Dehydrocorydaline alleviates sleep deprivation-induced persistent postoperative pain in adolescent mice through inhibiting microglial P2Y12 receptor expression in the spinal cord.

During adolescence, a second period of central nervous system (CNS) plasticity that follows the fetal period, which involves sleep deprivation (SD), becomes apparent. SD during adolescence may result in abnormal development of neural circuits, causing imbalance in neuronal excitation and inhibition, which not only results in pain, but increases the chances of developing emotion disorders in adulthood, such as anxiety and depression. The quantity of surgeries during adolescence is also consistently on the rise, yet the impact and underlying mechanism of preoperative SD on postoperative pain remain unexplored. This study demonstrates that preoperative SD induces upregulation of the P2Y12 receptor, which is exclusively expressed on spinal microglia, and phosphorylation of its downstream signaling pathway p38Mitogen-activated protein/Nuclear transcription factor-κB (p38MAPK/NF-κB)in spinal microglia, thereby promoting microglia activation and microglial transformation into the proinflammatory M1 phenotype, resulting in increased expression of proinflammatory cytokines that exacerbate persisting postoperative incisional pain in adolescent mice. Both intrathecal minocycline (a microglia activation inhibitor) and MRS2395 (a P2Y12 receptor blocker) effectively suppressed microglial activation and proinflammatory cytokine expression. Interestingly, supplementation with dehydrocorydaline (DHC), an extract of Rhizoma Corydalis, inhibited the P2Y12/p38MAPK/NF-κB signaling pathway, microglia activation, and expression of pro-inflammatory cytokines in the model mice. Taken together, the results indicate that the P2Y12 receptor and microglial activation are important factors in persistent postoperative pain caused by preoperative SD in adolescent mice and that DHC has analgesic effects by acting on these targets.

Sciatic nerve block downregulates the BDNF pathway to alleviate the neonatal incision-induced exaggeration of incisional pain via decreasing microglial activation.

Sciatic nerve block is under investigation as a possible therapeutic strategy for neonatal injury-induced exaggeration of pain responses to reinjury. Spinal microglial priming, brain-derived neurotrophic factor (BDNF) and Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) participate in exaggerated incisional pain induced by neonatal incision. However, effects of sciatic nerve block on exacerbated incisional pain and underlying mechanisms remain unclear. Here, we demonstrated that sciatic nerve block alleviates pain hypersensitivity and microglial activation in rats subjected to neonatal incision and adult incision (nIN-IN). Chemogenetic activation or inhibition of spinal microglia attenuates or mimics effects of sciatic nerve block on pain hypersensitivity, respectively. Moreover, α-amino-3-hydroxy- 5-methy- 4-isoxazole propionate (AMPA) receptor subunit GluA1 contributes to the exaggeration of incisional pain. The inhibition of BDNF or SHP2 blocks upregulations of downstream molecules in nIN-IN rats. Knockdown of SHP2 attenuates the increase of GluA1 induced by injection of BDNF in adult rats with only neonatal incision. The inhibition of microglia or ablation of microglial BDNF attenuates upregulations of SHP2 and GluA1. Additionally, sciatic nerve block downregulates the expression of these three molecules. Upregulation of BDNF, SHP2 or AMPA receptor attenuates sciatic nerve block-induced reductions of downstream molecules and pain hypersensitivity. Microglial activation abrogates reductions of these three molecules induced by sciatic nerve block. These results suggest that decreased activation of spinal microglia contributes to beneficial effects of sciatic nerve block on the neonatal incision-induced exaggeration of incisional pain via downregulating BDNF/SHP2/GluA1-containing AMPA receptor signaling. Thus, sciatic nerve block may be a promising therapy.

Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain.

To develop non-opioid therapies for postoperative incisional pain, we must understand its underlying molecular mechanisms. In this study, we assessed global gene expression changes in dorsal root ganglia neurons in a model of incisional pain to identify pertinent molecular pathways. Male, Sprague-Dawley rats underwent infiltration of 1% capsaicin or vehicle into the plantar hind paw (n = 6-9/group) 30 min before plantar incision. Twenty-four hours after incision or sham (control) surgery, lumbar L4-L6 dorsal root ganglias were collected from rats pretreated with vehicle or capsaicin. RNA was isolated and sequenced by next generation sequencing. The genes were then annotated to functional networks using a knowledge-based database, Ingenuity Pathway Analysis. In rats pretreated with vehicle, plantar incision caused robust hyperalgesia, up-regulated 36 genes and downregulated 90 genes in dorsal root ganglias one day after plantar incision. Capsaicin pretreatment attenuated pain behaviors, caused localized denervation of the dermis and epidermis, and prevented the incision-induced changes in 99 of 126 genes. The pathway analyses showed altered gene networks related to increased pro-inflammatory and decreased anti-inflammatory responses in dorsal root ganglias. Insulin-like growth factor signaling was identified as one of the major gene networks involved in the development of incisional pain. Expression of insulin-like growth factor -2 and IGFBP6 in dorsal root ganglia were independently validated with quantitative real-time polymerase chain reaction. We discovered a distinct subset of dorsal root ganglia genes and three key signaling pathways that are altered 24 h after plantar incision but are unchanged when incision was made after capsaicin infiltration in the skin. Further exploration of molecular mechanisms of incisional pain may yield novel therapeutic targets.

Evaluation of a Postoperative Pain-Like State on Motivated Behavior in Rats: Effects of Plantar Incision on Progressive-Ratio Food-Maintained Responding.

There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional postoperative pain manipulation on food-maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hr, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior.

[Postoperative pain therapy in Germany. Status quo]. / Therapie postoperativer Schmerzen in Deutschland. Aktueller Stand.

A great deal of progress has been made in the field of postoperative pain therapy in the last 20 years. Beginning from clinical trials on the effectiveness of individual procedures, such as epidural anesthesia and patient-controlled analgesia, a wide range of healthcare services research as well as basic research with human and animal experiments has been established. Whereas health services research in the 1980s and 1990s focused more on the implementation of acute pain services, outcome-oriented research approaches are nowadays the center of attention. Acute pain registries and pain certification projects initiated in Germany have to be mentioned particularly in this respect. Basic research papers from recent years increasingly address specific aspects of acute postoperative pain and have provided translational approaches that are applied around the world for studying neurobiological mechanisms of postoperative pain. At the same time, interdisciplinary cooperation in research projects has led to a better understanding of complex correlations regarding predictors and mechanisms (including psychosocial aspects) of acute and in recent times also chronic pain after surgery. In parallel, evidence-based medicine has found its way into acute pain medicine in Germany. In 2007, clinical acute pain therapy in Germany was enhanced by S3 level guidelines for the first time; however, the implementation is still incomplete. In future, questions concerning mechanism-based therapy of acute pain need to be equally in the center of attention of research, such as prevention of persisting pain after surgery and acute pain of different origins.

Cold Therapy for Pain Control in Pediatric Appendectomy Patients: A Randomized Controlled Trial.

PURPOSE: Topical ice has been shown to reduce pain scores and opioid use in adults with midline abdominal incisions. This study was designed to evaluate the efficacy of a cold therapy system in children following laparoscopic appendectomy. METHODS: Patients 7 years and older who underwent laparoscopic appendectomy at our institution from December 2021-September 2022 were eligible. Patients were randomized to standard pain therapy (control) or standard plus cold therapy (treatment) utilizing a modified ice machine system with cool abdominal pad postoperatively. Pain scores on the first 3 postoperative days (PODs), postoperative narcotic consumption, and patient satisfaction were analyzed. RESULTS: Fifty-eight patients were randomized, 29 to each group. Average survey response rate was 74% in control and 89% in treatment patients. There was no significant difference in median pain scores or narcotic use between groups. Cold therapy contributed to subjective pain improvement in 71%, 74%, and 50% of respondents on PODs 1, 2, and 3 respectively. CONCLUSION: A majority of patients reported cold therapy to be a helpful adjunct in pain control after appendectomy, though it did not reduce postoperative pain scores or narcotic use in our cohort - likely due to this population's naturally expedient recovery and low baseline narcotic requirement. TYPE OF STUDY: Randomized Controlled Trial. LEVEL OF EVIDENCE: Level I.

Additive antinociceptive action of intrathecal anandamide reuptake inhibitor and morphine in the management of post-incisional pain in rats.

Spinal opioids have mixed efficacy and their adverse effects force treatment cessation of postoperative pain. Consequently, there is an ongoing search for new therapeutic strategies. Here, we evaluated the analgesic efficacy of intrathecal UCM707, an anandamide reuptake inhibitor, and morphine combination. Firstly, we assessed the effects of morphine (1, 5 and 10 µg), UCM707 (75 µg) and its combination in the hot plate. Then, morphine + UCM707 at sub-effective doses was evaluated in a rat post-incisional pain model. In addition, µ-, CB1r-, CB2r- and TRPV1-antagonists were pre-administered before the combination. Activation of µ-opioid and CB1r, and Cnr1, Cnr2, Oprm1 and TRPV1 expressions were evaluated in the lumbar sacra and periaqueductal grey by [35 S]-GTPγS binding autoradiography and qPCR studies. In the hot plate, morphine (1 µg) and UCM707 (75 µg) induced a more robust analgesic effect than each drug alone. Morphine plus UCM707 did not modify µ-opioid nor CB1 receptor function in the PAG or LS. Cnr1 and TRPV1 expression increased in the lumbar sacra (LS). Morphine plus UCM707 significantly reduced post-incisional pain at 1 and 4 days after surgery. Cnr1, Cnr2 and TRPV1 expressions increased in the LS. Blockade of µ-opioid receptor reduced combination effects on days 1 and 4. CB1r- and CB2r-antagonism reduced morphine + UCM707 effects on days 1 and 4, respectively. CB1r and TRPV1-antagonism improved their antinociceptive effects on day 4. These results revealed a synergistic/additive analgesic effect of UCM707 and morphine combination controlling postincisional pain. CB1r, CB2r and TRPV1 contribute differently as central sensitization occurs.

A prospective evaluation of the risk factors for development of wound dehiscence and incisional hernia.

OBJECTIVE: Post-laparotomy wound dehiscence, evantration and evisceration are important complications leading to an increase in both morbidity and mortality. Incisional hernias are frequently observed following abdominal surgeries and their occurrence is related to various local and systemic factors. This study aims to analyze the factors affecting wound healing by investigating the parameters that may cause wound dehiscence, incisional hernia, sinus formation and chronic incisional pain. MATERIAL AND METHODS: The records of 265 patients who underwent major abdominal surgery were analyzed. The data on patient characteristics, medication, surgical procedure type, type of suture and surgical instruments used and complications were recorded. The patients were followed up with respect to sinus formation, incisional hernia occurrence and presence of chronic incision pain. Statistical analysis was performed using SPSS 10.00 program. The groups were compared via chi-square tests. Significance was determined as p<0.05. Multi-variate analysis was done by forward logistic regression analysis. RESULTS: 115 (43.4%) patients were female and 150 (56.6%) were male. Ninety-four (35.5%) patients were under 50 years old and 171 (64.5%) were older than 50 years. The median follow-up period was 28 months (0-48). Factors affecting wound dehiscence were found to be; creation of an ostomy (p=0.002), postoperative pulmonary problems (p=0.001) and wound infection (p=0.001). Factors leading to incisional hernia were; incision type (p=0.002), formation of an ostomy (p=0.002), postoperative bowel obstruction (p=0.027), postoperative pulmonary problems (p=0.017) and wound infection (p=0.011). CONCLUSION: Awareness of the factors causing wound dehiscence and incisional hernia in abdominal surgery, means of intervention to the risk factors and taking relevant measures may prevent complications. Surgical complications that occur in the postoperative period are especially related to wound healing problems.

Pre-incisional Preventive Precise Multimodal Analgesia May Enhance the Rehabilitation Process of Acute Postoperative Pain Following Total Laparoscopic Hysterectomy: A Randomized Controlled Trial.

BACKGROUND: There has been limited research regarding the effect of preventive precise multimodal analgesia (PPMA) on the duration of acute postoperative pain after total laparoscopic hysterectomy (TLH). This randomized controlled trial aimed to evaluate how PPMA affects pain rehabilitation. OBJECTIVES: Our primary objective was to reduce the duration of acute postoperative pain after TLH, including incisional and visceral pain. STUDY DESIGN: A double blind randomized controlled clinical trial. SETTING: Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China. METHODS: Seventy patients undergoing TLH were randomized to Group PPMA or Group Control (Group C) in a 1:1 ratio. Patients in Group PPMA were given PPMA through the pre-incisional administration of parecoxib sodium 40 mg (parecoxib is not approved for use in the US) and oxycodone 0.1 mg/kg as well as local anesthetic infiltration at the incision sites. In Group C, similar doses of parecoxib sodium and oxycodone were injected during uterine removal, and a local anesthetic infiltration procedure was performed immediately before skin closure. The index of consciousness 2 was utilized to titrate the remifentanil dosage in all patients to ensure sufficient analgesia. RESULTS: Compared with the Control, PPMA shortened the durations of incisional and visceral pain at rest (median, interquartile range [IQR]: 0, 0.0- 2.5) vs 2.0, 0.0-48.0 hours, P = 0.045; 24.0, 6.0-24.0 vs 48.0, 24.0-48.0 hours, P < 0.001; and during coughing 1.0, 0.0-3.0 vs 24.0, 0.3-48.0 hours, P = 0.001; 24.0, 24.0-48.0] vs 48.0, 48.0-72.0] hours, P < 0.001). The Visual Analog Scale (VAS) scores for incisional pain within 24 hours and visceral pain within 48 hours in Group PPMA were lower than those in Group C (P < 0.05). PPMA evidently decreased the VAS scores for incisional pain during coughing at 48 hours (P < 0.05). Pre-incisional PPMA significantly reduced postoperative opioid consumption (median, IQR: 3.0 [0.0-3.0] vs 3.0 [0.8-6.0] mg, P = 0.041) and the incidence of postoperative nausea and vomiting (25.0% vs 50.0%, P = 0.039). Postoperative recovery and hospital stay were similar between the 2 groups. LIMITATIONS: This research had some limitations, including that it was a single-center research with a limited sample size. Our study cohort did not represent the overall patient population in the People's Republic of China; therefore, the external validity of our findings remains limited. Furthermore, the prevalence of chronic pain was not tracked. CONCLUSION: Pre-incisional PPMA may enhance the rehabilitation process of acute postoperative pain after TLH.

The anti-nociceptive effect of BPC-157 on the incisional pain model in rats.

Background: The pentadecapeptide BPC-157 has been shown to have anti-inflammatory and wound healing effects on multiple target tissues and organs. Peptides have potent anti-inflammatory effects on periodontal tissues in rats with periodontitis. Few studies have investigated the effect of BPC-157 on pain after dental procedures or oral surgeries. The purpose of the present study was to investigate the antinociceptive effects of BPC-157 on postoperative incisional pain in rats. Methods: Sprague-Dawley rats were randomly divided into five groups: control (saline with the same volume), BPC10 (10 µg/kg of BPC-157), BPC20 (20 µg/kg of BPC-157), BPC40 (40 µg/kg of BPC-157), and morphine (5 mg/kg of morphine). A 1-cm longitudinal incision was made through the skin, fascia, and muscle of the plantar aspect of the hind paw in isoflurane-anesthetised rats. Withdrawal responses were measured using von Frey filaments at 0, 2, 6 h and 4, 7 d after incision. The formalin test was also performed to differentiate its anti-nociceptive effect from an inflammatory reaction or central sensitization. Pain behavior was quantified periodically in phases 1 and 2 by counting the number of flinches in the ipsilateral paw after injection with 30 µL of 5% formalin. Results: The threshold of mechanical allodynia was significantly increased in the BPC10, BPC20, BPC40 and morphine groups compared with that in the control group at 2 h. These increasing thresholds then returned to the levels of the control group. The BPC-157 group showed a much higher threshold at 4 days after incision than the control group. The thresholds of the BPC groups, except the morphine group, were normalized 7 days after incision.The flinching numbers of the BPC10, BPC20, BPC40 and morphine groups were significantly decreased in phase 1, but there was no decrease in the BPC-157 groups except the morphine group in phase 2. Conclusions: BPC-157 was effective only for a short period after incision. It was also effective during phase 1 but not during phase 2, as determined by the formalin test. BPC-157 might have a short antinociceptive effect, even though it has anti-inflammatory and wound healing effects.

Intrathecal Co-administration of Morphine Facilitated the Anti-nociceptive of Bupivacaine in a Rat Model of Acute Postoperative Pain.

INTRODUCTION: Bupivacaine is one of the commonly used agents for spinal anaesthesia. Moreover, co-administration with morphine can likely increase its anti-nociceptive effect bringing about a reduction in the required dose of bupivacaine. Though this has been observed clinically, preclinical studies on the efficacy of this drug combination are lacking. METHODS: Sprague Dawley rats, previously implanted with intrathecal catheters, were administered either bupivacaine (30 mcg) or morphine (30 mcg) or both bupivacaine and morphine (15 mcg each). These doses were determined following prior evaluation of different doses of bupivacaine (3, 10 and 30 mcg). Rats were subjected to hind paw incision under isoflurane anaesthesia, 15 min after drug administration. Anti-nociception was evaluated by estimating mechanical allodynia in a fixed peri-incisional area using von Frey filaments. This was done 4 h after the incision. RESULTS: Both bupivacaine and morphine attenuated allodynia though morphine was more effective. Co-administration of both drugs at half the doses increased the antinociceptive effect of bupivacaine to the 30 mcg dose level. CONCLUSION: The underlying reason for this enhanced anti-nociception could be the different neural mechanisms responsible for anti-nociception. Local anaesthetics inhibit the generation of action potentials by blocking sodium channels whereas opioids like morphine act through G-protein coupled mu opioid receptor-linked closure of calcium channels in presynaptic terminals. In conclusion, the addition of morphine can facilitate bupivacaine's anti-nociceptive effect following intrathecal administration. This information could have clinical relevance in the treatment of postoperative pain.

Preoperative Acute Sleep Deprivation Causes Postoperative Pain Hypersensitivity and Abnormal Cerebral Function.

Preoperative sleep loss can amplify post-operative mechanical hyperalgesia. However, the underlying mechanisms are still largely unknown. In the current study, rats were randomly allocated to a control group and an acute sleep deprivation (ASD) group which experienced 6 h ASD before surgery. Then the variations in cerebral function and activity were investigated with multi-modal techniques, such as nuclear magnetic resonance, functional magnetic resonance imaging, c-Fos immunofluorescence, and electrophysiology. The results indicated that ASD induced hyperalgesia, and the metabolic kinetics were remarkably decreased in the striatum and midbrain. The functional connectivity (FC) between the nucleus accumbens (NAc, a subregion of the ventral striatum) and the ventrolateral periaqueductal gray (vLPAG) was significantly reduced, and the c-Fos expression in the NAc and the vLPAG was suppressed. Furthermore, the electrophysiological recordings demonstrated that both the neuronal activity in the NAc and the vLPAG, and the coherence of the NAc-vLPAG were suppressed in both resting and task states. This study showed that neuronal activity in the NAc and the vLPAG were weakened and the FC between the NAc and the vLPAG was also suppressed in rats with ASD-induced hyperalgesia. This study highlights the importance of preoperative sleep management for surgical patients.

Objective and Quantitative Evaluation of Spontaneous Pain-Like Behaviors Using Dynamic Weight-Bearing System in Mouse Models of Postsurgical Pain.

Background: The paucity of objective and reliable measurements of pain-like behaviors has impeded the translatability of mouse models of postsurgical pain. The advanced dynamic weight-bearing (DWB) system enables evaluation of spontaneous pain-like behaviors in pain models. This study investigated the suitability and efficiency of the DWB system for assessing spontaneous pain-like behaviors and analgesic therapies in murine models of postsurgical pain. Methods: Male adult C57BL/6JJcl mice were subjected to multiple surgical pain models with distinct levels of invasiveness, including a superficial incisional pain model involving only hind paw skin incision, deep incisional pain model that also involved incision and elevation of the underlying hind paw muscles, and orthopedic pain model involving tibial bone fracture and fixation with a pin (fracture and pinning [F/P] model). Spontaneous pain-like behaviors post-surgery were evaluated using weight distribution, pawprint area of the operated paw in the DWB system, and guarding pain score. Mechanical hypersensitivity was assessed using the von Frey test. The therapeutic effects of analgesics (diclofenac and buprenorphine for the deep incision model and diclofenac for the F/P model) were evaluated using the DWB system and von Frey test. Results: The von Frey test demonstrated contradictory results between superficial and deep incisional pain models. The DWB system captured weight distribution changes in the operated hind paw, in accordance with the invasiveness and time course of wound healing in these surgical pain models. The reduction in weight-bearing on the operated paw correlated with guarding score, degree of paw swelling, and local expression of inflammatory mediators. DWB enabled accurate evaluation of the pharmacological effects of analgesics for detecting attenuation of surgery-induced weight-bearing changes in these models. Conclusion: The DWB system serves as an objective and reliable method for quantifying pain-like behaviors and evaluating the therapeutic effects of analgesics in mouse models of postsurgical pain models.

Microglial activation in the trigeminal spinal subnucleus interpolaris/caudalis modulates orofacial incisional mechanical pain hypersensitivity associated with orofacial injury in infancy.

PURPOSE: Infantile tissue injury induces sensory deficits in adulthood. Infantile facial incision (IFI) was reported to cause an enhancement of incision-induced mechanical hypersensitivity in adulthood due to acceleration of the trigeminal ganglion neuronal excitability. However, the effects of IFI on activation of microglia in the spinal trigeminal nucleus and its involvement in facial pain sensitivity is not well known. METHODS: A facial skin incision was made in the left whisker pad in infant (IFI) and/or adult rats (AFI). Mechanical head withdrawal threshold and microglial activation in the trigeminal spinal nucleus were analyzed. RESULTS: Mechanical pain hypersensitivity induced by AFI was significantly exacerbated and prolonged by IFI. The number of Iba1-immunoreactive cells in the trigeminal spinal nucleus following AFI was increased by IFI, suggesting that IFI facilitates microglial hyperactivation following AFI. Intraperitoneal administration of minocycline, a microglial activation inhibitor, suppressed the facial incision-induced microglial hyperactivation in the trigeminal spinal nucleus and the exacerbation of the facial mechanical pain hypersensitivity induced by IFI. CONCLUSION: These results suggest that facial trauma in infants causes hyperactivation of microglia in the trigeminal spinal nucleus following AFI, leading to the prolongation of the facial mechanical pain hypersensitivity.

Antinociceptive Effect of the Citrus Flavonoid Eriocitrinon Postoperative Pain Conditions.

BACKGROUND: Postoperative pain remains a major clinical problem as there are limited analgesic strategies that have been proven to be effective in preventing and relieving this type of pain. Natural products, including flavonoids, have distinct pharmacological properties and play an important role in the discovery of analgesic drugs. MATERIALS AND METHODS: In this study, the flavonoid eriocitrin (eriodictyol 7-O-rutinoside), which is the main flavonoid in lemon fruit (Citrus limon), was mechanistically investigated for its prospective antinociceptive effect in a mouse model of postoperative pain. The antinociceptive property was evaluated by utilizing both tonic (acetic acid-induced writhing behavior) and phasic (hot-plate) nociception modalities. The hindpaw incisional surgery was performed and hyperalgesia was assessed using von Frey filaments. RESULTS: The tested doses of eriocitrin significantly attenuated (P<0.01, P<0.001) the chemically-induced tonic visceral nociception (5, 10, 15, and 30 mg/kg) and acute phasic thermal nociception (10, 15, and 30 mg/kg). A significant dose-dependent reduction in the incisional nociceptive hyperalgesia was exhibited by eriocitrin, with a marked antinociception observed at doses of 15 mg/kg (P<0.05 during 30-60 minutes) and 30 mg/kg (P<0.05, P<0.01 during 30-120 minutes). CONCLUSION: The antinociceptive effect of eriocitrin (30 mg/kg) was strongly blocked by the antagonists of the opioid receptor, naltrexone, and GABAA receptor, bicuculline, thereby suggesting the involvement of opioidergic and GABAergic mechanisms in the nociception, reducing proclivity of eriocitrin during transmission of incisional nociception. These results concluded that eriocitrin has a potent antinociceptive effect in postoperative pain conditions, probably mediated through opioid and GABAA receptors.

Spinal N-Cadherin/CREB Signaling Contributes to Chronic Alcohol Consumption-Enhanced Postsurgical Pain.

BACKGROUND: It has been reported that N-cadherin and cAMP response element binding protein (CREB) in the spinal cord are critical for synaptogenesis and regulation of excitatory synapse function, which could underlie chronic pain development. The aim of the present study was to investigate the role of spinal N-cadherin/CREB signaling in postsurgical pain chronicity following chronic alcohol consumption. METHODS: C57BL/6 male mice were randomly assigned into different groups. Plantar incision was used to induce postsurgical pain. Chronic alcohol consumption was conducted by giving mice unlimited access to different concentrations of ethanol for five weeks. We measured paw withdrawal thresholds to test postsurgical pain. Using Western blotting, we examined the expression of N-Cadherin and CREB in the spinal dorsal horn. We further performed intrathecal injection of specific N-cadherin and CREB inhibitors to assess the role of spinal N-cadherin/CREB signaling in chronic alcohol consumption-enhanced postsurgical pain. RESULTS: We observed that the chronic alcohol consumption significantly prolonged postsurgical pain and enhanced plantar incision-increased N-cadherin expression and CREB phosphorylation at the Ser133 in the spinal cord. Intrathecal injection of specific N-cadherin and CREB inhibitors attenuated chronic alcohol consumption-prolonged postsurgical pain. CONCLUSION: Our results suggest that spinal N-cadherin/CREB signaling is involved in chronic alcohol consumption-caused postsurgical pain chronicity.

Acid-sensing ion channel 3 expression is increased in dorsal root ganglion, hippocampus and hypothalamus in remifentanil-induced hyperalgesia in rats.

BACKGROUND: Remifentanil induces hyperalgesia, but the underlying mechanisms are not fully understood. Acid-sensing ion channel 3 (ASIC3) plays a regulatory role in the pain pathway. This study aimed to explore the effect of remifentanil administration on postoperative pain and on ASIC3 expression at the prespinal and supraspinal levels in a rat model. METHODS: Rats were randomly allocated to the control, incision, remifentanil, and remifentanil + incision groups. Remifentanil was given by a 1-h intravenous infusion prior to plantar incision. Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured at different time points before and after incision to evaluate mechanical and thermal hyperalgesia, respectively. The dorsal root ganglion (DRG), hippocampus, and hypothalamus were obtained after sacrifice at 48 h post-incision for determination of the protein expression of ASIC3 using western blot. RESULTS: Remifentanil administration significantly induced mechanical and thermal hyperalgesia from 2 to 48 h after incision. In addition, remifentanil exposure remarkably stimulated ASIC3 protein expression in DRG, hippocampus, and hypothalamus of rats at 48 h after incision. CONCLUSION: Remifentanil-induced hyperalgesia is accompanied by increased ASIC3 expression at the DRG and supraspinal levels, implying a possible involvement of ASIC3 in remifentanil-induced hyperalgesia.

Perioperative Analgesic Effects of Preemptive Ultrasound-Guided Rectus Sheath Block Combined with Butorphanol or Sufentanil for Single-Incision Laparoscopic Cholecystectomy: A Prospective, Randomized, Clinical Trial.

PURPOSE: Pain after single-incision laparoscopic cholecystectomy (SILC), especially visceral pain, often troubles patients and doctors. Whether preemptive butorphanol can relieve visceral pain in patients undergoing SILC remains unknown. The goal of this study was to assess the efficacy of ultrasound-guided bilateral rectus sheath block (RSB) and butorphanol for perioperative analgesia in patients undergoing SILC. PATIENTS AND METHODS: Fifty-eight patients who met the criteria were randomly divided into two groups, both of which were given preemptive RSB. Patients were given either butorphanol 0.02mg/kg (group B, n=29) or sufentanil 0.1 µg/kg (group S, n=29) as preemptive analgesia. The primary outcome was the cumulative frequency of rescue analgesic request within 24 hours after operation. Secondary outcomes were numeric rating scale (NRS) scores (from 0 to 10) of incisional pain and visceral pain, the length of hospital stay and the incidence of postoperative adverse events. RESULTS: The frequency of postoperative rescue analgesic request of group S was significantly higher than that of group B (P=0.021). The NRS scores for visceral pain were lower in group B at 2, 6 and 12 hours after surgery than in group S (both P<0.001). The occurrence of postoperative nausea and vomiting (PONV) was significantly higher in group S. There were no significant differences between two groups for other outcomes. CONCLUSION: Butorphanol can provide sufficient visceral pain treatment after SILC than the dose of sufentanil in equal analgesic effect.

Role of Spinal Cord Akt-mTOR Signaling Pathways in Postoperative Hyperalgesia Induced by Plantar Incision in Mice.

Poor postoperative pain (POP) control increases perioperative morbidity, prolongs hospitalization days, and causes chronic pain. However, the specific mechanism(s) underlying POP is unclear and the identification of optimal perioperative treatment remains elusive. Akt and mammalian target of rapamycin (mTOR) are expressed in the spinal cord, dorsal root ganglion, and sensory axons. In this study, we explored the role of Akt and mTOR in pain-related behaviors induced by plantar incision in mice. Plantar incision activated spinal Akt and mTOR in a dose-dependent manner. Pre-treatment with Akt inhibitors intrathecally prevented the activation of mTOR dose-dependently. In addition, blocking the Akt-mTOR signaling cascade attenuated pain-related behaviors and spinal Fos protein expression induced by plantar incision. Our observations demonstrate that Akt-mTOR might be a potential therapeutic target for the treatment of POP.