Postoperative Pain Model Research Articles

Sulfamoyl benzamides as novel CB2 cannabinoid receptor ligands

Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.

In vitro and in vivo characterization of A‐796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models

Selective cannabinoid CB2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB2 in vitro functional assays. Additionally, its analgesic effects are mu-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB2 agonist. A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB1, CB2 and mu-opioid receptor antagonists. A-796260 exhibited high affinity and agonist efficacy at human and rat CB2 receptors, and was selective for the CB2 vs CB1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB2, but not CB1 or mu-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity. These results further confirm the therapeutic potential of CB2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB2 receptor pharmacology and for evaluating its role in the modulation of pain.

Incision-induced Pain Behaviors in the DBA/2 Mouse

Background: Because genetic manipulation is commonly accomplished in mice, mouse models for pain haveadvanced our understanding of the mechanisms of persistent pain. The purpose of this experimental study isto develop a mouse model for understanding incision induced postoperative pain.Methods: A longitudinal incision was made at the hindpaw of male DBA/2 mice. The withdrawal frequency(WF) from applications of von Frey filaments and the response frequency (RF) to blunt mechanical stimulationwere examined in an incision group and a control grouP. The withdrawal latency (WL) to radiant heat and apain score based on weight bearing were also measured. Tests were performed 1 day before incision, and2 hours, 1-3 days, 5 days and 7 days after incision.Results: The WF for the strongest filament was 35.0 t 9.1% before incision and this increased to 100.0i: 0% at 2 hours and to 65.0 + 9.1% at 7 days after incision. The RF to the blunt stimulus was 4.1 d: 4.1%before incision and 100.0 + 0.0% at 2 hours and 42.8 + 10.8% at 7 days after incision. The WL was 6.6+ 0.5 sec before incision and 2.4 + 0.3 sec at 2 hours and 5.9 + 0.6 sec at 7 days after incision. Thepain score increased from 1.1 d: 0.8 to 7.4 d: 1.5 at 2 days after incision.Conclusions: A mouse model of acute postoperative pain was developing by making a surgical incision inthe mouse hindpaw. Mechanical hyperalgesia and allodynia lasting for several days demonstrate that this modelhas similarities to the human post-operative pain state. Future studies will allow us to further investigate thegenetic and molecular mechanisms of incisional pain. (Korean J Pain 2008; 21: 18-26)

Expression of Spinal c-fos in a Rat Model of Postoperative Pain

Background: The oncogene, c-fos, is a useful marker of nociceptive neurons activated by various types of pain. However, the relationship between c-fos and acute pain induced by surgical incision has not been studied. The purpose of this study was to describe the expression of spinal c-fos in a rat model of postoperative pain. Methods: Sprague-Dawley rats were used to enumerate spinal fos-like immunoreactive (fos-LI)-positive neurons after making sham, skin, or skin-muscle incisions on the plantar surface of the rat hindpaw. The spinal cords were divided into the following 4 segments for immunohistochemical detection of fos-LI at 3 time points after the incision (4 hours, POD1, and POD3): thoracic, upper lumbar, lower lumbar, and sacral. For analysis of the laminar distribution of fos-LI, the dorsal horn was divided into three regions (I−II, III−IV, and V−VI). Results: The number of fos-LI was increased in the ipsilateral spinal dorsal horn in the lower lumbar segment 4 hours post-incision and was significantly greater in rats with skin-muscle incisions than in rats with skin-alone incisions. In the skin-muscle group, laminae I− II and V−VI had a greater number of fos-LI neurons than laminae III−IV. The increase in number of spinal fos-LI neurons normalized by POD1 and POD3. Conclusions: c-fos expression is confined to neurons of the spinal dorsal horn known to be activated by nociceptive stimulation. The larger the injury elicited, the greater the expression of c-fos, suggesting that the expression of c-fos can serve as a useful marker of activated nociceptive neurons caused by acute pain following surgical incision. Further study is required to elucidate why the degree of tissue injury affects the laminar distribution of c-fos expression. (Korean J Anesthesiol 2008; 54: 328∼34)

Secondary Hyperalgesia in the Postoperative Pain Model Is Dependent on Spinal Calcium/Calmodulin-Dependent Protein Kinase IIα Activation

Spinally administered non-N-methyl-D-aspartate (NMDA), but not NMDA, receptor antagonists block primary (1 degree) and secondary (2 degrees) mechanical hyperalgesia and spontaneous pain after plantar incision. Hyperalgesia after thermal stimulation is also mediated by non-NMDA, but not NMDA, receptors. Although previous pain behavior studies in the thermal stimulus model demonstrated distinct protein kinase involvement downstream from spinal non-NMDA receptor activation, protein kinase signaling mechanisms have not been examined in the postoperative pain model. In the present study, we investigated whether spinal calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) mediates 1 degree and/or 2 degrees hyperalgesia and spontaneous pain behavior after plantar incision. Catheterized rats received a 1 cm incision in the hindpaw and were tested over 2 days for responses to mechanical stimulation adjacent to or 1 cm away from the incision site. Some rats received intrathecal (IT) pretreatment with a CaMKIIalpha inhibitor (14, 34, or 104 nmol KN-93) or vehicle (5% dimethyl sulfoxide in sterile saline). Separate groups received IT 34 nmol or 104 nmol KN-93 and were tested for hindpaw weight bearing. Lumbar spinal cords were extracted 1 h after incision or sham treatment to measure phosphorylated CaMKIIalpha and alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid GLUR1-831 in Western immunoblots. Incision increased spinal CaMKIIalpha and GLUR1-831 phosphorylation. Although pretreatment with all doses of IT KN-93 reduced the development of 2 degrees hyperalgesia, only 34 nmol KN-93 appeared to have an effect on 1 degrees hyperalgesia. IT KN-93 did not affect nonevoked pain. Spinal sensitization underlying incision-evoked hyperalgesia involves spinal CaMKIIalpha activation and enhanced spinal alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) function.

Analgesic activity of metabotropic glutamate receptor 1 antagonists on spontaneous post-operative pain in rats

Activation of metabotropic glutamate (mGlu) receptors has previously been shown to play a role in inflammatory or neuropathic pain states. However, the role of mGlu type 1 receptors in post-operative pain remains to be investigated. In the present study, effects of potent and selective mGlu1 receptor antagonists A-841720, A-794282, A-794278, and A-850002 were evaluated in a skin incision-induced post-operative pain model in rats. Post-operative pain was examined 2 h following surgery using weight-bearing difference between injured and uninjured paws as a measure of spontaneous pain. In this model, A-841720, A-794282, A-794278, and A-850002 induced significant attenuation of spontaneous post-operative pain behavior, with ED50s of 10, 50, 50, and 65 μmol/kg i.p., respectively. Depending on the compound, significant motor side effects were also observed at 3 to 10 fold higher doses. These results support the notion that mGlu1 receptor activation plays a significant role in nociceptive transmission in post-operative pain, though motor impairment may be a limiting factor in developing mGlu1 receptor antagonists as novel analgesics.

Spinal release of the amino acids with a time course in a rat model of postoperative pain

The mechanisms underlying postoperative pain remain unclear. Neurotransmitters of excitatory and inhibitory amino acids play an important role in the transmission and modulation of pain in the spinal dorsal horn. This study aimed to investigate the changes of release of excitatory and inhibitory amino acids in the spinal cord during postoperative pain and to provide a novel theoretical basis for postoperative pain management. Loop microdialysis catheters were implanted subarachnoidally via the atlanto-occipital membrane in 16 healthy Sprague-Dawley rats. All rats without neural deficits were divided into two groups, Group A and Group B, following 5 days of recovery. The tubes for microdialysis were connected and 25 microl microdialysate sample for baseline value was collected after one-hour washout in each rat. A plantar incision in the right hind paws of rats in Group A were performed under 1.2% isoflurane. All rats in Group B were only anesthetized by 1.2% isoflurane for the same duration. The microdialysate samples were collected at 3 hours, 1 day, 2 days and 3 days after the incision (or isoflurane anesthesia in Group B) in both groups. The cumulative pain scores were also assessed at the above time-points. The amino acids in the microdialysate samples were tested using high performance liquid chromatography. Within Group A, the release of aspartate and glutamate at 3 hours after the incision was significantly higher than the baseline values and the release of glycine at 1 day after the incision significantly increased compared with the baseline values (P < 0.01). Within Group B, the release of neurotransmitters at each time point had no significant difference compared with the baseline values (P > 0.05). The release of aspartate and glutamate at 3 hours after the incision in Group A was significantly higher than that in Group B (P < 0.01). The release of glycine at 1 day after the incision in Group A significantly increased compared with Group B (P < 0.01). The cumulative pain scores at 3 hours, 1 day and 2 days after the incision in Group A were significantly higher than those in Group B (P < 0.01). The release of the excitatory amino acids occurs in the early phase of postoperative pain and might not be involved in the maintenance of pain in a rat model of incision pain. The release of inhibitory glycine lagged behind the excitatory amino acids. The implication of inhibitory glycine release remained to be established further.

Adenosine A1but Not A2aReceptor Agonist Reduces Hyperalgesia Caused by a Surgical Incision in Rats

Activation of A1 adenosine receptors (A1Rs) causes antinociception after nerve injury and inflammation. However, the role of A2a adenosine receptors (A2aRs) for pain processing is less clear. In the current study, the authors investigated the role of spinal adenosine A1Rs and A2aRs for the maintenance of mechanical hyperalgesia in an animal model for postoperative pain. Rats with intrathecal catheters were anesthetized and underwent plantar incision. Spontaneous pain behavior and withdrawal threshold to punctuate stimulation were measured before and after administration of intrathecal R-phenylisopropyl-adenosine (R-PIA; A1R agonist), 2-w p-2-carbonyl-ethyl-phenylethylaminox-5X-N-ethylcarboxami-doadenosine (CGS21680; A2aR agonist), or vehicle. In separate groups of animals, the effects of pertussis toxin, forskolin, glibenclamide, 4-aminopyridine, tetraethylammonium, apamin, charybdotoxin, or margatoxin on R-PIA-induced antinociception were examined. Intrathecal administration of 5 nmol R-PIA but not 10 nmol CGS21680 decreased nonevoked spontaneous pain behavior. Furthermore, intrathecal administration of R-PIA but not of CGS21680 increased withdrawal thresholds after incision. Pretreatment with pertussis toxin and administration of forskolin, glibenclamide, 4-aminopyridine, and tetraethylammonium inhibited R-PIA-induced antinociception. In addition, intrathecal administration of apamin, charybdotoxin, or margatoxin did not modify mechanical hypoalgesia mediated by R-PIA. Spinal A1Rs but not A2aRs play an important role in the maintenance of nonevoked and evoked pain behaviors after an incision. Furthermore, A1R-induced spinal antinociception is mediated by interactions with pertussis toxin-sensitive G proteins. In addition, the opening of adenosine triphosphate-sensitive K channels but not of calcium-activated potassium channels and voltage-gated Kv1.3 or Kv1.6 channels contribute to the antinociceptive effect of A1R agonists.

A mechanistic model for the sex-specific response to nalbuphine and naloxone in postoperative pain

We develop a mechanistic model for post-operative pain and apply it to describe the pharmacodynamic effects of the kappa-opioids nalbuphine and naloxone administered either alone or in combination in patients after surgical removal of one or more madibular third molar teeth. Data were obtained from 6 clinical studies in which a total of 304 patients were intravenously administered single doses of 2.5, 5, 10 or 20 mg of nalbuphine. Some groups also received 0.2 or 0.4 mg of naloxone. A total of 3,040 Visual analog scale (VAS) pain ratings were recorded at 20 min intervals for 3 h after drug administration. We used a two-site indirect action model to describe early and late pain and to incorporate the effect of nalbuphine and naloxone on pain over time. A mixed effects statistical model was used to account for inter- and intra-individual variability. Our model estimated the population average baseline pain score in men to be lower than that in women (68 vs. 76 mm on the 100 mm VAS scale). The model confirmed a late increase in pain (anti-analgesia) and estimated the lag time for the start of anti-analgesia to be 73 min after study drug administration. The maximum early phase pain score is 81.6 mm while the maximum anti-analgesia is 16.1 mm. The nalbuphine dose required to reduce early pain by 50% (ED(50)) was estimated to be 5.85 mg and the naloxone dose required to reduce late phase pain by 50% was estimated to be 0.5 mg. The model confirmed the results from conventional statistical analyses performed previously on individual studies.

Epidural Tezampanel, an AMPA/Kainate Receptor Antagonist, Produces Postoperative Analgesia in Rats

We evaluated the epidural administration of tezampanel, a non-N-methyl-d-aspartate receptor antagonist, in a rat model for postoperative pain. We sought to determine if this drug affects nociception when administered epidurally by testing its effects on responses to heat in normal rats. The effects of epidural tezampanel on pain-related behaviors in rats that underwent plantar incision were also studied. Rats were anesthetized and epidural catheters were placed. One day after epidural catheterization, the baseline heat withdrawal latency was measured. Epidural tezampanel or morphine was tested for analgesia by examining their effects against heat withdrawal latency. Motor function was also tested. Comparisons to subcutaneous drug administration were made. Other rats underwent plantar incision after epidural catheterization to assess pain behavior caused by incision. The effects of epidural tezampanel on the cumulative pain scoring, based on guarding, the withdrawal threshold to von Frey filament application, and the withdrawal latency to heat, were measured. The effects of epidural tezampanel on arterial blood pressure and heart rate were also tested. Both epidural morphine and epidural tezampanel increased withdrawal latency to heat. Only subcutaneous morphine affected heat withdrawal latency. After plantar incision, epidural tezampanel decreased the median guarding pain score, increased the heat withdrawal latency and increased the mechanical withdrawal threshold indicating analgesic effects. Arterial blood pressure and heart rate did not change after epidural drug administration. These experiments demonstrate that epidural administration of tezampanel produces analgesia to heat, motor side effects in some rats, and reduces pain behaviors caused by incision. No systemic analgesia was apparent using the largest dose.

Effects of Topical Application of Clonidine Cream on Pain Behaviors and Spinal Fos Protein Expression in Rat Models of Neuropathic Pain, Postoperative Pain, and Inflammatory Pain

Clonidine can effectively reduce pain and/or hypersensitivity. However, the antihypersensitivity effects of clonidine topically applied in cream (CC) have not been investigated. The authors evaluated effects of topical application of CC on pain behaviors and spinal Fos-like immunoreactivity in rats with hypersensitivity. Clonidine (30, 100, and 300 microg/g) was prepared in a cream base. In rat models of neuropathic pain, inflammatory pain, and postoperative pain, the authors evaluated effects of CC (0.1 g), topically applied onto the plantar surface of the injured or uninjured paw, on thermal hyperalgesia and mechanical allodynia to von Frey filaments. The authors also evaluated effects of CC on lumbar spinal Fos-like immunoreactivity. In neuropathic rats, CC applied onto the injured paw reduced thermal hyperalgesia and mechanical allodynia dose dependently, whereas CC applied onto the uninjured paw had no effect. The antihypersensitivity effects of CC were antagonized by intraperitoneal yohimbine (10 mg/kg). Further, CC reduced Fos-like immunoreactivity in neuropathic rats. In contrast, CC in a single dose had no effects on hyperalgesia, allodynia, or Fos-like immunoreactivity in rats with inflammatory or postoperative pain. In rats with postoperative pain, CC repeatedly applied for 6 days reduced thermal hyperalgesia, but not mechanical allodynia, in the postoperative days, whereas it had no effects on hyperalgesia or allodynia in those with inflammatory pain. Topical CC in concentrations examined significantly reduced hypersensitivity and lumbar spinal Fos-like immunoreactivity in rats with neuropathic pain, probably through activation of peripherally located alpha2 adrenoceptors. However, CC was only partially effective and totally ineffective in rats with postoperative pain and inflammatory pain, respectively.

Effect of fentanyl on glutamate release from nucleus accumbens to a rat model of postoperative pain

Effect of fentanyl on glutamate release from nucleus accumbens to a rat model of postoperative pain

Comparison of pre- versus post-incision administration of intraplantar indomethacin and MK886 in a rat model of postoperative pain

The amplification of pain long after the initial stimulus may be avoided if the treatment of pain is introduced before its initiation. However, conflicting evidence exists about the efficacy of such preemptive analgesia for the management of postoperative pain. This study compares the efficacy of intraplantar administration of indomethacin (a non-selective inhibitor of cyclooxygenase) and MK886 (an inhibitor of 5-lipoxygenase-activating protein), separately or in combination to produce preemptive analgesia in a model of surgical incisional pain in male Wistar rats. All incised rats (5 to 6 rats per group) had allodynia at 2, 6, and 24 h after surgery as evaluated using von Frey filaments. MK886, but not indomethacin (50 to 200 microg/paw), reduced the allodynia when injected either 1 h before or 1 h after surgery. The effect of preoperative MK886 (160 microg/paw) against incisional allodynia had a magnitude apparently similar to that produced by postoperative MK886. Pre-, but not postoperative MK886 (80 microg/paw) reduced the allodynia but the effect was seen only at 6 h after surgery. In contrast, MK886 (40 microg/paw) intensified the allodynia observed 2 h after the incision either injected before or after surgery. MK886 or indomethacin alone did not provide preemptive analgesia in the model of incisional pain. In contrast, the combination of MK886 with indomethacin reduced the allodynia more effectively when used before than after surgery, thus fulfilling the criteria for preemptive analgesia. In conclusion, preoperative inhibition of the local generation of both prostaglandins and leukotrienes by surgical incision may be an alternative to provide preemptive analgesia.

Characterization of a model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR)

Various surgical procedures, e.g. thoracotomy and inguinal hernia repair, frequently evoke persistent pain lasting for many months following the initial surgery. The essential prolonged tissue retraction required during such surgeries may account for the persistence and high incidence of postoperative pain in these patient populations. This study describes a new rat model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR), akin to a clinical procedure. Under anaesthesia, skin and superficial muscle of the medial thigh were incised and a small pair of retractors inserted. This tissue was retracted for 1h causing potential stretch of the saphenous nerve. SMIR surgery evoked persistent significant mechanical hypersensitivity to von Frey stimulation of the plantar ipsilateral hindpaw, compared to either pre-surgery responses or concurrent responses of sham-operated rats. SMIR-evoked mechanical hypersensitivity was observed by postoperative day 3, most prominent between postoperative days 10 and 13, persisted until at least postoperative day 22 and had dissipated by postoperative day 32. Overall, mechanical sensitivity of the SMIR contralateral paw and the sham ipsilateral paw did not significantly change from pre-surgery responses. SMIR did not evoke significant heat hyperalgesia or cold allodynia. Light microscopy of saphenous nerve sections did not show degeneration or oedema in the saphenous nerve at, or proximally or distally to, the surgical site. In addition, very little to no degeneration was detected with ATF3 staining in DRG from SMIR-operated rats. These data suggest that prolonged retraction of superficial tissue evokes a persistent pain syndrome that is not driven by neuronal damage.

The time course of inflammatory cytokine secretion in a rat model of postoperative pain does not coincide with the onset of mechanical hyperalgesia

We characterized the time course of inflammatory cytokine release at the site of injury and in plasma after surgery on the rat tail. Anesthetized Sprague-Dawley rats had a 20 mm long incision made through the skin and fascia of their tails. Control rats were anesthetized, but no incision was made. Blood and tissue samples were taken 2 h and 1, 2, 4, and 8 days after surgery and analysed by ELISA for interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and cytokine-induced neutrophil chemoattractant-1 (CINC-1). In another group of rats, daily behavioral measurements were made of the rats' responses to a blunt noxious mechanical stimulus (4 Newtons) applied to their tails. Primary hyperalgesia developed within 2 h of surgery and lasted for 6 days. The tissue concentrations of IL-1beta, IL-6, and CINC-1 increased within 24 h of surgery, and TNF-alpha concentration increased within 48 h of surgery. Thereafter, cytokine concentrations remained elevated for 4 (IL-1beta and IL-6) to 8 days (CINC-1, TNF-alpha) after surgery. Control animals did not develop hyperalgesia and no changes in cytokines concentrations were detected. Thus, in our model of postoperative pain, secretion of inflammatory cytokines IL-1beta, IL-6, TNF-alpha, and CINC-1 was not essential for the initiation of postoperative hyperalgesia.

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

접수일:2007년 9월 13일, 승인일:2007년 11월 5일 책임저자:윤명하, (501-757) 광주광역시 동구 학동 8번지 전남대학교병원 마취통증의학과 Tel: 062-220-6893, Fax: 062-232-6294 E-mail: mhyoon@jnu.ac.kr 이 논문은 2005년 정부(교육인적자원부)의 재원으로 한국학술진흥재단의 지원을 받아 수행된 연구임(KRF-2005-202-E00121). Received September 13, 2007, Accepted November 5, 2007 Correspondence to: Myung Ha Yoon Department of Anesthesiology and Pain Medicine, Choannm Natioal University Medical School, 8, Hak-dong, Dong-gu, Gwangju 501-757, Korea Tel: +82-62-220-6893, Fax: +82-62-232-6294 E-mail: mhyoon@jnu.ac.kr This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2005-202-E00121). 백서를 이용한 수술 후 통증 유발 모형에서 척수강 내로 투여한 Ginsenosides의 효과

Antihyperalgesic Effects of Ethosuximide and Mibefradil, T-type Voltage Activated Calcium Channel Blockers, in a Rat Model of Postoperative Pain

Background: A correlation between a T-type voltage activated calcium channel (VACC) and pain mechanism has not yet been established. The purpose of this study is to find out the effect of ethosuximide and mibefradil, representative selective T-type VACC blockers on postoperative pain using an incisional pain model of rats. Methods: After performing a plantar incision, rats were stabilized on pl astic mesh for 2 hours. Then, the rats were injected with ethosuximide or mibefradil, intraperitoneally and intrathecally. The level of withdrawal threshold to the von Frey filament near the incision site was determined and the dose response curves were obtained. Results: After an intraperitoneal ethosuximide or mibefradil injection, the dose-response curve showed a dose-dependent increase of the threshold in a withdrawal reaction. After an intrathecal injection of ethosuximide, the threshold of a withdrawal reaction to mechanical stimulation increased and the increase was dose-dependent. After an intrathecal injection of mibefradil, no change occurre d in either the threshold of a withdrawal reaction to mechanical stimulation or a dose-response curve. Conclusions: The T-type VACC blockers in a rat model of postoperative pain showed the antihyperalgesic effect. This effect might be due to blockade of T-type VACC, which was distributed in the peripheral nociceptors or at the supraspinal level. Further studies of the effect of T-type VACC on a pain transmission mechanism at the spinal cord level would be needed. (Korean J Pain 2007; 20: 92�� 99)

The Effects of Intrathecal Adenosine A1 Receptor Agonists (R-PIA) on the Morphine Tolerance in a Rat Model of Postoperative Pain

Analgesic tolerance to opioids has been described in both experimental and clinical conditions, which may limit their clinical utility. This study investigated the effects of intrathecal adenosine A1 receptor agonist (R-PIA) on spinal morphine tolerance. Methods: SD rats were given intrathecal injections of saline 10μl, R-PIA 10μg, morphine 10μg, or R-PIA plus morphine combinations for 7 days (R-PIA given for days 1-7; days 1-3; or days 5-7). Antiallodynic testing using von Frey filaments was carried out before and 30 minutes after the drug injection. On day 8, an antiallodynic dose-response curve was constructed and the 50% effective dose (ED50) for morphine (given alone) was calculated for each study group. Results: The coinjection group of R-PIA with morphine blocked the development of tolerance, as shown by the preservation of morphine antiallodynia over 7 days the concomitant decrease in the ED50 values on day 8, compared with the morphine-alone group. Although additive analgesia over days 1-7 cannot be ruled out, the reductions of the ED50 in the R-PIA and morphine combination group suggest some suppression of tolerance. Conclusions: These results suggest that intrathecal R-PIA prevents the development of spinal opioid tolerance. Future studies will be needed to examine the respective roles of supraspinal and peripheral sites of R-PIA and morphine interaction, and to investigate the mechanisms underlying the action of R-PIA on opioid tolerance.

A Pain Model After Gynecologic Surgery: The Effect of Intrathecal and Systemic Morphine

Despite recent recognition that visceral pain differs from somatic pain in its neurophysiologic basis and treatment modalities, most laboratory studies of postoperative pain use a model of superficial somatic injury, and there is no model of postoperative pain after gynecologic surgery. We describe spontaneous behavior in rats after laparotomy with or without noxious stimulation of the uterus and cervix to more specially address pain after gynecologic surgery. Female Sprague-Dawley rats received inhaled anesthesia only, anesthesia with laparotomy, or laparotomy plus 60 min of tonic distension of the lower uterine segment and cervix, followed by video observation of spontaneous behavior. Compared with anesthesia alone, laparotomy decreased some spontaneous behaviors (drinking water, grooming, and exploration). Laparotomy plus uterocervical manipulation further decreased these behaviors and increased abnormal behaviors (licking of the lower abdomen and squashing posture of the pelvis to the floor). Intrathecal and systemic morphine restored spontaneous behavior and reduced abnormal behaviors, with minor differences between routes of administration. These data suggest that specific behaviors may distinctly reflect somatic and visceral components of postoperative gynecologic pain, and that this model may be used to test novel therapies to relieve pain in this setting.

The Effect of the AMPA/Kainate Receptor Antagonist LY293558 in a Rat Model of Postoperative Pain

Non–N-methyl-D-aspartate (non-NMDA) glutamate receptor antagonists modify multiple pain transmission pathways and are of particular interest in analgesic development because of their capacity to interfere with evoked pain. Evoked pain is a problem for postoperative patients and is characteristic of the plantar incision model for postoperative pain. The purpose of this study was to assess the efficacy of a non-NMDA receptor antagonist LY293558 on mechanical hyperalgesia after plantar incision in the rat. Parenteral, intrathecal, or intraplantar administration of LY293558 was tested against the mechanical hyperalgesia that characterizes the model. Sprague-Dawley rats were assigned to 1 of 3 groups. LY293558 or vehicle was administered intraperitoneally, intrathecally, or intraplantarly. The hind paw withdrawal threshold to punctate stimulation by using von Frey filaments and response frequency to a nonpunctate stimulus directly to the wound were measured. Motor tests after administration of LY293558 were also examined in rats that did not undergo incision. The greatest dose of parenterally administered LY293558 (34 μmol/kg) decreased the responses to mechanical stimuli after plantar incision. Rotorod performance was decreased at these same times. Intrathecal injection of LY293558 (0.5 and 2.0 nmol) produced inhibition of mechanical sensitivity and produced lower extremity motor side effects. Repeated intrathecal administration produced sustained anesthesia for 24 hours but had no analgesic effect the next day. Local administration did not decrease response after incision. LY293558 was most effective for evoked pain when administered intrathecally. Perspective Control of evoked pain after surgery is inadequate but is linked to perioperative outcome. These data suggest that non-NMDA receptor antagonists like LY293558 will be most effective for evoked pain in postoperative patients if administered spinally.