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Wind-up (WU) is a progressive, frequency-dependent facilitation of spinal cord neurons in response to repetitive nociceptive stimulation of constant intensity. We identified a new WU-associated phenomenon in naïve mice (not exposed to noxious stimulation immediately prior to WU stimulation), which were subjected to a novel experimental protocol composed of three consecutive trains of WU stimulation. The 1st train produced a typical linear 'wind-up' curve as expected following a repeating series of stimuli; in addition, this 1st train sensitized ('primed') the nociceptive system so that the responses to two subsequent trains (inter-train interval of 10 min) were significantly amplified compared with the response to the 1st train. We named this augmented response potentiation-of-windup, or "PoW". The PoW phenomenon appears to be centrally mediated, as the augmented response was suppressed by administration of an NMDA receptor antagonist (MK-801) and by cutting the spinal cord. Furthermore, the PoW protocol is accompanied by enhanced pain behavior. The 'priming' effect of the 1st train could be mimicked by exposure to natural noxious stimuli prior to the PoW protocol. Presumably, the PoW phenomenon has not been previously reported due to a procedural reason: typically, WU protocols have been executed in 'primed' rather than naïve animals, i.e., animals exposed to nociceptive stimulation prior to the actual WU recording. Our findings indicate that the PoW paradigm can distinguish between 'naïve' and 'primed' states, suggesting its use as a tool for the assessment of central sensitization.

Reports regarding the ability of the anesthetic drug ketamine to attenuate the inflammatory response to surgery are conflicting. In this systematic review we examined the effect of perioperative ketamine administration on postoperative inflammation as assessed by concentrations of the biomarker interleukin-6 (IL-6).This study was based on a systematic search in PubMed, Scopus, Web of Knowledge, and the Cochrane Library. English written randomized controlled trials conducted in humans were eligible. To be included in the analysis, outcome had to relate to inflammation or immune modulation. Each study was reviewed independently by 2 assessors. Data were analyzed according to the GRADE's approach and reported in compliance with the PRISMA recommendations.Fourteen studies were eligible for evaluation (684 patients). Surgery was performed under general anesthesia, and ketamine was given before or during the surgery in varied doses Eight studies involved cardiopulmonary bypass operations, 4 were for abdominal surgery, 1 thoracic surgery, and 1 cataract surgery. Three studies were deemed of low quality. Nine studies measured IL-6 concentrations within the first 6 hours postoperatively; but in 3 studies, other potent anti-inflammatory drugs were used as premedication or during the operation; thus 6 studies (n = 331) were included in the meta-analysis. Using postoperative IL-6 concentrations as an outcome, ketamine had an anti-inflammatory effect; the meta-analysis showed a mean preoperative-postoperative IL-6 concentration difference (95% confidence interval) of -71 (-101 to -41) pg/mL.It can be concluded that intraoperative administration of ketamine significantly inhibits the early postoperative IL-6 inflammatory response. Future studies should further examine the anti-inflammatory effect of ketamine during major surgery, determine whether ketamine treatment alters functional outcomes, elucidate the mechanisms of its anti-inflammatory effect, and suggest an appropriate dosing regimen.

Aim: To find out which of the two predictors, Charlson co-morbidity index or vitamin B12, better estimates the risk of in-hospital mortality in seriously ill patients. Method: Electronic hospital records of 1509 elderly patients aged 65 and older were retrospectively surveyed. Results: Albumin, age and elevated vitamin B12 levels were significantly associated with increased in-hospital mortality. Charlson co-morbidity index was not significantly associated with death. The highest mortality (24.3%) was found in the group of patients who were concomitantly in the lowest albumin quartile and the highest vitamin B12 levels quartile. In this group, mortality increased significantly with age. By elasticity calculation, vitamin B12 capability to predict mortality was higher by ∼3 times than that of Charlson co-morbidity index. Conclusions: In view of the fact that vitamin B12 levels have been found to predict mortality, they should be measured in geriatric practice, in addition to albumin levels, as a practical and reliable tool for identifying high risk elderly hospitalized patients. Probably, a combination of two or more available and inexpensive routinely taken tests can give a better estimation of mortality than some complicated tools, like Charlson co-morbidity index.

Neuropathic pain is a chronic pain state resulting from peripheral nerve injury, characterized by hyperalgesia and allodynia. We have reported that mice with genetic impairment of IL-1 signaling display attenuated neuropathic pain behavior and ectopic neuronal activity. In order to substantiate the role of IL-1 in neuropathic pain, WT mice were implanted subcutaneously with osmotic micropumps containing either IL-1ra or vehicle. Two days following the implantation, two models of neuropathic pain were used; partial nerve injury (spinal nerve transection, SNT), or complete nerve cut (spinal neuroma model). Mechanosensitivity was assessed seven consecutive days following SNT, and on day 7 recordings of spontaneous ectopic activity were performed. In the spinal nerve neuroma model, autotomy scores were recorded up to 35 days. Vehicle-treated mice developed significant allodynia and autotomy, and clear ectopic activity (4.1±1.1% of the axons); whereas IL-1ra-treated mice did not display allodynic response, displayed delayed onset of autotomy and markedly reduced severity of autotomy scores, and displayed reduced spontaneous activity (0.8±0.4% of the axons). To test whether IL-1 is involved in maintenance of mechanical allodynia, a separate group of WT mice was treated with a single injection of either saline or IL-1ra four days following SNT, after the allodynic response was already manifested. Whereas saline-treated mice displayed robust allodynia, acute IL-1ra treatment induced long-lasting attenuation of the allodynic response. The results support our hypothesis that IL-1 signaling plays an important role in neuropathic pain and in the ectopic neuronal activity that underling its development.

Postoperative incisional pain is characterized by persistent acute pain in the area of the cut, and is associated with release of proinflammatory cytokines, including interleukin-1 (IL-1), which play important hyperalgesic and allodynic roles in various inflammatory conditions. In the present study, we tested the role of IL-1 signaling in postoperative incisional pain using three mouse strains impaired in IL-1 signaling due to deletion of the IL-1 type I receptor on a mixed genetic background (IL-1rKO) or congenic background (IL-1rKOCog), or due to transgenic over-expression of IL-1 receptor antagonist (IL-1raTG). We used the relevant wild-type (WT) mice both as controls for the mutant strains, and for assessing the effects of pharmacological blockade of IL-1-signaling. Mechanosensitivity was assessed using the von-Frey filament test before, and up to 4 days following plantar incision, an animal model of postoperative pain. WT mice developed significant allodynia in the incised, compared with the intact, hind-paw beginning 3h after the incision and lasting up to 48h postoperatively. In contrast, IL-1rKO, IL-1rKOCog, and IL-1raTG mice, as well as WT mice chronically treated with IL-1ra, did not display increased mechanical pain sensitivity in either hind-paw. To test the hypothesis that IL-1-signaling is also involved in the maintenance of postoperative pain, WT mice were acutely treated with IL-1ra 24h following the incision, when allodynia was already evident. This treatment reversed the allodynic response throughout the observation period. Together, these findings suggest that IL-1 plays a critical role in the development and maintenance of postoperative incisional pain.

Many neurotransmitters involved in pain perception transmit signals via G protein-coupled receptors (GPCRs). GPCR kinase 2 (GRK2) regulates agonist-induced desensitization and signaling of multiple GPCRs and interacts with downstream molecules with consequences for signaling. In general, low GRK2 levels are associated with increased responses to agonist stimulation of GPCRs. Recently, we reported that in mice with reduced GRK2 levels, inflammation-induced mechanical allodynia was increased. In addition, mice with impaired interleukin (IL)-1 beta signaling did not develop mechanical allodynia after L5 spinal nerve transection (SNT). We hypothesized that in the L5 SNT model mechanical allodynia would be associated with reduced neuronal GRK2 levels in the spinal cord dorsal horn and that IL-1 beta signaling would be required to induce both the decrease in GRK2 and mechanical allodynia. We show here that in wild type (WT) mice L5 SNT induces a bilateral decrease in neuronal GRK2 expression in the lumbar spinal cord dorsal horn, 1 and 2 weeks after L5 SNT. No changes in GRK2 were observed in the thoracic segments. Moreover, spinal cord GRK2 expression was not decreased in IL-1R(-/-) mice after L5 SNT. These data show that IL-1 beta signaling is not only required for the development of mechanical allodynia, but also to reduce neuronal GRK2 expression. These results suggest a functional relation between the L5 SNT-induced IL-1 beta-mediated decrease in GRK2 and development of mechanical allodynia.

Exposure to stressful stimuli is often accompanied by reduced pain sensitivity, termed "stress-induced analgesia" (SIA). In the present study, the hypothesis that interleukin-1 (IL-1) may play a modulatory role in SIA was examined. Two genetic mouse models impaired in IL-1-signaling and their wild-type (WT) controls were employed. Another group of C57 mice was acutely administered with IL-1 receptor antagonist (IL-1ra). Mice were exposed to 2min swim stress at one of three water temperatures: 32 degrees C (mild stress), 20-23 degrees C (moderate stress), or 15 degrees C (severe stress); and then tested for pain sensitivity using the hot-plate test. Corticosterone levels were assessed in separate groups of WT and mutant mice following exposure to the three types of stress. Mild stress induced significant analgesia in the two WT strains and saline-treated mice, but not in the mutant strains or the IL-1ra-treated mice. Similarly, mild stress induced significantly elevated corticosterone levels in WT mice, and blunted corticosterone response in mutant mice. In contrast, both WT and mutant strains, as well as IL-1ra-treated mice, displayed analgesic and corticosterone responses following moderate and severe stress. Interestingly, the analgesic response to moderate stress was markedly potentiated in the mutant strains, as compared with their WT controls. The present results support our previous findings that in the absence of IL-1, stress response to mild stress is noticeably diminished. However, the analgesic response to moderate stress is markedly potentiated in mice with impaired IL-1 signaling, corroborating the anti-analgesic role of IL-1 in several pain modulatory conditions, including SIA.

Interleukin-1 beta (IL-1beta) and its endogenous IL-1 receptor antagonist (IL-1Ra) play an important role in inflammatory response and in pain modulation. It has recently been shown that polymorphism of the IL-1beta and IL-1Ra genes may account for variation in the production of these cytokines. The present study examined the hypothesis that polymorphism of IL-1beta and IL-1Ra genes is involved in pain sensitivity and morphine consumption in the immediate postoperative period. Genetic polymorphism was determined in 76 women undergoing transabdominal hysterectomy. The genotype of IL-1Ra was determined using PCR amplification of the variable number of tandem repeats (VNTR) of 86 base pair (bp) in intron 2, while for IL-1beta the cytosine to thymine transition at codon -511 of the promoter was determined by PCR. Morphine consumption and pain scores were evaluated in the first postoperative 24 h. The study group was divided based on morphine consumption to three sub-groups: low morphine consumers (LMC) (28 mg/24 h), medium morphine consumers (MMC) (28-38 mg/24 h), and high morphine consumers (HMC) (38 mg/24 h). Patients consuming the least amount of morphine postoperatively showed significant lower pain scores. IL-1Ra genetic polymorphism of the MMC group was significantly different compared to the other two groups. No difference in IL-1beta gene polymorphism was found among the three sub-groups. Since IL-1Ra polymorphism is known to affect the levels of both IL-1Ra and IL-1, cytokines associated with modulation of pain sensitivity and morphine analgesia, it is suggested that IL-1Ra genetic polymorphism may contribute to the variation in postoperative morphine consumption.

CCK involvement in stress- and pain-responsiveness was examined by studying the beha- vior of infant (11-12-days-old) and adult OLETF rats that do not express CCK1 receptors. Infant odor- and texture-preferences were also assessed. We hypothesized that OLETF rats will show behavioral patterns similar to those previously observed after CCK1 antagonist administration. Rate of separation-induced ultrasonic vocalization was significantly greater in OLETF compared to controls, in two separate studies. Infant pups of the two strains did not differ in odor- and texture-preference tests. OLETF rats showed consistently longer hot- plate paw-lift (as infants, in two separate studies) and paw-lick (as adults) latencies. Summary: OLETF pups vocalized in isolation more than controls and showed relative hypoalgesic responses, evident also in adulthood, in concordance with the pharmacological literature.

Background: This study examined the role of glucocorticoids (GC) and interleukin-1 (IL-1) in regulating the production of brain prostaglandin E2 (PGE2) in response to surgical stress. Methods: Surgical stress was induced in rats by laparotomy or exploration of the carotid. PGE2 ex vivo production was measured in the frontal cortex or central amygdala of adrenalectomized rats, or of rats treated with either the GC type II receptor blocker (RU38486) or synthetic GC (dexamethasone). IL-1 involvement in mediating PGE2 response to surgical stress was examined in IL-1 receptor type I deficient (IL-1rKO) mice. Results: Surgical stress elevated serum corticosterone and increased PGE2 production by the frontal cortex and the central amygdala. A more pronounced PGE2 response was found in adrenalectomized rats and in rats treated with RU38486, whereas administration of dexamethasone inhibited stress-induced PGE2 production. IL-1rKO mice exhibited lower PGE2 production in the frontal cortex under basal condition and failed to increase PGE2 production in response to surgical stress. Conclusions: Surgical stress-induced production of brain PGE2 is specifically regulated by GC via the mediation of type II corticosteroid receptors. Normal IL-1 signaling is required for the production of brain PGE2 under basal conditions and in response to surgical stress.

Background: Recently, new drugs and techniques for the treatment of postoperative pain were introduced, with the goal of enhancing opiates' analgesia while minimizing their side-effects. Cholinergic agents play an antinociceptive role, but their clinical use is quite limited, due to side-effects. Physostigmine is a cholinesterase inhibitor, which crosses the blood–brain barrier and elevates brain acetylcholine level. Physostigmine can produce analgesia by itself, and enhance opiate analgesia; but these effects are of short duration following bolus administration. Methods: We compared pain intensity and morphine consumption in two postoperative treatment groups: One group received continuous physostigmine infusion combined with morphine-based patient-controlled analgesia (PCA), and the other received PCA alone. Cholinergic anti-inflammatory pathways have recently been described. We therefore also compared changes in proinflammatory cytokine production in the two pain management groups. Results: Continuous infusion of physostigmine combined with morphine-based PCA in the postoperative period significantly reduced opiate consumption, and enhanced the analgesic response. Patients in the physostigmine group also exhibited reduced ex-vivo production of the proinflammatory cytokine, IL-1β. At the same time, physostigmine increased nausea and vomiting, mostly in the first 2 h of the postoperative period. Conclusions: Physostigmine combined with morphine in the postoperative period reduced morphine consumption, enhanced analgesia, and attenuated production of the proinflammatory cytokine, IL-1β. This latter finding may account for the decreased pain observed in this group; this cytokine is known to mediate basal pain sensitivity and induce hyperalgesia in inflammatory conditions. Taking into account the other potential beneficial effects of physostigmine, we suggest that a continuous infusion of physostigmine should be considered as a useful component in multimodal postoperative analgesia.

Objectives: Opiates, which serve an integral role in anesthesia, suppress immune function, particularly natural killer cell cytotoxicity (NKCC). NK cells play an important role in tumor and metastasis surveillance. We reported that large-dose fentanyl anesthesia induced prolonged suppression of NKCC in patients undergoing abdominal surgery. The immune modulatory effects of opiates may depend on the interaction between dose and time of administration. The present study examined the effects of different doses of fentanyl, administered at different time points relative to tumor inoculation, on NKCC and on experimental tumor metastasis in rats. Methods: Fischer 344 rats were injected with low or high doses of fentanyl, 6 or 2 h before, simultaneously with or 1 h after being inoculated intravenously with MADB106 tumor cells. Lung tumor retention (LTR) was assessed 4 h after, and lung tumor metastases were counted 3 weeks after tumor inoculation. NKCC was assessed 1 h after the fentanyl injection. Results: At all time points, except 6 h before tumor inoculation, fentanyl (0.1–0.3 mg/kg) induced a dose-dependent increase in MADB106 LTR (2.3- to 74-fold). An intermediate dose of fentanyl (0.15 mg/kg) doubled the number of lung metastasis, and, within animal, suppressed NKCC and increased MADB106 LTR in a correlated manner. Conclusion: These findings indicate that fentanyl suppresses NKCC and increases the risk of tumor metastasis. Suppression of NK cells at a time when surgery may induce tumor dissemination can prove to be critical to the spread of metastases. It is suggested that the acute administration of a moderate dose of opiates during surgery should be applied cautiously, particularly in cancer patients.

Background The postoperative period is associated with increased production of proinflammatory cytokines, which are known to augment pain sensitivity, among other effects. In a previous study, the authors found that patients treated with patient-controlled epidural analgesia (PCEA) exhibited attenuated proinflammatory cytokine response in the postoperative period. In the present study, the authors examined whether preemptive analgesia continued with PCEA may further attenuate the proinflammatory cytokine response and reduce pain sensitivity in the postoperative period. They compared cytokine production in two groups of patients, one receiving PCEA, the other receiving preemptive epidural analgesia continued by PCEA. Methods Female patients hospitalized for transabdominal hysterectomy were randomly assigned to one of two pain management techniques: PCEA or preemptive epidural analgesia followed by PCEA (PA + PCEA). Postoperative pain was assessed using the visual analog scale. Blood samples were collected before, 24, 48, and 72 h following surgery. Production of the following cytokines was assessed in stimulated peripheral blood mononuclear cells: interleukin (IL)-1beta, tumor necrosis factor alpha, IL-6, IL-1ra, IL-10, and IL-2. Results Patients of the PA + PCEA group exhibited lower pain scores throughout the 72 h postoperatively, compared with patients of the PCEA group. In patients of the PA + PCEA group in the postoperative period, production of IL-1beta, IL-6, IL-1ra, and IL-10 was significantly less elevated, while IL-2 production was significantly less suppressed. Conclusions Proinflammatory cytokines are key mediators of illness symptoms, including hyperalgesia. The present results suggest that preemptive epidural analgesia is associated with reduced postoperative pain and attenuated production of proinflammatory cytokines.

Background Unintentional perioperative hypothermia is a common complication of anesthesia and surgery associated with adverse effects on several systems, including impaired wound healing and more frequent wound infections. Mild hypothermia affects various immune functions. In the current study, the authors sought to determine whether immune alterations in the perioperative period might be induced, at least in part, by impaired thermoregulation during this period. Methods Sixty patients undergoing abdominal surgery were randomly assigned to two thermal care groups: routine care or forced-air warming. The patients' anesthetic care was standardized. Venous blood samples were collected 90 min before induction of anesthesia and immediately, 24 h, and 48 h after surgery. White cells were separated and frozen. Peripheral blood mononuclear cells were used to test cytokine production (interleukins [IL] -1beta, -2, and -6; tumor necrosis factor-alpha [TNF-alpha]), mitogens-induced proliferation, and natural killer NK cell cytotoxicity. Plasma cortisol levels were also determined. Results Patients in the normothermia group maintained normal body core temperature, whereas temperature decreased by approximately 1 degree C in the hypothermia group. Mitogenic responses were suppressed in cells from patients in the hypothermia but not in the normothermia group 24 and 48 h after surgery. Proinflammatory cytokine (IL-1beta, IL-6, TNF-alpha) production increased in both groups, although the production of IL-1beta was significantly higher in the normothermia group 24 h after surgery. Production of IL-2 was suppressed in the hypothermia but not in the normothermia group at 24 h. Conclusions Mild perioperative hypothermia suppressed mitogen-induced activation of lymphocytes and reduced the production of certain cytokines, IL-1beta and IL-2, and in this way may contribute to the immune alterations observed in the perioperative period.

Prenatal exposure to opiates can adversely affect fetal development, resulting in long-term growth retardation and impairments in physiological and behavioral functions. In the present study we studied long-term effects of prenatal morphine exposure on immune functions, including the activity of natural killer (NK) cells and the febrile and behavioral responses to lipopolysaccharide (LPS). Pregnant Fischer 344 rats were given increasing doses of morphine in slow release emulsion during gestational days 12–18. Control rats were injected with vehicle and were either pair fed to morphine rats or fed ad lib. Postnatal experiments were conducted when offspring were 10–12 weeks old. Compared to both control groups, rats prenatally exposed to morphine exhibited: 1) suppressed cytotoxic activity of NK cells; 2) reduced LPS-induced fever measured by a biotelemetric system; 3) reduced hyperalgesia measured by the hot-plate test at 30 min, and augmented hypoalgesia at 2–6 h post-LPS; 4) higher open-field activity in saline-treated animals, and more pronounced suppression of activity in LPS-injected animals; 5) LPS-induced reduction of food consumption, body weight, and social exploration, which did not differ from the reduction observed in control animals. These findings indicate that prenatal exposure to morphine induces long-term impairment of host–defense mechanisms, which may render the offspring more susceptible to infectious diseases.

Conditioned place preference (CPP) is a commonly used method for assessing the rewarding qualities of drugs, including opiates. In the present study, we examined long-term effects of prenatal morphine on morphine-associated place preference. Pregnant Fischer 344 rats were given increasing doses of morphine (0.75-12.0 mg/day) in slow-release emulsion during gestational days 12-18. Control rats were injected with vehicle and were fed either with morphine rats or ad libitum. At birth, all litters were culled to 8 pups and fostered to naive dams. Testing began when rats were 10-12 weeks old. Rats prenatally exposed to morphine exhibited a significantly higher preference for the morphine-paired compartment, suggesting that prenatal morphine induces a long-lasting enhancement of its reinforcing effect. Thus, prenatal morphine may result in enhanced activity and/or sensitivity of the endogenous opiate system, thereby placing the organism at higher risk for opiate drug abuse.

The endogenous opiate system plays a role in fetal sexual differentiation during development. We examined long-term effects of prenatal morphine on adult sexual behavior in male rats. Pregnant Fischer 344 rats were given increasing doses of morphine (0.75-12.0 mg/day) in slow-release emulsion during gestational days 12-18. Control rats were injected with vehicle and were either pair-fed with morphine rats or ad lib fed. At birth, all litters were culled to eight pups and fostered to naive dams. Testing began when rats were 10-12 weeks old. Masculine behavior was assessed using receptive stimulus females and recording instances of mount, intromission, and ejaculation. Feminine receptivity of the male rats was assessed following castration and priming with ovarian hormones; lordosis quotient of the experimental males was recorded using stimulus male studs. Males prenatally exposed to morphine exhibited normal rates of male copulatory behavior but a significantly higher lordosis quotient, suggesting that prenatal morphine induced long-lasting feminizing effects.

Surgical stress and general anesthesia suppress immune functions, including natural killer cell cytotoxicity (NKCC). This suppression could be attributable, at least in part, to opiates. We have previously shown that large-dose fentanyl administration suppressed NKCC in rats. The present study sought to compare the effects of two anesthetic protocols, based on large- (LDFA) versus small (SDFA)-dose fentanyl anesthesia on NKCC in the perioperative period. Forty patients were included in this study; half were assigned to each protocol of anesthesia. In each anesthetic group, half the patients were undergoing surgery for malignant diseases, and half for benign conditions. Blood samples were collected during the perioperative period. NKCC was assessed using the chromium release assay. Initially, both types of anesthesia similarly suppressed NKCC, with a peak effect 24 h after surgery. The two types of anesthesia, however, differed in the rate of recovery of NKCC suppression. By the second postoperative day, NKCC returned to control values in the SDFA patients, whereas NKCC was still significantly suppressed after LDFA. These results indicate that LDFA causes prolonged suppression of NK cell function. Whether this suppression might have a long-term impact on the overall outcome, especially in cancer patients, remains to be determined.

Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical.

Surgical stress and general anesthesia can suppress immune function and thus may increase postsurgical infections and tumor metastasis. We previously reported that two narcotics commonly used in high-dose opiate anesthesia (fentanyl and sufentanil) suppress natural killer (NK) cell activity in rats. Such doses of narcotics also cause respiratory depression accompanied by hypoxia, hypercarbia, and acidosis, which might account for the observed narcotic-induced NK suppression. In the present study, we compared the effects of fentanyl on NK activity in ventilated and non-ventilated rats. Fentanyl significantly suppressed NK cell activity to the same magnitude in the two groups, although the groups significantly differed in CO2 and O2 levels. The fact that high-dose fentanyl-induced NK suppression can be demonstrated in ventilated rats accentuates the relevance of these findings to clinical studies showing NK suppression in the immediate postoperative period. Such immunosuppression could be a risk factor for patients undergoing surgery, especially in cancer-related operations.

The effects of acute and chronic ethanol administration on tumor progression and metastasis were studied in rat models of leukemia and breast cancer, respectively. Acute administration of 1.5–3.5 g of ethanol/kg body weight significantly reduced survival of rats injected with CRNK-16 leukemia cells in a dose-related manner. Acute administration of 2.5–3.5 g of ethanol/kg body weight, one hour before tumor inoculation, or chronic consumption of liquid diet containing ethanol for two weeks before and three weeks after tumor inoculation, significantly increased the number of lung metastases of MADB106 mammary adenocarcinoma. The ethanol-induced increase in the number of metastases was not correlated with plasma levels of corticosterone and was not altered by the opiate antagonist naltrexone. Incubation of spleen cells in vitro in the presence of ethanol, at concentrations comparable to those measured in the blood of ethanol-treated rats, significantly suppressed natural killer (NK) cell activity against MADB106 cells in a standard chromium-release assay and decreased the binding of effector to MADB106 tumor cells. However, neither acute nor chronic ethanol administration in vivo altered splenic NK activity against this tumor in the same in vitro assay, in which the ethanol would have been washed away. These results suggest that, in the presence of ethanol, tumor progression is facilitated. The possibility that this facilitation is related to ethanol-induced impairment of the normal tumoricidal interaction between NK and tumor cells is discussed.

Pain may contribute to cognitive decline, which is a common complication in the early postoperative period. We compared the effects of two common pain management techniques, intravenous patient-controlled analgesia (PCA-IV) and patient-controlled epidural analgesia (PCEA), on cognitive functioning in the immediate postoperative period. Patients hospitalized for elective surgery were randomly assigned to one of the treatment groups (30 patients per group). A battery of objective, standardized neuropsychological tests was administered preoperatively and 24 hours after surgery. Pain intensity was also evaluated. Nonoperated volunteers served as controls. Patients of the PCA-IV group exhibited significantly higher pain scores than did patients of the PCEA group. PCA-IV patients exhibited significant deterioration in the postoperative period in all the neuropsychological measures, while the PCEA patients exhibited significant deterioration only in one cognitive index, compared to controls.

The suppression of natural killer (NK) cell cytotoxicity by footshock stress can be attenuated by opioid antagonists, implicating endogenous opioids in its mediation. A stress paradigm that induces NK suppression that is not blocked by the opioid antagonist naltrexone is reported. This stress paradigm is also shown to cause analgesia and elevated plasma corticosterone levels that are not attenuated by naltrexone. In the first experiment, a significant suppression of NK cell cytotoxicity after forced swimming was demonstrated in Fischer 344 rats treated with either saline or naltrexone, compared with nonstressed controls. Significantly higher corticosterone levels were evident in both stressed groups. In the second experiment, the same stress paradigm was shown to cause significant analgesia in the tail-flick test, whereas no differences were seen between groups pretreated with saline and naltrexone. It is concluded that opioids need not always be involved in the suppression of NK cell cytotoxicity by stress.

Inflammatory cytokines and the cholinergic system have been implicated in the effects of stressors on mood and memory; however, the underlying mechanisms involved and the potential interrelationships between these pathways remain unclear. To address these questions, we administered neuropsychological tests to 33 generally healthy surgery patients who donated blood samples several days prior to undergoing moderate surgery (baseline), on the morning of the surgery (i.e., a psychological stressor), and one day after surgery. Eighteen control subjects were similarly tested. Serum levels of inflammatory cytokines, acetylcholinesterase (AChE) activity, and the stressor-inducible AChE-R variant were measured. An elevation in anxiety levels, an increase in depressed mood, and a decline in declarative memory were observed on the morning of the surgery, prior to any medical intervention, and were exacerbated one day after surgery. The surgical stressor-induced elevated IL-1 beta levels, which contributed to the increased depressed mood and to the post-surgery increase in AChE-R expression. The latter increase, which was also predicted by pre-surgery AChE-R and post-surgery mood disturbances, was associated with exacerbated memory impairments induced by surgery. In addition, elevated levels of AChE-R on the morning of the surgery predicted the post-surgery elevation in IL-6 levels, which was associated with amelioration of the memory impairments induced by surgery. Taken together, these findings suggest that exposure to a surgical stressor induces a reciprocal up-regulation of AChE-R and pro-inflammatory cytokines, which are involved in regulating the surgery-induced mood and memory disturbances.

The postoperative period is associated with neuroendocrine, metabolic, and immune alterations, which are the combined result of tissue damage, anesthesia, postoperative pain, and psychological stress. Limited evidence indicates that pain management in the postoperative period can affect the outcome of the surgery, reducing cardiac, pulmonary, and metabolic complications. Recent evidence indicates that pain and immune factors, especially proinflammatory cytokines, mutually interact and influence each other. A series of animal studies demonstrates that effective preemptive analgesia improved postoperative recovery, and this effect was enhanced by coadministration of IL-1ra together with the preemptive analgesics. Furthermore, preemptive analgesia attenuated surgery-induced PGE(2) production in the amygdala and the activation of the HPA axis. IL-1 signaling is required for the production of amygdala PGE(2) in response to surgical stress, and may thus affect the physiological and psychological aspects of surgical stress. These reports suggest that short-term effective analgesia can have long-lasting beneficial effects on surgery recovery. They further suggest that IL-1 blockade should be considered in the clinical management of pain associated with peripheral or nerve injury. Another series of human studies describes an interaction between the effectiveness of postoperative pain relief and surgery-associated immune alterations: In three separate studies, the more effective pain management technique was associated with diminished surgery-induced immune alterations, especially diminished elevation of IL-1. Reduced elevation of postoperative IL-1 and effective pain relief may both contribute to an attenuated illness response and a better surgery outcome.

The present study compared three postoperative pain management techniques in patients undergoing lower abdominal surgery: intermittent opiate regimen (IOR), patient-controlled analgesia (PCA), and patient-controlled epidural analgesia (PCEA), on cortisol and prolactin levels during the first 48h postoperatively. Ninety-two patients scheduled for a lower abdominal surgery, were randomly assigned to one of three study groups: IOR ( N =31), PCA ( N =31), and PCEA ( N =30). Patients of the IOR group received postoperatively 50–75mg of pethidine IM on demand. Patients of the PCA group received a loading dose of morphine (3–4mg), followed by 1mg bolus of morphine IV per demand. Patients of the PCEA group received 3ml of 0.1% bupivacaine plus 2μg/ml of fentanyl per demand, with continuous background infusion of 6ml/h. Venous blood samples were collected preoperatively, and 24 and 48h after surgery, and were later assayed for serum cortisol and prolactin levels. Patients of the PCEA group exhibited diminished postoperative elevation of serum cortisol levels at 24 and 48h (24.4, 18.6μg/dl, respectively) compared with both IOR (31.9, 21.9) and PCA (28.5, 22.3) groups. Similarly, patients of the PCEA group exhibited diminished postoperative elevation of serum prolactin level (20.7, 15.7ng/mL) compared with PCA (24.9, 17.1) group. The present results indicate that the PCEA technique offers an advantageous treatment associated with reduced postoperative pain, and attenuated neuroendocrine response.

We examined the effects of two perioperative pain management techniques on recovery after laparotomy, as assessed by body weight (BW) and food consumption (FC). All rats received a preoperative intrathecal mixture of morphine plus bupivacaine combined with one of two treatments: (a) injection of slow-release morphine at the end of the surgery or (b) an antiinflammatory drug, interleukin-1 receptor antagonist (IL-1ra), combined with the preoperative mixture. Laparotomy significantly decreased FC and BW. Both analgesic treatments resulted in a faster recovery of FC and BW. This beneficial effect was more pronounced in the group receiving preoperative analgesics combined with IL-1ra.Effective perioperative pain management can improve postoperative recovery. We studied the effects of two preoperative pain management techniques on recovery after laparotomy in rats. Both analgesic treatments resulted in a faster recovery, especially preoperative analgesics combined with interleukin-1 receptor antagonist.

Peripheral nerve injury may lead to neuropathic pain, which is often associated with mechanical and thermal allodynia, ectopic discharge of from injured nerves and from the dorsal root ganglion neurons, and elevated levels of proinflammatory cytokines, particularly interleukin-1 (IL-1). In the present study, we tested the role of IL-1 in neuropathic pain models using two mouse strains impaired in IL-1 signaling: Deletion of the IL-1 receptor type I (IL-1rKO) and transgenic over-expression of the IL-1 receptor antagonist (IL-1raTG). Neuropathy was induced by cutting the L5 spinal nerve on one side, following which mechanical and thermal pain sensitivity was measured. Wild-type (WT) mice and the parent strains developed significant allodynia and hyperalgesia in the hind-paw ipsilateral to the injury compared with the contralateral hind-paw. The mutant strains, however, did not display decreased pain threshold in either hind-paw. Pain behavior was also assessed by cutting the sciatic and saphenous nerves and measuring autotomy scores. WT mice developed progressive autotomy, beginning at 7 days post-injury, whereas the mutant strains displayed delayed onset of autotomy and markedly reduced severity of the autotomy score. Electrophysiological assessment revealed that in WT mice a significant proportion of the dorsal root axons exhibited spontaneous ectopic activity at 1, 3, and 7 days following spinal nerve injury, whereas in IL-1rKO and IL-1raTG mice only a minimal number of axons exhibited such activity. Taken together, these results suggest that IL-1 signaling plays an important role in neuropathic pain and in the altered neuronal activity that underlies its development.

Surgical stress is the combined result of tissue injury, anesthesia, and postoperative pain. It is characterized by elevated levels of adrenocorticotropin (ACTH), corticosterone (CS), and elevated levels of prostaglandin E2 (PGE2) in the periphery and in the spinal cord. The present study examined the effects of perioperative pain management in rats undergoing laparotomy on serum levels of ACTH, CS, and on the production of PGE2 in several brain regions, including the amygdala. The amygdala is known to modulate the pituitary-adrenal axis response to stress. We, therefore, also examined the effects of bilateral lesions in the central amygdala (CeA) on laparotomy-induced activation of the pituitary-adrenal axis in rats. In the first experiment, rats either underwent laparotomy or were not operated upon. Half the rats received preemptive analgesia extended postoperatively, the other received saline. ACTH, CS serum levels, and ex vivo brain production of PGE2 were determined. In the second experiment, rats underwent bilateral lesions of the CeA. Ten days later, rats underwent laparotomy, and ACTH and CS serum levels were determined. Laparotomy significantly increased amygdala PGE2 production, and CS and ACTH serum levels. This elevation was markedly attenuated by perioperative analgesia. Bilateral CeA lesions also attenuated the pituitary-adrenal response to surgical stress. The present findings suggest that the amygdala plays a regulatory role in mediating the neuroendocrine response to surgical stress. Effective perioperative analgesia attenuated the surgery-induced activation of pituitary-adrenal axis and PGE2 elevation. The diminished elevation of PGE2 may suggest a mechanism by which pain relief mitigates pituitary-adrenal axis activation.

Pain sensitivity reflects a balance between pain facilitatory and inhibitory systems. To characterize the relationships between these systems we examined the interactions between the analgesic effects of morphine and the anti-analgesic effects of the pro-inflammatory cytokine interleukin-1 (IL-1). We report that administration of a neutral dose of IL-1β abolished morphine analgesia in mice, whereas acute or chronic blockade of IL-1 signaling by various IL-1 blockers (IL-1 receptor antagonist (IL-1ra), α-melanocyte-stimulating hormone, or IL-1 tri-peptide antagonist) significantly prolonged and potentiated morphine analgesia. Morphine-induced analgesia was also extended in strains of mice genetically impaired in IL-1 signaling (mice with transgenic over-expression of IL-1 receptor antagonist, deletion of the IL-1 receptor type I, or deletion of the IL-1 receptor accessory protein). The finding that IL-1 produces a marked anti-analgesic effect, suggests that it may also be involved in the development of opiate tolerance. Indeed, genetic or pharmacological blockade of IL-1 signaling prevented the development of tolerance following repeated morphine administration. Moreover, acute administration of IL-1ra in wild type mice, either immediately following the cessation of acute morphine analgesia, or following the development of chronic morphine tolerance, re-instated the analgesia, suggesting that blockade of the IL-1 system unmasks the analgesic effect of morphine. These findings suggest that morphine produces an IL-1-mediated homeostatic response, which serves to limit the duration and extent of morphine analgesia and which underlies the development of tolerance.

Background: Only two thirds of patients with major depression (MD) respond to antidepressants. Thus, far applicable predictors of responsiveness to selective serotonergic reuptake inhibitors (SSRIs) have not been found. Cumulative evidence linking serotonergic depletion and cognition led us to hypothesize that the neuropsychological functioning of major depression patients may predict their responsiveness to SSRI antidepressants. Methods: Fifty-five patients meeting DSM-IV criteria for major depression and strict inclusion and exclusion criteria underwent an extensive clinical and neuropsychological assessment prior to the initiation of selective serotonergic treatment. Following 6 weeks of treatment, severity of depression was reassessed, yielding a responsiveness score by which classification of each subject as a responder or nonresponder was made. The study was double blind. Results: Logistic regression yielded neuropsychological indices, which significantly predicted the probability of depressed patients to respond favorably to SSRIs. Responders were characterized by better functioning in “simple” tasks and by worse functioning in “complex” tasks compared to nonresponders. No differences were found for more lateralized right or left hemisphere functions between responders and nonresponders. Limitations: Drug treatment comprised of SSRIs but was not standardized. Responsiveness was assessed following 6 weeks of treatment providing for initial amelioration rather than full remission. Placebo response was not controlled for. These limitations may influence the interpretation of the findings. Conclusions: The present findings suggest that responders and nonresponders to SSRIs might be distinguished by their neuropsychological functioning before treatment. If our findings are replicated, more efficient treatment might be practiced.

Surgery is associated with immune alterations, which are the combined result of tissue damage, anesthesia, postoperative pain, and psychological stress. In the present study, we compared the effects of several postoperative pain management techniques on postoperative immune function. Patients hospitalized for abdominal surgery were randomly assigned to one of three postoperative pain management techniques: opiates on demand (intermittent opiate regimen [IOR]), patient-controlled analgesia (PCA), and patient-controlled epidural analgesia (PCEA). Postoperative pain was assessed. Blood samples were collected before and 24, 48, and 72 h after surgery. Production of interleukin (IL)-1beta, IL-2, and IL-6, natural killer cell cytotoxicity, and lymphocyte mitogenic responses were assessed. Patients of the PCEA group exhibited lower pain scores in the first 24 h after surgery compared with patients of the IOR and PCA groups. Mitogenic responses were suppressed in all groups in the first 24 h, returned to preoperative values by 72 h in the PCEA group, but remained suppressed in the PCA group. Production of IL-1beta and IL-6 increased in the IOR and PCA groups, whereas it remained almost unchanged in the PCEA group. Patients receiving an epidural mixture of opiate and local anesthetics (PCEA group) exhibited reduced suppression of lymphocyte proliferation and attenuated proinflammatory cytokine response in the postoperative period.

The cytokine interleukin-1 (IL-1) has been implicated in modulation of pain perception under various inflammatory conditions. The present study examined the hypothesis that IL-1 signaling is also involved in pain sensitivity under normal, non-inflammatory states, using three mouse models of impaired IL-1 signaling: targeted deletion of the IL-1 receptor type I or the IL-1 receptor accessory protein, and transgenic over-expression of IL-1 receptor antagonist within the brain and spinal cord. Thermal and mechanical pain sensitivity was assessed using the paw-flick, hot-plate, and von Frey tests. All mutant strains displayed significantly lower pain sensitivity, compared with their respective wild-type control strains, and with their parent strains (C57BL/6, CBA and 129), in all tests. In contrast, mice with targeted deletion of the p55 or p75 TNF receptor, or of interleukin-18, displayed normal or higher pain sensitivity compared to their respective controls. To differentiate between developmental vs. on-going effects of IL-1, mice were chronically treated with IL-1 receptor antagonist (IL-1ra) via osmotic micropumps, either in adulthood or prenatally (throughout the last 2 weeks of gestation). Adult mice that were treated with IL-1ra either in adulthood or in utero, displayed lower pain sensitivity, similar to mice with impaired IL-1 signaling. These findings suggest that basal pain sensitivity is genetically, developmentally and tonically influenced by IL-1 signaling.

Opiates, which serve an integral role in anesthesia, suppress immune function, particularly natural killer cell cytotoxicity (NKCC). NK cells play an important role in tumor and metastasis surveillance. We reported that large-dose fentanyl anesthesia induced prolonged suppression of NKCC in patients undergoing abdominal surgery. The immune modulatory effects of opiates may depend on the interaction between dose and time of administration. The present study examined the effects of different doses of fentanyl, administered at different time points relative to tumor inoculation, on NKCC and on experimental tumor metastasis in rats.Fischer 344 rats were injected with low or high doses of fentanyl, 6 or 2 h before, simultaneously with or 1 h after being inoculated intravenously with MADB106 tumor cells. Lung tumor retention (LTR) was assessed 4 h after, and lung tumor metastases were counted 3 weeks after tumor inoculation. NKCC was assessed 1 h after the fentanyl injection.At all time points, except 6 h before tumor inoculation, fentanyl (0.1-0.3 mg/kg) induced a dose-dependent increase in MADB106 LTR (2.3- to 74-fold). An intermediate dose of fentanyl (0.15 mg/kg) doubled the number of lung metastasis, and, within animal, suppressed NKCC and increased MADB106 LTR in a correlated manner.These findings indicate that fentanyl suppresses NKCC and increases the risk of tumor metastasis. Suppression of NK cells at a time when surgery may induce tumor dissemination can prove to be critical to the spread of metastases. It is suggested that the acute administration of a moderate dose of opiates during surgery should be applied cautiously, particularly in cancer patients.

Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS-induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-alpha mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.

Activation of the immune system during various medical conditions produces neural, neuroendocrine, and behavioral effects. The psychological and physiological effects of immune activation resemble many characteristics of depression. The essential features of depression are depressed mood and loss of interest or pleasure in all, or almost all activities (anhedonia). Several associated symptoms are also present, including, appetite disturbance, change in body weight, sleep disturbance, psychomotor disturbance, fatigue, loss of energy, and difficulty in thinking or concentrating (DSM-IV, 1994). Depression is also characterized by specific alterations in the functioning of neurochemical and neuroendocrine systems, including monoaminergic systems and the hypothalamic-pituitary-adrenal (HPA) axis (Brown, Steinberg, & van Praag, 1994; Holsboer, 1995). Most of these psychological and neuroendocrine symptoms appear both in humans and animals during diseases that involve immune activation. Based on these findings, and on several additional lines of evidence that will be presented below, we have recently argued that immune activation is involved in the etiology and symptomatology of depression associated with various medical conditions (Yirmiya, 1997).

In the present study, we examined long-term effects of prenatal morphine on pain response and on preference for sweet solutions. Pregnant Fischer 344 rats were given increasing doses of morphine (0.75-12.0 mg/day) in slow-release emulsion, during gestational days 12-18. Control rats were injected with vehicle and were either pair-fed to morphine rats, or ad libitum fed. At birth, all litters were culled to 8-10 pups (half males and half females) and cross-fostered to naive, surrogate dams. Testing began when rats were 10-12 week old. Rats prenatally exposed to morphine exhibited higher analgesia in response to a morphine challenge, and a greater preference for saccharin solution as compared with both control groups. These findings indicate that prenatal morphine induces long-lasting alterations of systems involved in reward processes and in opiate analgesia, perhaps by modulating endogenous opiate systems.

The involvement of endogenous opiates in the differentiation of sexual behavior was tested by exposing rat fetuses to continuous naltrexone during the last 9 days of gestation. Time-mated female rats received oral naltrexone, 40 mg/kg/day, via their drinking water, from gestational day 13 until parturition. Early motor development, measured by swimming ability in 7-, 9-, and 11-day-old offspring of the treated dams, was unaffected by prenatal naltrexone. Adult male offspring were given three tests of male sexual behavior, then castrated, primed with ovarian hormones, and given two tests of feminine receptivity (lordosis quotient). Prenatal naltrexone facilitated masculine behavior and suppressed feminine receptivity: latencies to first mount and to ejaculation were shorter, mount rate was higher, and lordosis quotient was lower in naltrexone-treated rats, compared with control animals. These findings implicate endogenous opiates in prenatal organization of sex-specific behavioral dispositions.

Opiates and endogenous opioid peptides play an important role in reward-mediated behaviors, including self-stimulation. Two strains of rats, LC2-Hi and LC2-Lo, selectively bred for high vs. low rate of lateral hypothalamic self-stimulation, were employed in the present study. Quantitative autoradiography was performed on brains of adult male rats of each strain, using the mu opioid receptor agonist 3H-DAGO. Strain differences in receptor density were observed in the nucleus accumbens and in ventral areas of the hippocampus.

Publisher Summary This chapter discusses stress-induced immune modulation in animals. Stress is associated with alterations of humoral and cellular immune mechanisms in both laboratory animals and humans. Decreased response to mitogens and antigens, reduced lymphocyte-mediated cytotoxicity, reduced delayed hypersensitivity, diminished skin graft rejection and graft-versus-host reactivity, and suppressed antibody response have all been observed after stress. The studies of stress-induced analgesia make it clear that stress can be a physiological trigger for an intrinsic analgesia mediated by opioid peptides. However, these findings make it equally clear that another, nonopioid mechanism of analgesia also exists. Taking advantage of the possibility to dissect stress into parameters causing opioid and nonopioid forms of analgesia might help account for some of the variability in the literature on stress and immunity. Endogenous opioids play a modulatory role in the immune system, and their effects depend on various factors. One such factor is the concentration of these peptides used in vitro. β-endorphin either enhances or inhibits the proliferative response of human lymphocytes and of natural-killer cell activity depending on the concentration added to the media.