal clonidine and MK-801 alone produced dose-dependent reductions of tactile hyperesthesia: ED50 9 micro gram and 10 micro gram, respectively. With the fixed-dose analysis, the log dose-response curves showed a left shift that considerably exceeds the theoretical curve made by a simple sum of the effects of clonidine alone and with MK-801 (1 micro gram). With the isobolographic analysis, the combination ED50 was found to be statistically less than the theoretical additive dose combination. lntrathecal atipamezole, an alpha2 antagonist, reversed the effects of clonidine and the clonidine/MK-801 mixture but not MK-801 alone. The side effect of clonidine was sedation and urination and that of MK-801 was motor weakness at doses above 10 micro gram. These effects were considerably less severe in rats after equiactive doses in the combination group.     

Interaction between the Spinal Melanocortin and Opioid Systems in a Rat Model of Neuropathic Pain

Background: The authors recently demonstrated that administration of the melanocortin-4 receptor antagonist SHU9119 decreased neuropathic pain symptoms in rats with a sciatic chronic constriction injury. The authors hypothesised that there is a balance between tonic pronociceptive effects of the spinal melanocortin system and tonic antinociceptive effects of the spinal opioid system. Therefore, they investigated a possible interaction between these two systems and tested whether opioid effectiveness could be increased through modulation of the spinal melanocortin system activity.

Methods: In chronic constriction injury rats, melanocortin and opioid receptor ligands were administered through a lumbar spinal catheter, and their effects on mechanical allodynia were assessed by von Frey probing.

Results: Naloxone (10-100 [mu]g) dose-dependently increased allodynia (percent of maximum possible effect of -67 +/- 9%), which is in agreement with a tonic antinociceptive effect of the opioid system. SHU9119 decreased allodynia (percent of maximum possible effect of 60 +/- 13%), and this effect could be blocked by a low dose of naloxone (0.1 [mu]g), which by itself had no effect on withdrawal thresholds. Morphine (1-10 [mu]g) dose-dependently decreased allodynia (percent of maximum possible effect of 73 +/- 14% with the highest dose tested). When 0.5 [mu]g SHU9119 (percent of maximum possible effect of 47 +/- 14%) was given 15 min before morphine, there was an additive antiallodynic effect of both compounds.     

Antiallodynic Effect of Intrathecal Gabapentin and Its Interaction with Clonidine in a Rat Model of Postoperative Pain

Background: Systemic administration of gabapentin was shown previously to attenuate mechanical allodynia in a rat model of postoperative pain. Because intrathecal administration of gabapentin is effective in other hypersensitivity states, the authors tested its effect in the postoperative model, its interaction with another antiallodynic agent (clonidine), and a possible mechanism of gabapentin action (entry into sites of action via an L-amino acid transporter).

Methods: Male Sprague-Dawley rats were anesthetized with halothane, and an incision of the plantaris muscle of right hind paw induced punctate mechanical allodynia. Withdrawal threshold to von Frey filament application near the incision site was determined before and 2 h after surgery. Then, an intrathecal injection was performed and thresholds were determined every 30 min for 3 h thereafter.

Results: Paw incision induced a mechanical hypersensitivity (mechanical threshold > 25 g before incision and < 5 g after). Intrathecal gabapentin dose-dependently (10-100 [mu]g) reduced mechanical allodynia. Intrathecal injection of an inhibitor of L-amino acid transporters or a competitor for this transporter, L-leucine, did not reverse the intrathecal effect of gabapentin. The ED50 of intrathecal gabapentin, clonidine, and their combination were 51, 31, and 9 [mu]g, respectively, and isobolographic analysis showed synergy between gabapentin and clonidine.     

Effect of Methylprednisolone on Neuropathic Pain and Spinal Glial Activation in Rats

Background: Basic data are lacking regarding the efficacy and mechanisms of action of corticosteroids in neuropathic pain. Because recent studies indicate that spinal glial activation mediates the pathologic pain states, the authors sought to determine the effects of systemic and intrathecal methylprednisolone on the development and maintenance of neuropathic pain and spinal glial activation in a rat model.

Methods: Rats were anesthetized, and L5 and L6 spinal nerves were tightly ligated. Then, continuous infusion of systemic (4 mg [middle dot] kg-1 [middle dot] day-1) or intrathecal (80 [mu]g [middle dot] kg-1 [middle dot] day-1) methylprednisolone or saline was started. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively with von Frey and Hargreaves tests, respectively. Spinal astrocytic activation was evaluated with glial fibrillary acidic protein immunoreactivity on day 7. In other groups of rats, continuous 3-day treatment with intrathecal methylprednisolone or saline was started 7 days after spinal nerve ligation, when neuropathic pain had already developed. Behavioral tests and immunostaining were performed up to 3 weeks after the treatment.

Results: Spinal nerve ligation induced mechanical allodynia and thermal hyperalgesia on days 4 and 7 postoperatively. Glial fibrillary acidic protein immunoreactivity was remarkably enhanced on day 7. Both systemic and intrathecal methylprednisolone inhibited the development of neuropathic pain states and glial activation. Three-day treatment with intrathecal methylprednisolone reversed existing neuropathic pain state and glial activation up to 3 weeks after the treatment.     

The Antiallodynic Effects of Intrathecal Cholinesterase Inhibitors in a Rat Model of Neuropathic Pain

Background: This study determined the effect of intrathecally administered cholinesterase inhibitors, edrophonium and neostigmine, on nerve injury-induced, touch-evoked allodynia and identified the pharmacologic characteristics of this action.

Methods: Rats were prepared with tight ligation of the left L5 and L6 spinal nerves and with lumbar intrathecal catheters fitted for long-term monitoring. Edrophonium (3, 10, 30, or 100 [micro sign]g) or neostigmine (0.3, 1, 3, or 10 [micro sign]g) was administered intrathecally. Tactile allodynia and motor weakness were assessed. To evaluate the pharmacologic characteristics of the activity, a muscarinic receptor antagonist or a nicotinic receptor antagonist was administered intrathecally before edrophonium or neostigmine was injected. To compare the action of subtype antagonists, the M1 muscarinic receptor antagonist pirenzepine, the M (2) antagonist methoctramine, the M3 antagonist 4-DAMP (diphenylacetoxy-N-methypiperidine), and the M4 antagonist tropicamide were administered intrathecally before cholinesterase inhibitors were injected.

Results: Intrathecal edrophonium or neostigmine produced a dose-dependent antagonism of the touch-evoked allodynia. Neostigmine resulted in a moderate effect on motor weakness at doses of 3 and 10 [micro sign]g. Pretreated with intrathecal atropine but not mecamylamine yielded a complete antagonism of the effects of the cholinesterase inhibitors. In addition, antiallodynia produced by edrophonium (100 [micro sign]g) was reversed by pretreatment with methoctramine, 4-DAMP, tropicamide, and pirenzepine. In the neostigmine (10 [micro sign]g) group, only M1 antagonist pirenzepine had a moderate effect on reversal of increased allodynic threshold.     

Antiallodynic Effect of Intrathecal Neostigmine Is Mediated by Spinal Nitric Oxide in a Rat Model of Diabetic Neuropathic Pain

Background: Intrathecal administration of acetylcholinesterase inhibitors produces antinociception in both animals and humans, but their effect on diabetic neuropathic pain has not been studied. In the current study, we determined the antiallodynic effect of intrathecal injection of an acetylcholinesterase inhibitor, neostigmine, in a rat model of diabetic neuropathic pain. In addition, since acetylcholine can increase release of nitric oxide in the spinal cord, we studied the role of spinal endogenous nitric oxide in the action of intrathecal neostigmine in diabetic neuropathic pain.

Methods: Rats were rendered diabetic with an intraperitoneal 50-mg/kg injection of streptozotocin. Intrathecal catheters were inserted, with tips in the lumbar intrathecal space. Mechanical allodynia was determined by application of von Frey filaments to the hind paw. We first determined the dose-dependent effect of intrathecal neostigmine on allodynia. The role of spinal nitric oxide in the action of intrathecal neostigmine was then examined through intrathecal treatments with a neuronal nitric oxide synthase inhibitor (TRIM), a nitric oxide scavenger (PTIO), l-arginine, or d-arginine.

Results: The diabetic rats developed a sustained tactile allodynia within 4 weeks after streptozotocin injection. Intrathecal injection of 0.1-0.5 [mu]g neostigmine dose-dependently increased the withdrawal threshold in response to application of von Frey filaments. Intrathecal pretreatment with 30 [mu]g TRIM or 30 [mu]g PTIO abolished the antiallodynic effect of intrathecal neostigmine. Furthermore, the inhibitory effect of TRIM on the action of intrathecal neostigmine was reversed by intrathecal injection of 100 [mu]g l-arginine but not d-arginine.     

Effects of Clonidine on Postoperative Nausea and Vomiting in Breast Cancer Surgery

Background: Postoperative nausea and vomiting (PONV) is still common, especially among female patients. Our hypothesis is that coinduction with clonidine reduces the incidence of PONV in adult patients undergoing breast cancer surgery.

Methods: Sixty-eight women premedicated with midazolam were randomly allocated to coinduction with intravenous clonidine (group C) or placebo (group P) in this prospective, double-blind study. Anesthesia was standardized (laryngeal mask airway, fentanyl, propofol, sevoflurane, nitrous oxide, and oxygen). Hemodynamic parameters and the requirements for propofol, sevoflurane, and the postoperative need for ketobemidone were noted. The primary endpoints studied were the number of PONV-free patients and patient satisfaction with respect to PONV.

Results: Patients in group C had a significantly reduced need for propofol (P < 0.04) and sevoflurane (P < 0.01) and a reduced early need for ketobemidone (P < 0.04). There were significantly more PONV-free patients in group C compared with group P (20 and 11 of 30, respectively;P < 0.04). The number needed to treat was 3.3 (95% confidence interval, 1.8, 16.9). Intraoperative blood pressure, postoperative heart rate, and postoperative blood pressure were all significantly lower in group C compared with group P, but were not considered to be of clinical importance. No negative side effects were recorded.     

加巴喷丁治疗神经病理性疼痛的理论与临床应用

加巴喷丁（Gabapentin，又名Neurontin）是近年来广泛应用于治疗癫痫的药物，亦是当前国外临床应用与研究的热点课题。国内对此药的认识刚刚起步，而且被定为抗癫痫类药物，实际上它是属于一种治疗神经病理性疼痛的镇痛药。国内已有文章介绍。加巴喷丁于1993年首先在英国上市用于治疗癫痫大发作，同年美国FDA批准其临床应用。此后成为世界范围广泛应用于治疗癫痫的新药；     

Topical 2% Amitriptyline and 1% Ketamine in Neuropathic Pain Syndromes: A Randomized, Double-blind, Placebo-controlled Trial

Background: A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of topical 2% amitriptyline, 1% ketamine, and a combination of both in treating patients with neuropathic pain.

Methods: Ninety-two patients with diabetic neuropathy, postherpetic neuralgia, or postsurgical/posttraumatic neuropathic pain with allodynia, hyperalgesia, or pinprick hypesthesia were randomly assigned to receive one of four creams (placebo, 2% amitriptyline, 1% ketamine, or 2% amitriptyline-1% ketamine combined). The primary outcome measure was change in average daily pain intensity (baseline week vs. final week) using an 11-point numerical pain rating scale. Secondary outcomes included the McGill Pain Questionnaire, measures of allodynia and hyperalgesia, and patient satisfaction.

Results: A reduction in pain scores of 1.1-1.5 units was observed in all groups, and there was no difference between groups. Blood concentrations revealed no significant systemic absorption. Minimal side effects were encountered.     

Systemic Antiinflammatory Corticosteroid Reduces Mechanical Pain Behavior, Sympathetic Sprouting, and Elevation of Proinflammatory Cytokines in a Rat Model of Neuropathic Pain

Background: Chronic pain models are commonly defined as either nerve-injury or inflammation models, but recent work suggests inflammatory processes are important in nerve injury-induced pain.

Methods: In the rat spinal nerve ligation model, the authors examined effects of systemic corticosteroid triamcinolone acetonide (TA) on the cytokine protein profile and sympathetic sprouting in the axotomized sensory ganglia, excitability of sensory neurons, and mechanical sensitivity.

Results: By postoperative day 3, marked increases (5- to 16-fold) in monocyte chemoattractant protein-1, growth-related oncogene (GRO/KC or CXCL1), and interleukin (IL)-6 were observed, whereas IL-4 and IL-2 levels fell more than fourfold. The increased cytokines and number of sympathetic basket formations in the sensory ganglia were reduced toward normal values by TA given starting at the time of injury. Interleukin-4 and IL-2 levels were not restored by TA. Systemic TA also reduced the firing rate and incidence of bursting activity, but not the overall incidence of spontaneous activity, in large- and medium-sized neurons. Mechanical hypersensitivity on postoperative day 3 was reduced by TA, and some effect could still be observed 4 days after cessation of TA. However, starting TA at day 7 was ineffective.     

局部应用丝裂霉素C对大鼠坐骨神经运动功能的影响

目的 观察局部应用不同浓度的丝裂霉素C (mitomycin C,MMC)对大鼠坐骨神经运动功能的影响.方法 30只健康SD大鼠,随机分为5组,每组6只.充分显露大鼠右侧坐骨神经,术中各组分别以棉片浸透生理盐水(A组,对照组)或0.1 mg/mL(B组)、0.3 mg/mL(C组)、0.5 mg/mL(D组)、0.7 mg/mL(E组)的MMC,包裹于暴露的坐骨神经周围5 min.术后3d通过斜板实验及足迹分析实验结果来评价坐骨神经运动功能的变化.结果 a)斜板试验:术后3d,各剂量MMC组及对照组斜板试验角度比较,差异无统计学意义(P＞0.05);b)足迹分析实验:术后3d,各剂量MMC组及对照组坐骨神经功能指数比较,差异无统计学意义(P)＞0.05).结论 局部应用浓度不超过0.7mg/mL的MMC不会对大鼠坐骨神经的运动功能产生明显影响.     

Role for Cyclooxygenase 2 in the Development and Maintenance of Neuropathic Pain and Spinal Glial Activation

Background: Lines of evidence have indicated that cyclooxygenase 2 plays a role in the pathophysiology of neuropathic pain. However, the site and mechanism of its action are still unclear. Spinal glia has also been reported to mediate pathologic pain states. The authors evaluated the effect of continuous intrathecal or systemic cyclooxygenase-2 inhibitor on the development and maintenance of neuropathic pain and glial activation in a spinal nerve ligation model of rats.

Methods: Continuous intrathecal infusion of meloxicam (32 or 320 [mu]g [middle dot] kg-1 [middle dot] day-1) or saline was started immediately after L5-L6 spinal nerve ligation. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively. Spinal astrocytic activation was evaluated with glial fibrially acidic protein immunoreactivity on day 7. In other groups of rats, continuous intrathecal meloxicam was started 7 days after spinal nerve ligation, and effects on established neuropathic pain and glial activation were evaluated. Last, effects of continuous systemic meloxicam (16 mg [middle dot] kg-1 [middle dot] day-1) on existing neuropathic pain and glial activation were examined.

Results: Intrathecal meloxicam prevented the development of mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation. It also inhibited spinal glial activation responses. In contrast, when started 7 days after the nerve ligation, intrathecal meloxicam did not reverse established neuropathic pain and glial activation. Systemic meloxicam started 7 days after ligation partially reversed neuropathic behaviors but not glial activation.     

术后延长吸氧时间对老年全膝关节置换术病人术后疼痛、炎症因子及免疫功能的影响

目的 探讨术后延长吸氧时间对老年全膝关节置换术（TKA）病人术后疼痛、炎症因子及免疫功能的影响。方法 选取2022年1月至2023年1月西安交通大学第二附属医院收治的拟行TKA治疗的病人142例,男65例,女77例;年龄（73.35±7.30）岁。采用随机数字表法将病人分为观察组和对照组,每组71例。对照组病人术后给予8 h的常规鼻导管低流量（3 L/min）吸氧,观察组在对照组的基础上延长吸氧时间至术后48 h。观察两组术前和术后8、24、48 h简易精神状态检查量表（MMSE）评分和疼痛视觉模拟量表（VAS）评分,术前和术后8、48 h血清炎症因子和免疫功能指标水平;术前和术后24、48 h脉搏血氧饱和度（SpO₂）、心率和呼吸频率情况。结果 观察组术后24、48 h MMSE评分显著高于对照组（P＜0.05）,VAS评分显著低于对照组（P＜0.05）。两组术后24、48 h VAS评分较术前均显著降低（P＜0.05）。对照组术后各时点MMSE评分较术前均显著降低（P＜0.05）,观察组术后8、24 h MMSE评分显著降低（P＜0.05）。观察组术后24、48 h SpO2显著高于对照组（P＜0.05）,心率、呼吸频率显著低于对照组（P＜0.05）。观察组术后48 h白介素-10（IL-10）、CD³⁺、CD⁴⁺、CD⁸⁺、CD⁴⁺/CD⁸⁺水平显著高于对照组（P＜0.05）,白介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）水平显著低于对照组（P＜0.05）。与术前比较,两组术后8、48 h血清IL-6、TNF-α水平均显著升高（P＜0.05）,CD³⁺、CD⁴⁺、CD⁸⁺、CD⁴⁺/CD⁸⁺水平均显著降低（P＜0.05）。结论 术后延长吸氧时间可降低老年TKA病人疼痛,提高病人术后免疫功能,改善炎症因子水平。     

Cardiorespiratory and Spinal Cord Blood Flow Effects of Intrathecal Neostigmine Methylsulfate, Clonidine, and Their Combination in Sheep

Background: Intrathecal neostigmine may produce analgesia by itself and may enhance analgesia from spinal clonidine. Before clinical trials, the spinal cord blood flow effects of these drugs alone and in combination should be examined in animals.

Methods: Conscious, nonpregnant ewes with indwelling vascular and thoracic spinal catheters received intrathecal injection of 0.2 or 2 mg neostigmine, 0.2 mg clonidine, or 2 mg neostigmine plus 0.2 mg clonidine. Mean systemic and pulmonary arterial and central venous pressures, heart rate, and cardiac output were monitored, arterial blood was sampled for blood gas tensions and pH, and spinal cord blood flow was determined by colored microsphere injection before and at 15, 60, and 240 min after spinal study drug injection.

Results: Neostigmine alone did not affect cardiorespiratory variables or spinal cord blood flow. Intrathecal clonidine alone decreased systemic arterial and central venous pressures, whereas these effects were not observed with addition of neostigmine. Clonidine or neostigmine alone or the combination of clonidine and neostigmine did not affect spinal cord blood flow.     

Effects of Laparotomy on Spontaneous Exploratory Activity and Conditioned Operant Responding in the Rat: A Model for Postoperative Pain

Background: Treatment of postsurgical pain is a major use of analgesics, particularly after abdominal surgery. Analgesics display a number of limiting side effects, including sedation, cognitive impairment, and ileus. Although several postoperative rodent models have been developed, these models do not address these concerns.

Methods: A model is presented in the rat in which a subcostal incision is performed, penetrating into the peritoneal cavity. The behavioral effects of this surgical procedure are assessed using exploratory locomotor activity and conditioned operant responding. The effects of morphine and ketorolac were assessed in both behavioral paradigms.

Results: Laparotomy decreased ambulation and rearing by approximately 50% 24 h after surgery, and stereotypy (small confined movements) was affected to a lesser degree. The effects of laparotomy on conditioned operant responding were more complex. Total number of sucrose pellets earned was decreased for 2-3 days after laparotomy; however, the amount of time required was increased for up to 2 weeks. Morphine reversed the effects of surgery on ambulation and stereotypy but not rearing, and the dose-effect curve for morphine was shifted to the left by 5 mg/kg ketorolac. Ketorolac produced significant improvement in operant responding after laparotomy, and coadministration of ineffective doses of morphine and ketorolac produced a positive response.     

Effect of Systemic and Intrathecal Morphine in a Rat Model of Postoperative Pain

Background: To learn more about persistent pain after an incision, a rat model for postoperative pain has been developed. To further evaluate this model, the authors examined the effect of intrathecal (IT) and subcutaneous (SC) morphine, effective for postoperative pain relief in patients, on pain behaviors immediately after surgery and 1 day after surgery.

Methods: Rats were anesthetized with halothane, and a 1-cm incision was made in the plantar aspect of the foot and closed. After recovery, the rats were placed on an elevated plastic mesh floor, and withdrawal threshold was determined using calibrated von Frey filaments (15-522 mN) applied from beneath the test cage to an area adjacent to the wound at the heel. Pain behaviors also were assessed using the response frequency to a nonpunctate mechanical stimulus and a cumulative pain score.

Results: Mechanical hyperalgesia and nonevoked pain behaviors were present on the day of surgery and 1 day after surgery. Administration of either SC (0.3-3.0 mg/kg) or IT (0.16-5.0 micro gram) morphine reversibly increased the withdrawal threshold. The response frequency to the nonpunctate stimulus and the nonevoked pain scores also were decreased by 3 mg/kg of SC or 5 micro gram of IT morphine. Naloxone (1 mg/kg) reversed morphine-produced hypoalgesia.