Systemic administration of a ß2-adrenergic receptor agonist reduces mechanical allodynia and suppresses the immune response to surgery in a rat model of persistent post-incisional hypersensitivity.

Beta 2 adrenergic receptor (ß2 AR) activation in the central and peripheral nervous system has been implicated in nociceptive processing in acute and chronic pain settings with anti-inflammatory and anti-allodynic effects of ß2-AR mimetics reported in several pain states. In the current study, we examined the therapeutic efficacy of the ß2-AR agonist clenbuterol in a rat model of persistent postsurgical hypersensitivity induced by disruption of descending noradrenergic signaling in rats with plantar incision. We used growth curve modeling of ipsilateral mechanical paw withdrawal thresholds following incision to examine effects of treatment on postoperative trajectories. Depletion of spinal noradrenergic neurons delayed recovery of hypersensitivity following incision evident as a flattened slope compared to non-depleted rats (-1.8 g/day with 95% CI -2.4 to -1.085, p < 0.0001). Chronic administration of clenbuterol reduced mechanical hypersensitivity evident as a greater initial intercept in noradrenergic depleted (6.2 g with 95% CI 1.6 to 10.8, p = 0.013) and non-depleted rats (5.4 g with 95% CI 1.2 to 9.6, p = 0.018) with plantar incision compared to vehicle treated rats. Despite a persistent reduction in mechanical hypersensitivity, clenbuterol did not alter the slope of recovery when modeled over several days (p = 0.053) or five weeks in depleted rats (p = 0.64). Systemic clenbuterol suppressed the enhanced microglial activation in depleted rats and reduced the density of macrophage at the site of incision. Direct spinal infusion of clenbuterol failed to reduce mechanical hypersensitivity in depleted rats with incision suggesting that beneficial effects of ß2-AR stimulation in this model are largely peripherally mediated. Lastly, we examined ß2-AR distribution in the spinal cord and skin using in-situ hybridization and IHC. These data add to our understanding of the role of ß2-ARs in the nervous system on hypersensitivity after surgical incision and extend previously observed anti-inflammatory actions of ß2-AR agonists to models of surgical injury.

Microarray analyses of the dorsal root ganglia support a role for innate neuro-immune pathways in persistent pain in experimental osteoarthritis.

OBJECTIVE: Following destabilization of the medial meniscus (DMM), mice develop experimental osteoarthritis (OA) and associated pain behaviors that are dependent on the stage of disease. We aimed to describe changes in gene expression in knee-innervating dorsal root ganglia (DRG) after surgery, in order to identify molecular pathways associated with three pre-defined pain phenotypes: "post-surgical pain", "early-stage OA pain", and "persistent OA pain". DESIGN: We performed DMM or sham surgery in 10-week old male C57BL/6 mice and harvested L3-L5 DRG 4, 8, and 16 weeks after surgery or from age-matched naïve mice (n = 3/group). RNA was extracted and an Affymetrix Mouse Transcriptome Array 1.0 was performed. Three pain phenotypes were defined: "post-surgical pain" (sham and DMM 4-week vs 14-week old naïve), "early OA pain" (DMM 4-week vs sham 4-week), and "persistent OA pain" (DMM 8- and 16-week vs naïve and sham 8- and 16-week). 'Top hit' genes were defined as P < 0.001. Pathway analysis (Ingenuity Pathway Analysis) was conducted using differentially expressed genes defined as P < 0.05. In addition, we performed qPCR for Ngf and immunohistochemistry for F4/80+ macrophages in the DRG. RESULTS: For each phenotype, top hit genes identified a small number of differentially expressed genes, some of which have been previously associated with pain (7/67 for "post-surgical pain"; 2/14 for "early OA pain"; 8/37 for "persistent OA pain"). Overlap between groups was limited, with 8 genes differentially regulated (P < 0.05) in all three phenotypes. Pathway analysis showed that in the persistent OA pain phase many of the functions of differentially regulated genes are related to immune cell recruitment and activation. Genes previously linked to OA pain (CX3CL1, CCL2, TLR1, and NGF) were upregulated in this phenotype and contributed to activation of the neuroinflammation canonical pathway. In separate sets of mice, we confirmed that Ngf was elevated in the DRG 8 weeks after DMM (P = 0.03), and numbers of F4/80+ macrophages were increased 16 weeks after DMM (P = 0.002 vs Sham). CONCLUSION: These transcriptomics findings support the idea that distinct molecular pathways discriminate early from persistent OA pain. Pathway analysis suggests neuroimmune interactions in the DRG contribute to initiation and maintenance of pain in OA.

Sufentanil postoperative analgesia reduce the increase of T helper 17 (Th17) cells and FoxP3+ regulatory T (Treg) cells in rat hepatocellular carcinoma surgical model: A randomised animal study.

BACKGROUND: Surgery-related pain and opioids might exacerbate immune defenses in immunocompromised cancer patients which might affect postoperativd overall survival. Sufentanil is a good postoperative pain control drug,the present study aimed to figure out whether it effect T cell immunity in rat hepatocellular carcinoma surgical model. METHODS: A rat hepatocellular carcinoma (HCC) models was established by N-nitrosodiethylamine. Forty-eight of them were randomly divided into 3 equal groups: surgery without postoperative analgesia (Group C), surgery with morphine postoperative analgesia (Group M), surgery with sufentanil postoperative analgesia (Group S). Each animal underwent a standard left hepatolobectomy, and intraperitoneally implanted with osmotic minipumps filled with sufentanil, morphine or normal saline according to the different group. The food and water consumptions, body weight changes, locomotor activity and mechanical pain threshold (MPT) were observed. The ratio of CD4+/CD8+, proportions of Th1, Th2, Th17 and Treg cells in blood were detected using flow cytometry. The liver function and the rats' survival situation of each group were observed. RESULTS: The food and water consumption, locomotor activity and MPT of group C declined than those of group S and M on d1, d2, d3 (P < 0.05). The CD4+/CD8+ ratio and the proportion of Th1 cells were significantly higher while the proportion of Th2, Th17 and Treg cells were significantly lower in group S and group M compared with group C. The rats of group S have higher CD4+/CD8+ ratio on d3, while lower proportion of Treg cells on d7 compared with group M. The plasma ALT and AST values in group C were significantly higher than that of group S and group M on both d3 and d7. There were not significant differences in mortality rate between 3 groups. CONCLUSIONS: Sufentanil and morphine postoperative analgesia in HCC rats accepted hepatectomy could relieve postoperative pain, promote the recovery of liver function after surgery, alleviate the immunosuppressive effect of pain. Furthermore, Compared to morphine, sufentanil might have a slighter effect on CD4+/CD8+ ratio and Treg frequencies. Therefore, sufentanil postoperative analgesia is better than morphine in HCC hepatectomy rats.

Morphine immunomodulation prolongs inflammatory and postoperative pain while the novel analgesic ZH853 accelerates recovery and protects against latent sensitization.

BACKGROUND: Numerous studies have identified the proinflammatory, pronociceptive effects of morphine which ultimately exacerbate pain. Our novel endomorphin analog ZH853 does not produce proinflammatory effects on its own and gives potent, long-lasting analgesia. This study investigates whether ZH853's lack of interaction with the neuroimmune system reduces the risk of prolonged pain. METHODS: Adult male Sprague-Dawley rats were subjected to one of two treatment paradigms. Either (1) chronic pain followed by chronic treatment with morphine, ZH853 or vehicle, or (2) chronic drug administered prior to pain induction. Complete Freund's adjuvant (CFA) was injected or paw incision surgery was performed on the left hind plantar foot pad. Drugs were administered through Alzet osmotic minipumps at a rate of 1 µl/h for 5 days at appropriate doses based on prior experiments. Animals were tested for mechanical allodynia and thermal hyperalgesia using von Frey filaments and the Hargreaves apparatus, respectively. Additionally, several gait parameters were measured using the CatWalk XT. When all animals had recovered from pain, 1 mg/kg of naltrexone was administered to test for development of latent sensitization (LS). A second set of animals was used to investigate dorsal horn inflammation following CFA and drug treatment. ANOVAs were used to assess differences between drug treatment groups. RESULTS: As expected, morphine increased and prolonged pain in all experiments compared to vehicle treatment. However, ZH853 treatment reduced the overall time spent in pain and the severity of pain scores compared to morphine. ZH853 not only reduced inflammation versus morphine treatment but also, in some instances, acted as an anti-inflammatory drug compared to vehicle treatment. Finally, ZH853 prevented the development of LS while vehicle- and morphine-treated animals showed robust relapse to pain. CONCLUSIONS: ZH853 has a favorable side effect profile versus morphine and provides superior analgesia in a number of pain states. We now know that chronic use of this compound reduces time spent in a chronic pain state, the opposite of common opioids like morphine, and reduces the risk of LS, making ZH853 an excellent candidate for clinical development in humans for inflammatory and postoperative pain.

Induction of suppressor of cytokine signaling 3 via HSF-1-HSP70-TLR4 axis attenuates neuroinflammation and ameliorates postoperative pain.

Postoperative pain is a common form of acute pain that, if not managed effectively, can become chronic pain. Evidence has shown that glia, especially microglia, mediate neuroinflammation, which plays a vital role in pain sensitization. Moreover, toll-like receptor 4 (TLR4), the tumor necrosis factor receptor (TNF-R), the interleukin-1 receptor (IL-1R), and the interleukin-6 receptor (IL-6R) have been considered key components in central pain sensitization and neuroinflammation. Therefore, we hypothesized that activation of the body's endogenous "immune brakes" will inhibit these receptors and achieve inflammation tolerance as well as relieve postoperative pain. After searching for potential candidates to serve as this immune brake, we identified and focused on the suppressor of cytokine signaling 3 (SOCS3) gene. To regulate SOCS3 expression, we used paeoniflorin to induce heat shock protein 70 (HSP70)/TLR4 signaling. We found that paeoniflorin significantly induced SOCS3 expression both in vitro and in vivo and promoted the efflux of HSP70 from the cytoplasm to the extracellular environment. Furthermore, paeoniflorin markedly attenuated incision-induced mechanical allodynia, and this effect was abolished by small interfering RNAs targeting SOCS3. These findings demonstrated an effective and safe strategy to alleviate postoperative pain.

Suppression of Wnt5a, but not Wnts, relieves chronic post-thoracotomy pain via anti-inflammatory modulation in rats.

With regard to post-surgical pain, the incidence of chronic post-thoracotomy pain (CPTP) is second only to that caused by amputation and the underlying mechanism remains elusive. The emerging role of Wnts has been confirmed in the pathogenesis of neuropathic and inflammatory pain, both of which are known components of CPTP. We investigated whether Wnt3a and Wnt5a were involved in the development of CPTP, concerning their regulation of inflammatory responses in a previously established rat model. We observed up regulated protein levels of Wnt3a, Wnt5a, ß-catenin, and TLR4, along with activated astrocytes and pro-inflammatory cytokines, in both dorsal root ganglia and the spinal cord dorsal horn. Furthermore, intrathecal inhibition of Wnt5a but not Wnts relieved mechanical hyperalgesia, down regulated expression of TLR4, and inactivated astrocytes and pro-inflammatory cytokines. These results suggest Wnt5a, but not Wnts, contributes to the development of CPTP, possibly by regulating the inflammatory response.

A prospective study concerning the relationship between metal allergy and post-operative pain following total hip and knee arthroplasty.

PURPOSE: A prospective study was conducted to detect whether a relationship exists between metal allergy and post-operative pain in total hip and knee arthroplasty patients. We postulated that to some extent a relationship does exist between them. MATERIALS AND METHODS: Patients who had undergone total hip and knee arthroplasty surgery because of hip and knee disease were included. The exclusion criteria were patients who were treated with immunosuppressor two weeks pre-operatively, skin conditions around the patch testing site, and other uncontrollable factors. Each patient agreed to patch testing for three days before surgery. Photographic images before patch testing, two and three days after patch testing were obtained to evaluate the final incidence of metal allergy. The patch tests contained 12 metal elements; chromium, cobalt, nickel, molybdenum, titanium, aluminium, vanadium, iron, manganese, tin, zirconium, and copper. Two independent observers evaluated the images. The results were divided into a non-metal allergy group and a metal allergy group. Pre-operative and postoperative VAS score, lymphocyte transforming test, and X-rays were collected to detect the relationship between metal allergy and post-operative pain following total hip and knee arthroplasty. RESULTS: There were 96 patients who underwent pre-operative patch testing. The overall metal allergy rate was 51.1% (49/96) in our study. Nickel, cobalt, manganese, and tin were the most common allergic metal elements in our study. Nine inappropriate cases were excluded, and 87 patients were finally included in our study. There were 36 metal allergy and 26 non-metal allergy patients in the THA group, while 11 metal allergy and 14 non-metal allergy patients were found in the TKA group. We found no relationship existed between metal allergy and post-surgery pain in total hip and knee arthroplasty. CONCLUSION: Pain caused by metal allergy usually presents as persistent and recurrent pain. The white cell count, C-reactive protein, erythrocyte sedimentation rate and postoperative radiographs were not affected. Currently, patch testing and lymphocyte transforming tests are used for metal allergy diagnosis. We deemed that a relationship between post-surgery pain and metal allergy in total hip and knee patients may exist to some extent. Larger samples and longer follow-up time are essential for further study.

[ASSESSMENT OF POSTOPERATIVE PAIN SYNDROME AT SINGLE-PORT TRANSUMBILICAL LAPAROSCOPIC CHOLECYSTECTOMY COMPARED TO TRADITIONAL LAPAROSCOPIC CHOLECYSTECTOMY].

The article analyzes the dynamics of postoperative pain at single-port transumbilical laparoscopic cholecystectomy compared to traditional laparoscopic cholecystectomy. It is shown that the intensity of pain in patients who have undergone laparoscopic procedures through a single transumbilical access was significantly less than in patients with traditional laparoscopic intervention. Furthermore, the use of a single-port transumbilical laparoscopic cholecystectomy accompanied by a smaller increase in the concentration of proinflammatory cytokines compared with patients who had laparoscopic procedures through four trocar accesses.

[Effects of epidural anesthesia on stress-induced immune supression during major corrective spine surgery].

STUDY DESIGN: A prospective, randomized study wias performed to compare two anesthetic methods. OBJECTIVE: To evaluate the effect of epidural analgesia on postoperative pain, endocrine- metabolic and inflammatory stress response and cellular inmmune responses during major corrective spine surgetry. METHODS: The study included 350 patients aged 15 to 65 who were randomly allocated to two equal groups. Group I (n=205) had continuous epidural analgesia (E4) and sevoflurane anesthesia during surgety and continuous epidural analgesia with ropivacaine and fentanil after surgery; Group 2 (n= 145) had general anesthesia with sevoflurane and fentanil and systemic administration of opioids after surgery. Patient pain, PONV syndrome, mobility, and satisfaction were measured after surgery along with plasma levels ofcortisol, ghmcose, interleukins IL-1ß, IL-6, and IL-10 during and after surgemy C-reactive protein (CRP), and cell-surface receptor expression of immune cells (cluster of differentiation) HLA-DR+/CD3-, HLA-DR+/CD3+, HILA-DR, CD3, CD4, CD8, CD16, CD19 CD16/56+, and CD16/56+/CD3+) were measured perioperatively. RESULTS: In group 1, there were significantly less pain, less nausea, earlier mobility, and higher satisfaction than those in group 2. Group I has also demonstrated significantly less plasma levels of glucose, cortisol, CRP, IL-lß, IL-6, IL-10 at various stages. The ratio of CD4/CD8 (p=0.001) and B cells (p=0.01) have increased by postoperative day 3 in group 1. NK-cells (CD16/56+) have decreased significantly by day 3 after surgery (p=0.001) compared to the group 2. T-lymphocytes, (CD3) have decreased in all patients, but they were significantly lower in patients receiving opioids, compared wiith EA. CONCLUSIONS: Polerfulr afferent stimulation in major corrective spine surgery accompanied by immunosuppression for at least a wieek after surgery. EA reduces the surgical stress response, prevents postoperative lymphocyte apoptosis and thus, increases stress and infectious resistance.

[Effect of early multimodal rehabilitation on postoperative recovery after abdominal hysterectomy].

UNLABELLED: Purpose of the study was to evaluate the impact of the use of enhanced recovery after surgery for the postoperative period, and the inflammatory response after hysterectomy. INTRODUCTION: Methods Prospectively, 50 patients ASA 1-2 aged 42-72 years were randomized into two groups: the ERAS group (n = 25) and the control group (CG) with traditional perioperative management (n = 25). combined spinal and epidural anesthesia technique was used in all patients. Patient-controlled epidural analgesia in the ERAS group and multimodal analgesia with combination of paracetamol, tramadol and ketoprofen in the control group were used postoperatively. We measured plasma concentrations of interleukin-6 (IL-6), interleuki-nIL-1beta (IL-1beta) and C-reactive protein (CRP) preoperatively and at 24 hours and 7 days after surgery. Data were analyzed by Mann-Whitney U test and presented as median (25th- 75th percentiles). RESULTS: There was no statistically significant differences in the IL-6 and IL-1beta concentrations throughout the study. At 6 and 24 hours the pain severity of according to VAS was higher in the control group at rest and on coughing during all study stages. We found no correlation between the level of pain and plasma concentrations of IL-1beta and IL-6. The plasma concentration of CRP in the control group was higher at 24 hours and at 7 days after surgery: (P < 0.01). Level of CRP in the control group tended to increase during the observation period. CONCLUSIONS: In our study, the serum concentration of IL-6 and IL-1beta did not depend on the method of postoperative pain management. Using the ERAS protocol reduced postoperative plasma concentration of CRP. The increased level of CRP in the control group may be related with autoimmune reaction in wound due to delayed mobilization of patients.

A comparison of different dosages of a continuous preperitoneal infusion and systemic administration of ropivacaine after laparotomy in rats.

INTRODUCTION: To further explain the mechanisms of action involved in the analgesic effect of a local anesthetic wound infusion, we evaluated parietal and visceral sensitivity as well as indices of inflammation after laparotomy and administration of a local anesthetic. Ropivacaine was administered at different dosages by a continuous infusion using a multiholed catheter in the preperitoneal position or systemically in rats. METHODS: Nine groups of rats received 2 injections after laparotomy or sham surgery: (1) a bolus injection (ropivacaine or saline) via a preperitoneal catheter and (2) an IM injection (IM) (ropivacaine or saline). These injections were followed by a continuous infusion (ropivacaine or saline) in the preperitoneal catheter for 24 hours and 1 IM injection every 8 hours. Mechanical and visceral thresholds after stimulation were evaluated 3 times during the 48 hours after surgery. Stimulated production of tumor necrosis factor α, and interleukin 1ß in whole-blood cultures were measured by enzyme-linked immunosorbent assay. The ropivacaine plasma concentration was measured by gas chromatography. RESULTS: Preperitoneal infusion of high doses of ropivacaine and systemic ropivacaine similarly prevented mechanical and visceral sensitivity alterations and led to a better functional recovery. The analgesic effect of systemic administration was associated with an anti-inflammatory effect. CONCLUSION: In the current study, high-dose ropivacaine administered via a preperitoneal infusion or systemic boluses had the same effect on mechanical and visceral sensitivity after laparotomy. Moreover, systemic administration was associated with an anti-inflammatory effect. The merits of the comparable benefit of systemic and high-dose preperitoneal infusion of ropivacaine need to be confirmed with further studies.

Cross-talk between NKT and regulatory T cells (Tregs) in modulation of immune response in patients with colorectal cancer following different pain management techniques.

Natural killer T (NKT) and regulatory T cells (Tregs) play an important role in innate immune response. Natural killer (NK) and NKT cells are indispensable factors in the body's ongoing defense against tumor development, as well as viral infection. NKT cells are a subset of T cells that shares properties of natural killer cells and conventional T cells. They are involved in innate immune responses, tumor rejection, post transplantation immunotherapy, immune surveillance and control of autoimmune diseases. They may also play both protective and harmful roles in the progression of certain autoimmune diseases, such as diabetes, lupus, atherosclerosis, and allergen-induced asthma. Immune surveillance involves the process whereby precancerous and malignant cells are recognized by the host immune system as damaged and are consequently targeted for elimination. The pharmacological management of postoperative pain in patients with malignancies uses very different techniques whose possible cytotoxic functions we still known very poor. The present study compared effects of two different postoperative pain management techniques in patients undergoing colorectal cancer surgery on the innate immunity. Our data indicate that the patients with colorectal cancer have significantly increased the percentage of Tregs and NKT cells. The values were statistically higher during epidural analgesia in comparison with intravenous analgesia, indicating that epidural pain management technique ameliorate the immune suppression after surgery.

[Immunity and cytokine status after surgeries on the large intestine].

The aim of our study was to examine the effect of individual schemes of multimodal analgesia on indicators of immunity and inflammation markers after operations on the colon. Patients of group 1 (n=15) received paracetamol, lornoxicam and epidural ropivacaine, 2nd group of patients (n=15)-paracetamol, epidural ropivacaine and tramadol. Comparison group (n=10) patients underwent patient controlled analgesia by promedol. Before surgery, 1st and 3rd days after surgery we examined the contents of cytokines in plasma: interleukin 12p70, interleukin 10, interleukin 6, and TNF. Before surgery and at 5-7 days after surgery indicators of cellular, fagocytal and humoral immunity were monitored. Before surgery patients with colorectal cancer revealed changes in the indices of different components of immunity, as well as an increase in pro-and anti-inflammatory cytokines compared with healthy donors. Multimodal analgesia in patients after operations on the colon is not accompanied by changes in plasma concentrations of cytokines and parameters of immune status in comparison with monoanalgesia by promedol.

Continuous subcutaneous instillation of bupivacaine compared to saline reduces interleukin 10 and increases substance P in surgical wounds after cesarean delivery.

BACKGROUND: Recent evidence suggests that locally delivered local anesthetics may exert tissue-damaging effects such as chondrolysis after intraarticular injection. Alteration of the inflammatory response is a potential mechanism for local anesthetic-induced tissue toxicity. In this study, we tested the effects of continuous local anesthetic infiltration on the release of inflammatory and nociceptive mediators in skin wounds after cesarean delivery. METHODS: Thirty-eight healthy women undergoing cesarean delivery with spinal anesthesia were enrolled in this study, and were randomized to receive subcutaneous surgical wound infiltration with bupivacaine 5 mg/mL or saline at 2 mL/h for 24 hours after cesarean delivery. Wound exudate was sampled at 1, 3, 5, 7, and 24 hours after cesarean delivery using a subcutaneous wound drain technique. Cytokines, chemokines, substance P, prostaglandin E(2), and nerve growth factor were assayed using multiplex Bio-Plex® (Bio-Rad, Hercules, CA) and enzyme-linked immunosorbent assays. RESULTS: Bupivacaine wound infusion resulted in a significant decrease of interleukin 10 and increase of substance P in wounds compared with saline infusion (area under the 24-hour concentration-time curve; P < 0.001). No statistically significant differences were detected for other cytokines, nerve growth factor, and prostaglandin E(2). CONCLUSIONS: This study demonstrates that the continuous administration of clinically used doses of bupivacaine into wounds affects the local composition of wound mediators. Observed changes in interleukin 10 are compatible with a disruption of antiinflammatory mechanisms. Whether such modulation combined with the release of the proinflammatory mediator substance P results in an overall proinflammatory wound response will require future studies of wound healing.

The role of interleukin-1 in wound biology. Part II: In vivo and human translational studies.

BACKGROUND: In the accompanying paper, we demonstrate that genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production through altering the amount of interleukin (IL)-1 produced. We further investigate the role of IL-1 in incisional wound biology and its effect on wound chemokine production in vivo and whether this mechanism could be active in human subjects. METHODS: A well-characterized murine model of incisional wounding was used to assess the in vivo role of IL-1 in wound biology. The amount of 7 different cytokines/chemokines produced within an experimentally induced skin incision on a mouse paw and the nociceptive response was analyzed in mice treated with an IL-1 inhibitor. We also investigated whether human IL-1ß or IL-1α stimulated the production of chemokines by primary human keratinocytes in vitro, and whether there was a correlation between IL-1ß and chemokine levels in 2 experimental human wound paradigms. RESULTS: Administration of an IL-1 receptor antagonist to mice decreased the nociceptive response to an incisional wound, and reduced the production of multiple inflammatory mediators, including keratinocyte-derived chemokine (KC) and macrophage inhibitory protein (MIP)-1α, within the wounds. IL-1α and IL-1ß stimulated IL-8 and GRO-α (human homologues of murine keratinocyte-derived chemokine) production by primary human keratinocytes in vitro. IL-1ß levels were highly correlated with IL-8 in human surgical wounds, and at cutaneous sites of human ultraviolet B-induced sunburn injury. CONCLUSIONS: IL-1 plays a major role in regulating inflammatory mediator production in wounds through a novel mechanism; by stimulating the production of multiple cytokines and chemokines, it impacts clinically important aspects of wound biology. These data suggest that administration of an IL-1 receptor antagonist within the perioperative period could decrease postsurgical wound pain.

The effects of electroacupuncture on TH1/TH2 cytokine mRNA expression and mitogen-activated protein kinase signaling pathways in the splenic T cells of traumatized rats.

BACKGROUND: Surgical trauma contributes to postoperative immune suppression, which is associated with an increased susceptibility to subsequent infections. Electroacupuncture (EA) can alleviate pain and exert immunoregulatory effects. However, the mechanism underlying the immnuomodulation effects of EA is not fully elucidated. Therefore, we investigated the effects of EA on T helper (Th)1/Th2 cytokine production and mRNA expression and evaluated the signaling regulatory mechanism of EA effects. METHODS: Rats were divided into four groups (n = 24 each): control, trauma, trauma (T) + sham EA, and T + EA. EA was applied to Zusanli (ST36) and Lanwei (Extra37) acupoints at 20 min after surgery for 30 min, and then performed once a day on postoperative days 1-5. Splenic T cells were isolated and the production and mRNA expression of interleukin (IL)-2, interferon-gamma, IL-4, and IL-10 were assayed. The activation of mitogen-activated protein kinase and the DNA binding activity of nuclear factor (NF)-kappaB and activator protein (AP)-1 were examined. RESULTS: Paw withdrawal threshold and paw withdrawal latency were significantly increased in the T + EA group compared with the trauma group from postoperative day 1 (paw withdrawal threshold: 5.8 +/- 0.7 vs 3.0 +/- 0.7 g; paw withdrawal latency: 7.0 +/- 0.8 vs 4.5 +/- 0.5 s; P < 0.001) to day 5 (9.0 +/- 0.6 vs 5.5 +/- 0.6 g; 12.0 +/- 1.3 vs 7.0 +/- 0.8 s; P < 0.001). Th1 cytokine (IL-2 and interferon-gamma) production and mRNA expression in splenic T cells of traumatized rats were significantly decreased on postoperative day 3 (P < 0.001, trauma group versus control group), whereas Th2 cytokine (IL-4 and IL-10) production and mRNA expression were increased (P < 0.001). This was accompanied with a significant depression in the activity of extracellular-regulated protein kinase (ERK)1/2, p38, NF-kappaB, and AP-1 (P < 0.001, trauma group versus control group). EA administration increased Th1 cytokine protein and mRNA expression, suppressed Th2 cytokine protein and mRNA expression (P < 0.05, T + EA group versus trauma group), and increased the activity of ERK1/2, p38, NF-kappaB, and AP-1 (P < 0.001, T + EA group versus trauma group). CONCLUSIONS: EA regulates a balance between Th1 and Th2 cytokines at protein and mRNA levels in splenic T cells, and, at least in part, involves the signaling pathways of ERK1/2, p38, NF-kappaB, and AP-1. The findings suggest that EA may improve immune suppression after surgical trauma.

Effects of anesthetics and analgesics on natural killer cell activity.

Surgical excision of cancerous tumors and the human stress response can lead to metastasis of tumor cells. Furthermore, the medications used during the perioperative period (eg, opioids and anesthetic agents) have been shown to inhibit or suppress natural killer (NK) cell activity, one of the body's main defenses against spread of cancer. There are currently no anesthetic regimens that have been shown to completely reverse surgical stress-induced suppression of NK cell activity. However, there may be anesthetic techniques that attenuate surgical suppression of NK cell activity. This article reviews the effects of various anesthetics and analgesics on NK cell activity and suggests techniques to attenuate the suppressive effects of these compounds.

Preoperative clonidine or levobupivacaine--effect on systemic inflammatory stress response.

With perioperative pain control it is possible to supervise immune system, release of inflammation mediators, and influence on treatment outcome. Use of analgetics before the pain stimulus (preventive analgesia) obstruct development of neuroplastic changes in central nervous system, and reduces pain. Investigation hypothesis was that preoperative epidural clonidine is more efficient in blockade of systemic inflammatory stress response comparing to levobupivacaine. Patients were allocated to three groups, according to preoperative epidural use of clonidine, levobupivacaine or saline (control group). Before operation, 1 h after the beginning, 1 h, 6 h, 12 h and 24 h after the operation following parameters were analyzed: interleukine-6, C-reactive protein and leukocyte count. There were no significant differences between groups in age, gender, body mass index and operation time. In preoperative clonidine group, we found significant reduction in interleukine-6 levels throughout investigation time, compared to preoperative levobupivacaine group and control group. Also, C-reactive protein was significantly lower at the end of investigation, compared to other two groups. Leukocyte count was lower, and within the normal range in all investigation times only in preoperative clonidine group. We demonstrated significant difference that support importance of clonidine central effect on pain pathways and systemic inflammatory blockade.

Lymphocyte Transformation Testing (LTT) in Cases of Pain Following Total Knee Arthroplasty: Little Relationship to Histopathologic Findings and Revision Outcomes.

BACKGROUND: The utilization of lymphocyte transformation testing (LTT) has increased for diagnosing metal sensitivity associated with total knee arthroplasty (TKA), but its validity for the diagnosis of TKA failure due to an immune reaction has not been established. In this study, we sought to characterize the relationship of a positive LTT result to histopathologic findings and clinical and functional outcomes. METHODS: This was a retrospective study of 27 well-fixed, aseptic, primary TKA cases in which the patient had persistent pain and/or stiffness and underwent revision due to a suspected metal allergy to nickel, as determined on the basis of positive LTT. Revision procedures were performed by a single experienced arthroplasty surgeon. Periprosthetic tissue samples obtained at the time of revision surgery were scored using the aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) scoring system. RESULTS: Eight patients were categorized as mildly reactive; 8 patients, moderately reactive; and 11 patients, highly reactive to nickel by LTT. The predominant findings on routine histopathologic analysis were fibrosis and varying degrees of lymphocytic infiltration in 17 (63%) of the 27 cases. The average ALVAL score of the cohort was 3.1 ± 1.9, of a maximum score of 10. Average Knee Society Score (KSS) values improved post-revision, as did range of motion (all p < 0.01). Neither LTT stimulation index as a continuous variable nor as a categorical variable (mildly reactive, moderately reactive, highly reactive) was correlated with ALVAL score, pre-revision function (as assessed by KSS-clinical, KSS-functional, and range of motion), or change in function at the most recent follow-up (0.015 < r < 0.30, 0.13 < p < 0.95). In addition, the ALVAL score did not correlate significantly with either pre-revision or post-revision KSS or range of motion (0.061 < r < 0.365, 0.09 < p < 0.88). CONCLUSIONS: On the basis of this analysis, including histopathologic assessment, LTT results alone were insufficient for the diagnosis of TKA failure due to an immune reaction. A positive LTT may not indicate that an immune reaction is the cause of pain and stiffness post-TKA. The role of LTT in assessing TKA failure from an immune reaction needs further investigation. Diagnostic criteria for such TKA failure need to be established. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Effect of Preoperative Uric Acid Level and Neutrophil / Lymphocyte Ratio on Preoperative and Postoperative Visual Analogue Pain Scores in Patients with Lumbar Disc Herniation: A Cross-Sectional Study.

AIM: To determine the relationship between the serum urate (SU) level, neutrophil / lymphocyte ratio (NLR), and pain severity using preoperative and postoperative visual analogue scale (VAS) scores in patients with lumbar disc herniation (LDH). MATERIAL AND METHODS: This single-center, cross-sectional study included 20 consecutive patients who were operated for LDH by the same surgeon. The patients'pre- and postoperative UA levels, NLRs, and intensity severity VAS scores were investigated. Preoperative magnetic resonance imaging (MRI) findings, serum UA levels, and neutrophil and lymphocyte counts were recorded. Pain severity was recorded preoperatively and at 6 months postoperatively. Effects of the preoperative SU levels and NLRs on the pre- and postoperative VAS scores were statistically assessed. RESULTS: Statistically significant positive correlation coefficients were determined between NLR and the preoperative and postoperative VAS scores. Negative correlation coefficients were found between the SU levels and preoperative VAS scores; in contrast, positive correlation coefficients were found between the SU levels and the postoperative VAS scores. CONCLUSION: Our results demonstrate the importance of not ignoring the serum UA level and NLR in pre- and postoperative pain in patients with LDH. Nevertheless, further extensive studies are warranted.