Rat Model Of Postoperative Pain Research Articles

The Effect of Tissue pH Values of a Wound on Pain Behaviors in an Acute Pain Model of the Rat

Background: There is a suggestion that tissue acidosis may contribute to the induction of pain in inflammation and ischemia. High local proton concentrations have been found in painful inflammatory and ischemic conditions. We assessed tissue pH and pain behavior in a rat model for postoperative pain. Methods: An incision of skin, fascia, and muscle was performed in the right foot. Pain behaviors to von Frey, blunt probe stimulation, and resting pain were evaluated on the incised feet. Then tissue pH was measured in each of the five rats at 4 hours, 1, 2, 4, and 7 days after incision. Results: The withdrawal threshold to von Frey was decreased, the response frequency to blunt probe and pain scores were elevated from 4 hours to 1-2 days after the incision. The deep tissue pH decreased from pH 7.16 in sham to pH 6.95, 6.90, 6.89, and 6.95 at 4 h and 1, 2, and 4 days after incision respectively. Conclusions: In this study, the tissue pH of the wound decreased after surgery. However, the change of tissue pH was not always consistent with pain behaviors. Our results suggest that tissue acidosis may relate partially to the induction of pain after tissue injury.

Role of endogenous ATP at the incision area in a rat model of postoperative pain.

The aim of the present study is to characterize the role of endogenous ATP leaked from damaged cells in a rat model of postoperative pain using behavioural and immunocytochemical approaches. We found that systemic (i.v.) and local (incision area) administration of a P2 receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) before surgery significantly attenuated mechanical allodynia caused by an incision of the plantar surface of the hindpaw. Furthermore, PPADS significantly reduced the incision-evoked c-Fos protein expression, a marker of neuronal activity, in the dorsal horn of the spinal cord. The present findings suggest that excitatory signaling by endogenous ATP leaked from damaged cells via PPADS-sensitive P2 receptors is necessary for the induction of the postoperative pain characterized by mechanical allodynia.

The effects of peripheral administration of a novel selective antagonist for prostaglandin E receptor subtype EP(1), ONO-8711, in a rat model of postoperative pain.

Mechanically evoked pain, also known as incident pain, induced by coughing or deep breathing after surgery leads to potentially devastating consequences. It is generally thought that the prostaglandin receptor- (especially, the receptor for prostaglandin E(2), EP receptor) mediated sensitization of sensory nerve fibers is a key contributor to the generation of hyperalgesia. We examined whether a peripherally administered novel selective EP(1) antagonist, ONO-8711, would be a potential analgesic for incision-induced mechanical hyperalgesia. We used a rat model of postoperative pain introduced by Brennan et al. (1). Withdrawal thresholds to punctate stimulation and response frequencies to nonpunctate mechanical stimulation were determined by using von Frey filaments applied adjacent to the wound and directly to the incision site of the hind paw, respectively. Mechanical hyperalgesia to punctate and nonpunctate stimuli was observed 2 and 24 h after the incision. ONO-8711 (2, 10, or 50 microg) or saline was administered subcutaneously into the hind paw on the ipsilateral side to the incision. ONO-8711 significantly (P < 0.01) increased the withdrawal thresholds to punctate mechanical stimulation and significantly (P < 0.01) decreased the response frequencies to nonpunctate mechanical stimulation in a dose- and time-dependent manner 2 and 24 h after the incision. We conclude that EP(1) receptor-mediated sensitization of sensory nerve fibers may contribute to the generation of mechanical hyperalgesia produced by incisional surgery, and that the EP(1) receptor antagonist ONO-8711 may be an option for treatment of postoperative pain, especially incident pain. The peripheral administration of an antagonist for EP(1) receptor that is a subtype of prostaglandin E receptors can inhibit the mechanical hyperalgesia induced by a surgical incision.

Alterations in ascending dorsal horn neurons by a surgical incision in the rat foot.

Little is known about the mechanisms of pain caused by a surgical incision. The authors have developed a rat model of postoperative pain characterized by decreased withdrawal thresholds to punctate mechanical stimuli after plantar incision. The present studies examined the response characteristics of dorsal horn neurons receiving input from the plantar aspect of the foot before and after a plantar incision placed adjacent to the low threshold area of the receptive field (RF). Individual dorsal horn neurons from the lumbar enlargement were antidromically identified and characterized as low threshold, wide dynamic range (WDR), and high threshold (HT) based on their responses to brush and pinch. Thresholds (in millinewtons), the pinch RF, and stimulus-response functions (SRFs) to von Frey filaments characterized the neurons. SRFs were analyzed using area under the curve. Changes in background activity, punctate mechanical thresholds, SRFs, and RF were recorded after an incision was made adjacent to the most sensitive area of the RF. In all cells, an incision increased background activity; this remained elevated in 3 of 9 HT and 16 of 28 WDR neurons 1 h later. The SRFs were enhanced in 10 of 27 WDR neurons and in 2 of 8 HT cells after incision. Only the WDR neurons were responsive to filaments that produced withdrawal responses after incision in behavioral experiments. Increases in the RFs outside of the injured area occurred after incision in 15 of 29 WDR and 2 of 9 HT cells. A plantar incision caused dorsal horn cell activation and central sensitization. Because the threshold of HT neurons did not decrease to the range of the withdrawal responses in behavioral experiments, particular WDR dorsal horn neurons likely contribute to the reduced withdrawal threshold observed in behavioral experiments. Both WDR and HT neurons are capable of transmitting enhanced responses to strong punctate mechanical stimuli after incision.

The mechanical antihyperalgesic effect of intrathecally administered MPV-2426, a novel alpha2 -adrenoceptor agonist, in a rat model of postoperative pain.

MPV-2426 is a novel alpha2-adrenoceptor agonist developed for spinal pain therapy. It has proved to be effective in physiologic and neuropathic conditions. In the current study its effectiveness on mechanical hyperalgesia was assessed in a rat model of postoperative pain. Rats with intrathecal catheters were anesthetized with pentobarbital, and a 1-cm incision was made in the plantar aspect of the foot and closed. During postoperative days 1 and 2 the antihyperalgesic effects induced by intrathecal MPV-2426, clonidine, and dexmedetomidine were determined by assessing the hind limb withdrawal threshold to calibrated von Frey hairs applied to the skin of the hind paw adjacent to the wound. MPV-2426 administered into the lumbar spinal cord produced a dose-dependent (0.3-10 microg) attenuation of the mechanical hyperalgesia, and this antihyperalgesic effect was completely reversed by yohimbine (1 mg/kg, subcutaneous), an alpha2-adrenoceptor antagonist. Dexmedetomidine (1-3 microg) produced an equipotent antihyperalgesic effect, whereas the effect of clonidine (1-10 microg) was markedly weaker. MPV-2426 (10 microg in 20 microl) administered adjacent to the wound did not produce any effect. Preoperative treatment with an antihyperalgesic dose of MPV-2426 did not prevent the development of hyperalgesia. Intrathecal MPV-2426 dose-dependently attenuates postoperative hyperalgesia to mechanical stimulation because of an action on alpha2 adrenoceptors. Its antihyperalgesic action is as effective as that produced by dexmedetomidine and is considerably stronger than that produced by clonidine. However, preoperative treatment with MPV-2426 does not prevent the development of postoperative hyperalgesia.

Antiallodynic effect of intrathecal gabapentin and its interaction with clonidine in a rat model of postoperative pain.

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). 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. Paw incision induced a mechanical hypersensitivity (mechanical threshold > 25 g before incision and < 5 g after). Intrathecal gabapentin dose-dependently (10-100 microg) 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 microg, respectively, and isobolographic analysis showed synergy between gabapentin and clonidine. Intrathecal gabapentin is effective against tactile allodynia that occurs after paw incision, and interacts synergistically with clonidine. Unlike results in vitro, gabapentin does not obligatorily need to enter cells via the L-amino acid transporter mechanism to achieve its effects in vivo.

Anti-allodynic effects of oral COX-2 selective inhibitor on postoperative pain in the rat.

To examine the effect of a cyclooxygenase (COX)-2 inhibitor on the maintenance of mechanical allodynia induced by skin incision (an animal model of postoperative incident pain) in the rat. Also, to compare the effect of a COX-2 inhibitor with that of a nonselective COX-1 and COX-2 inhibitor and B2 receptor antagonist. A 1 cm longitudinal skin incision was made in the plantar aspect of the foot. JTE522 (1-100 mg x kg(-1)), a COX-2 inhibitor, indomethacin (1-30 mg x kg(-1)), a nonselective COX-1 and COX-2 inhibitor, or FR173657 (10 and 100 mg x kg(-1)), a bradykinin B2 receptor antagonist, was administered orally five minutes after the end of the surgery. The level of mechanical allodynia was assessed by measuring the frequency of foot withdrawal in response to the application of a 12.5 g on Frey filament at 2, 4, 6, 8 and 24 hr after the drug administration. Oral administration of JTE522 or indomethacin attenuated the maximum response frequency in a dose-dependent manner at a dose between 1 and 30 mg x kg(-1) (P < 0.05). Oral FR 173657, (100 mg x kg(-1)), had no effect on the maximum response frequency. These data indicated that a COX-2 inhibitor attenuated the level of mechanical allodynia in the rat model of postoperative pain.

Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain

Ziconotide (SNX-111), a selective blocker of neuronal N-type voltage-sensitive calcium channels, is antinociceptive when it is administered intrathecally. It is currently under clinical investigation for the treatment of malignant and non-malignant pain syndromes. The present study was undertaken to compare and contrast antinociceptive properties of ziconotide, morphine and clonidine in a rat model of post-operative pain. Post-operative pain was produced by making a longitudinal incision through the skin, fascia, and muscle of the plantar aspect of the left hindpaw. This procedure produced immediate (0.5 h after surgery) and long-lasting (4–7 days post-surgery) heat hyperalgesia and mechanical allodynia in the injured hindpaw. Pain thresholds in the contralateral hindpaw were unaffected. Administered one day after incisional surgery, intrathecal ziconotide blocked established heat hyperalgesia in the injured hindpaw in a dose-dependent manner yielding an ED50 of 0.1 μg (49 pmol) but had no effect on heat-induced nociceptive responses in the normal hindpaw. Intrathecal ziconotide (0.3 μg (112 pmol)) also produced a long-lasting (>4 h) but reversible (<24 h) blockade of established mechanical allodynia. Administered one day after surgery, intrathecal bolus injection of morphine dose-dependently blocked heat hyperalgesia in the injured hindpaw with an ED50 of 1.6 μg (2.1 nmol) and heat nociceptive responses in the normal hindpaw with an ED50 of 2.7 μg (3.6 nmol). The effects were immediate and short-lasting (≤1 h). Intravenous bolus injection of 3 mg/kg (1.1 μmol/kg) ziconotide, administered either before or after incisional surgery, had no effect on thermal pain thresholds measured in either the injured or normal hindpaw. In contrast, intraperitoneal injections of 2 mg/kg (2.6 μmol/kg) morphine and 2.5 mg/kg (9.4 μmol/kg) clonidine blocked heat hyperalgesia in the injured hindpaw; morphine, but not clonidine, also elevated thermal (heat) nociceptive response thresholds in the normal hindpaw. The results of this study show that intrathecal ziconotide is antinociceptive in a rat incisional model of post-operative pain and is more potent, longer acting, and more specific in its actions than intrathecal morphine.

Effects of Intrathecal Magnesium Sulphate in a Rat Model of Postoperative Pain

Background : The mechanical hyperalgesia tbat follows peripheral tissue injury results from peripheral and central sensitization. Central sensitization is initiated and maintained by wmdup that can be prevented by N-methyl-D-aspartate (NMDA) antagonists. NMDA antagonists, therefore, have the potential to prevent and treat pain, although clinical uses are limited because of their side effects. This study was designed to evaluate the analgesic action of intrathecal (IT) magnesium sulphate in a rat model of postoperative pain and investigate the analgesic mechanism of magnesium. Methods : Forty-two Sprague-Dawley rats (300±20 g) were prepared with a chronic IT catheter. Under brief enflurane anesthesia, a 1-cm incision including skin, muscle and fascia was made in the plantar aspect of the hind paw and closed. Normal saline, magnesium (30, 100, 300, 600㎍), NMDA 50 ng or NMDA 50 ng with magnesium 300㎍ was administered via the IT catheter after recovery. Response frequency, using Von Frey filaments, comulative pain scores and mator deficits were assessed. Results : The mechanical hyperalgesia and nonevoked pain behaviots decreased significantly at 1 h or 1 h and 3 h after IT injection of magnesium 100 ㎍ or 300 ㎍ compared to the saline group without profound motor deficits in a rat model of postoperative pain. However, the rats administered with magnesium 600 pg were lethargic due to severe motor weakness. Bffective duration of magnesium decreased significantly in the group of NMDA 50 ng with magnesium 300 pg compared to that of magnesium 300 pg administered alone, but the initial effects were similar between the two groups. Conclusions: We conclude that 1T magnesium sulphate can modulate nociceptive processing after tissue injury and the analgesic mechanism of magnesium is involved in NMDA receptors. Magnesium, therefore, may offer a therapeutic agent for postoperative pain and may be an agent that prevents postoperative pain from changing to pemistent pathological pain. (Korean J Anesthesiol 2000; 39: 889 -899)

Effect of Intrathecal ACEA-1021 in a Rat Model for Postoperative Pain

Abstract: Drugs antagonizing glycine at the N -methyl-D -aspartate (NMDA) receptor have been developed to improve efficacy, increase specificity, and, perhaps, reduce side effects. The purpose of this study was to examine the effect of intrathecally (IT) administered acea-1021, a glycine receptor antagonist at the NMDA receptor complex, in a rat model of postoperative pain. Rats with IT catheters were anesthetized and underwent a plantar incision. Two hours later, withdrawal threshold to punctate stimulation was determined by applying calibrated von frey filaments adjacent to the wound. In another group, the response frequency to a plastic disk, a blunt, nonpunctate mechanical stimulus applied directly on the incision also was measured. In unincised rats, NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), Or kainate (KA) was administered it 30 minutes after acea-1021 or vehicle. Spontaneous nociceptive behaviors (SNB) caused by it excitatory amino acids (EAAS) were counted. In the vehicle-treated group, the median withdrawal threshold for punctate stimulation decreased from 522 mn before incision to 61 mn or less for 4 hours after incision. In 3 separate groups, the median withdrawal threshold increased to 61, 118, and 332 mn 30 minutes after it administration of 10, 30, and 60 nmol of acea-1021, respectively. In 3 other groups, it administration of 10, 30, and 60 nmol of acea-1021 decreased the response frequency to the blunt mechanical stimulus from 95 ± 13 or greater to 78 ± 40%, 67 ± 37%, and 22 ± 27% 30 minutes after drug injection, respectively. Sixty nmol of acea-1021 inhibited SNBS caused by IT NMDA, KA, and AMPA. IT administration of acea-1021 decreased incision-induced pain behaviors in this rat model. Acea-1021 blocked SNB by NMDA, KA, and AMPA. These data, coupled with previous studies, suggest that inhibition of pain behaviors by it acea-1021 is produced by blockade of spinal non-NMDA receptors.

Primary and secondary hyperalgesia in a rat model for human postoperative pain.

Previously, the authors developed and characterized a rat model for postoperative pain to learn more about pain produced by incisions. In this study, the responses to heat and mechanical stimuli were evaluated directly on or adjacent to the incision and at varying distances from the incision. Rats were anesthetized with halothane and incisions were made at different locations in the plantar aspect of the foot. The response frequency to a blunt mechanical stimulus, the withdrawal threshold to von Frey filaments (15-522 mN), and the withdrawal latency to radiant heat were measured. Rats were tested before surgery, 2 h later, and then daily through postoperative day 9. After plantar incision, persistent hyperalgesia was observed immediately adjacent to or directly on the incision to punctate and blunt mechanical stimuli, respectively. The withdrawal threshold to punctate stimuli applied 1 cm from the incision was decreased through postoperative day 1. In a transitional area, between the distant and adjacent sites, the withdrawal threshold was intermediate and the duration of hyperalgesia was transient. Heat hyperalgesia was persistent but present when the stimulus was applied to the site of injury but not to a distant site. Robust primary hyperalgesia to punctate and blunt mechanical stimuli was present. Hyperalgesia distant to the wound, or secondary hyperalgesia, occurred in response to punctate mechanical stimuli, was short-lived, and required greater forces. These results suggest that the most persistent pain behaviors in this model are largely primary hyperalgesia.

Enadoline, a selective κ-opioid receptor agonist shows potent antihyperalgesic and antiallodynic actions in a rat model of surgical pain

Enadoline is a highly selective and potent κ-opioid receptor agonist. This report describes and compares the activities of enadoline and morphine in a rat model of postoperative pain. A 1 cm incision through the muscle and skin of the plantar surface of the right hind paw induced thermal hyperalgesia as well as static and dynamic allodynia lasting at least 2 days. Postoperative testing was carried out using the plantar test for thermal hyperalgesia, von Frey hairs for static allodynia and light stroking with a cotton bud for dynamic allodynia. A single i.v. dose of enadoline 15 min before surgery dose-dependently (1–100 μg/kg) blocked the development of thermal hyperalgesia as well as static and dynamic allodynia for over 24 h with respective MEDs of ≤1, 10 and 10 μg/kg. The administration of enadoline (100 μg/kg, i.v.), 1 h after surgery, completely blocked the maintenance of the hyperalgesic and allodynic responses, but its duration of action was much shorter (2 h) than when administered before surgery. Previous studies have shown that administration of morphine (1–6 mg/kg, s.c.) 0.5 h before surgery can prevent the development of thermal hyperalgesia with a MED of ≤1 mg/kg, but it has little effect on static allodynia. In the present study similar administration of morphine (1–3 mg/kg), unlike enadoline, had no effect on the development of dynamic allodynia. Morphine dose-dependently (1–6 mg/kg, s.c.) potentiated isoflurane-induced sleeping time and respiratory depression in the rat. However, whilst enadoline also (1–1000 μg/kg, i.v.) potentiated isoflurane-induced sleeping time, it did not cause respiratory depression. It is suggested that enadoline may possess therapeutic potential as a pre-emptive antihyperalgesic and antiallodynic agent.

Intrathecal Metabotropic Glutamate Receptor Antagonists Do Not Decrease Mechanical Hyperalgesia in a Rat Model of Postoperative Pain

Spinal metabotropic glutamate receptors (mGluR) have been implicated in hyperalgesia after injury. The purpose of this study was to examine the effects of intrathecal (IT) mGluR antagonists on mechanical hyperalgesia in a rat model of human postoperative pain. The hindpaw withdrawal threshold to punctate stimulation using von Frey filaments and the response frequency to a nonpunctate stimulus applied directly to the wound were also measured. The effects of 1T (+)-alpha-methyl-carboxyphenylglycine ([+]-MCPG), (S)-carboxyphenylglycine ([S]-4-CPG), (RS)-alphacyclopropyl-4-phosphonophenylglycine ([RS]-CPPG) and L-2-amino-3-phosphonopropionic acid (L-AP3) on incision-induced mechanical hyperalgesia were examined. The withdrawal thresholds to punctate stimuli were not different from vehicle treatment after the IT administration of (+)-MCPG (100, 500 nmol), (S)4CPG (30, 100 nmol), (RS)-CPPG (100, 500 nmol), or L-AP3 (1, 30, 100 nmol). None of the IT mGluR antagonists decreased the response frequency to the nonpunctate stimulus. The largest dose of (+)-MCPG produced sufficient receptor antagonism because spontaneous nociceptive behaviors caused by the IT administration of a mGluR agonist were reduced. Spinal metabotropic glutamate receptors antagonists, antinociceptive in some models of persistent pain, are not necessary for the maintenance of mechanical hyperalgesia in this rat model, which suggests that blockade of spinal metabotropic glutamate receptors may not be useful for the treatment of pain after surgery.

Intrathecal Metabotropic Glutamate Receptor Antagonists Do Not Decrease Mechanical Hyperalgesia in a Rat Model of Postoperative Pain

Intrathecal Metabotropic Glutamate Receptor Antagonists Do Not Decrease Mechanical Hyperalgesia in a Rat Model of Postoperative Pain

Intrathecal Neostigmine in a Rat Model of Postoperative Pain

Intrathecal Neostigmine in a Rat Model of Postoperative Pain

Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain

Evidence indicates that excitatory amino acids (EAAs) like glutamate and aspartate are important in the processing of nociceptive information in the dorsal horn of the spinal cord. Recently, the role of particular EAA receptors in pain transmission and facilitated pain states has been examined utilizing spinal administration of specific receptor antagonists. Most investigators have studied the involvement of N-methyl- d-aspartate (NMDA) EAA receptors in hyperalgesia and nociception; less is known about the importance of non-NMDA EAA receptors in animal models of persistent pain. To study the role of spinal non-NMDA EAA receptors in pain behaviors caused by an incision, we examined the effect of i.t. administered non-NMDA EAA receptor antagonists in a rat model of postoperative pain. Rats with i.t. catheters were anesthetized and underwent a plantar incision. Withdrawal threshold to punctate stimulation applied adjacent to the wound using von Frey filaments, response frequency to application of a non-punctate stimulus applied directly to the wound and non-evoked pain behaviors were measured before and after administration of i.t. 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX), or vehicle. A separate group of animals were also tested for motor impairment caused by these drugs. In the vehicle-treated group, the median withdrawal threshold for punctate hyperalgesia decreased from 522 mN before surgery to 39 mN 2 h later; hyperalgesia was persistent. Intrathecal administration of 5 or 10 nmol of NBQX returned the withdrawal threshold toward preincision values; the median withdrawal thresholds were 158 and 360 mN, respectively. Intrathecal administration of 10 nmol of DNQX similarly increased the withdrawal threshold after incision. In separate groups of animals, i.t. administration of 5 or 10 nmol of NBQX decreased the response frequency to a non-punctate stimulus applied directly to the incision from 100±0% 2 h after surgery to 22±11 and 0±0% 30 min after drug injection, respectively. Similar results were observed with i.t. administration of 10 nmol of DNQX. Intrathecal NBQX also inhibited non-evoked pain behavior. In conclusion, non-NMDA receptor antagonists produced a marked decrease in pain behaviors in this model of postoperative pain. Thus, non-NMDA receptors are important for the maintenance of short-term pain behaviors caused by an incision and drugs blocking these receptors may be useful for the treatment of postoperative pain in patients.

Lack of effect of intrathecally administered N-methyl-D-aspartate receptor antagonists in a rat model for postoperative pain.

Evidence from experiments by others indicates an important role for excitatory amino acids activating spinal n-methyl-d-aspartate (NMDA) receptors in models of persistent pain. The purpose of this study was to examine the effect of intrathecal (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801), a noncompetitive NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (AP5), a competitive NMDA receptor antagonist, and N-G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on pain behaviors in a rat model of postoperative pain. Rats with intrathecal catheters were anesthetized and underwent a plantar incision. Withdrawal threshold to punctate stimulation applied adjacent to the wound, response frequency to application of a nonpunctate stimulus applied directly to the wound, and nonevoked pain behaviors were measured before and after intrathecal administration of MK-801 or AP5. The effect of intrathecal L-NAME on mechanical hyperalgesia was also examined. Mechanical hyperalgesia increased and was persistent after plantar incision and was not decreased by intrathecal administration of 4, 14, or 40 nmol MK-801 or 10 nmol AP5. Only the greatest dose of AP5, 30 nmol, caused a small decrease in punctate and nonpunctate hyperalgesia. Intrathecal L-NAME had no effect. Neither intrathecal MK-801 nor intrathecal AP5 affected nonevoked pain behaviors. The greatest doses caused motor deficits. Unlike intrathecal and systemic morphine, intrathecal NMDA receptor antagonists did not modify pain behaviors in this rat model of postoperative pain. These data suggest that NMDA receptors do not play an important role in the maintenance of postoperative pain behaviors and that NMDA receptor antagonists, administered spinally by themselves during the postoperative period, will not be useful for the treatment of postoperative pain in humans.

Effect of systemic and intrathecal morphine in a rat model of postoperative pain.

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. 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. 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 micrograms) 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 micrograms of IT morphine. Naloxone (1 mg/kg) reversed morphine-produced hypoalgesia. This is the first study to demonstrate that mechanical hyperalgesia to a nonpunctate stimulus occurs after a surgical incision in the rat. This rat model of postoperative has several similarities to postoperative patients: mechanical hyperalgesia to punctate and nonpunctate stimuli, nonevoked pain, and pain behaviors inhibited by SC and IT morphine. This model also may be useful for predicting analgesia by investigational agents for postoperative pain.