Low anterior resection syndrome (LARS): cause and effect and reconstructive considerations.

Between 25 and 80% of patients undergoing a low or very low anterior resection will suffer postoperatively, from a constellation of symptoms including fecal urgency, frequent bowel movements, bowel fragmentation and incontinence, collectively referred to as the low anterior resection syndrome (LARS). The etiology of LARS is multifactorial with the potential of sphincter injury during anastomosis construction, alterations in anorectal physiology, the development of a pudendal neuropathy, and a lumbar plexopathy with exacerbation of symptoms if there is associated anastomotic sepsis or the use of adjuvant and neoadjuavnt therapies. The symptoms of LARS may be obviated in part by the construction of a neorectal reservoir which may take the form of a colonic J-pouch, a transverse coloplasty, or a side-to-end anastomosis. This review outlines the factors contributing to LARS symptomatology along with the short- and medium-term functional results of comparative trials with the different types of neorectal reconstructions.

Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity.

The cytotoxic activity of natural killer cells was investigated in rats subjected to one of two inescapable footshock stress paradigms, both of which induce analgesia, but only one via activation of opioid mechanisms. Splenic natural killer cell activity was suppressed by the opioid, but not the nonopioid, form of stress. This suppression was blocked by the opioid antagonist naltrexone. Similar suppression of natural killer activity was induced by high doses of morphine. These results suggest that endogenous opioid peptides mediate the suppressive effect of certain forms of stress on natural killer cell cytotoxicity.

Intrinsic mechanisms of pain inhibition: activation by stress.

Portions of the brain stem seem normally to inhibit pain. In man and laboratory animals these brain areas and pathways from them to spinal sensory circuits can be activated by focal stimulation. Endogenous opioids appear to be implicated although separate nonopioid mechanisms are also evident. Stress seems to be a natural stimulus triggering pain suppression. Properties of electric footshock have been shown to determine the opioid or nonopioid basis of stress-induced analgesia. Two different opioid systems can be activated by different footshock paradigms. This dissection of stress analgesia has begun to integrate divergent findings concerning pain inhibition and also to account for some of the variance that has obscured the reliable measurement of the effects of stress on tumor growth and immune function.

Stress and pain responses in rats lacking CCK1 receptors.

UNLABELLED: CCK involvement in stress- and pain-responsiveness was examined by studying the behavior 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.

Postoperative pain, morphine consumption, and genetic polymorphism of IL-1beta and IL-1 receptor antagonist.

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.

Stress-induced suppression of natural killer cell cytotoxicity in the rat: a naltrexone-insensitive paradigm.

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.

Illness, cytokines, and depression.

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.

Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth.

Exposure to stress has been associated with alterations in both immune function and tumor development in man and laboratory animals. In the present study, we investigated the effect of a particular type of inescapable footshock stress, known to cause an opioid mediated form of analgesia, on survival time of female Fischer 344 rats injected with a mammary ascites tumor. Rats subjected to inescapable footshock manifested an enhanced tumor growth indicated by a decreased survival time and decreased percent survival. This tumor enhancing effect of stress was prevented by the opiate antagonist, naltrexone, suggesting a role for endogenous opioid peptides in this process. In the absence of stress, naltrexone did not affect tumor growth.

Activating endogenous opioid systems by electroconvulsive shock or footshock stress inhibits recurrent kindled seizures in rats.

Electroconvulsive shock (ECS) significantly decreased the behavioral manifestations of seizures elicited by amygdaloid stimulation in kindled rats. This anticonvulsant effect was significantly reduced by the opiate antagonist, naloxone, and by the development of morphine tolerance. A form of footshock stress known to cause opioid-mediated analgesia had a similar anticonvulsant effect, whereas another form causing non-opioid analgesia did not. These results suggest that the anticonvulsant effects of ECS and stress are mediated by the release of endogenous opioids.

Stimulation of the hypothalamic paraventricular nucleus produces analgesia not mediated by vasopressin or endogenous opioids.

The analgesic effect of electrical stimulation of the hypothalamic paraventricular nucleus (PVN) was studied. Additionally, the involvement of vasopressin and opioid peptides in this process was examined by comparing vasopressin-deficient (Brattleboro) and Long-Evans rats and by administering the opiate antagonist naloxone. Rats were chronically implanted with a stimulating electrode in the parvocellular (PVN-Pc) and magnocellular (PVN-Mg) divisions of the PVN. At least 10 days after surgery, the analgesic effects of PVN stimulation were examined in lightly anesthetized rats, using the tail-flick method, and in unanesthetized rats, using the hot-plate test. PVN stimulation produced marked analgesia in both tests. Current threshold for analgesia was lower from PVN-Pc than from PVN-Mg. Threshold did not differ significantly between Brattleboro and Long-Evans rats and was not affected by naloxone administration. The results indicate that the PVN is part of the brain's pain inhibitory system, and show that the analgesia induced by PVN stimulation is not mediated by either vasopressin or opioid peptides.

Natural killer cell activity in vasopressin-deficient rats (Brattleboro strain).

Several lines of evidence suggest that the neuropeptide vasopressin is involved in the regulation of the immune system. We explored this possibility by comparing the cytotoxic activity of natural killer (NK) cells in Brattleboro (DI) rats, which are homozygous for diabetes insipidus and lack vasopressin, and Long-Evans (LE) rats, the strain from which DI rats were derived. Additionally, we compared the effects of swim stress, morphine administration and vasopressin replacement on NK cell activity in these two strains. In DI rats, NK cell activity, determined by a standard 4-h chromium-release assay, was significantly higher than in LE rats. Both swim stress and morphine administration suppressed NK activity in DI and LE rats. There was no difference in the level of suppression between the two strains. Vasopressin replacement normalized water intake in DI rats, but had no significant effect on NK cell activity. DI rats exhibited lower plasma corticosterone levels, which were not elevated by vasopressin replacement. The results suggest that the lack of vasopressin in DI rats elevates baseline NK cell activity, probably via mechanisms that are secondary to the vasopressin deficiency (e.g. lower corticosterone levels). Neither vasopressin nor other hormones affected by vasopressin deficiency seem to be involved in the acute modulating effects of stress and morphine on NK cells.

Behavioral and electrographic effects of opioids on kindled seizures in rats.

Our laboratory previously suggested that opioid peptides are released by an amygdaloid kindled seizure and may affect the elicitation of a subsequent seizure. The present study examined the effects of morphine, naloxone, enkephalin analogues, and conditions of morphine tolerance and withdrawal on the severity and duration of a series of amygdaloid kindled seizures. The results suggest two distinct opiate/opioid actions on seizures. The first is an anticonvulsant effect on the behavioral manifestations of seizures. This effect is seen following a high dose (50 mg/kg) of morphine or a low dose (6 mg/kg) of enkephalin analogue (LY146104), and is reversed by naloxone. The second is a naloxone-reversible prolonging effect of the high dose of morphine on the electrographic components of the seizures. Receptor affinities of these various opiate/opioid drugs suggest that these two actions are mediated by different receptors which appear not to include high affinity mu receptors.

Effects of footshock stress and morphine on natural killer lymphocytes in rats: studies of tolerance and cross-tolerance.

Exposure to a form of footshock stress known to cause opioid-mediated analgesia suppresses the cytotoxic activity of natural killer (NK) cells in rats. This suppression is blocked by the opioid antagonist, naltrexone and is mimicked by morphine administration, suggesting mediation by opioid receptors. Supporting this hypothesis, we now report that the morphine-induced suppression of NK activity shows tolerance after 14 daily injections. The NK-suppressive effect of stress, however, shows neither tolerance with repetition nor cross-tolerance in morphine-tolerant rats.

Age related change of optokinetic nystagmus in healthy subjects: a study from infancy to senescence.

BACKGROUND: Optokinetic nystagmus (OKN) gain is asymmetrical between temporal to nasal (TN) and nasal to temporal (NT) stimulation in infancy and decreases at older ages. The age at which OKN gain becomes symmetrical and decreases is debated. The aim was to investigate OKN over the whole lifespan in a large sample of healthy subjects. METHODS: In a prospective, cross sectional study OKN was tested monocularly using TN and NT small field stimulation. Stimulation velocity was 15 degrees /s and 30 degrees /s for children aged under 1 year (n = 97), and 15 degrees /s, 30 degrees /s, 45 degrees /s, and 60 degrees /s for older subjects (1-9 years, n = 66; 10-89 years, n = 86). Gain was measured using infrared oculography. RESULTS: Significant OKN gain asymmetry in favour of TN versus NT stimulation was found during the first 5 months of life (p<0.05). Only at 11 months of age was OKN symmetrical in 100% of the subjects. The percentage of children with symmetrical OKN decreased with increasing stimulus velocity. OKN gain increased in the second and third years (p<0.05 for 15 degrees /s), remained stable until 50 years of age, and showed a small but significant decrease afterwards for the tested velocities (between 6% and 18%, p<0.05). CONCLUSIONS: Infrared oculography is an accurate method to assess OKN, especially in children. Knowledge about change of OKN in healthy subjects could be helpful to interpret OKN in patients with abnormal binocular vision or lesions of the central nervous system.

Comparison of mu opioid receptors in brains of rats bred for high or low rate of self-stimulation.

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.

An electrophysiological correlate of amphetamine revealed motor imbalance in albino rats.

Ten out of eleven Wistar rats displayed a reliable interhemispheric asymmetry of the secondary slow negative wave (SNW) of the visual evoked potential. A more synchronized EEG was observed on the side of facilitated SNW. The analysis of rotation directionality in the rotometer of these rats after IP (+)-amphetamine administration (1.25 mg/kg) showed that rats reliably rotated towards the side with a more facilitated SNW. It is believed that an imbalance of nigrostriatal DA content underlies the interhemispheric asymmetry of EEG and evoked potentials.

Prenatal exposure to morphine alters analgesic responses and preference for sweet solutions in adult rats.

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.

Prenatal exposure to morphine feminizes male sexual behavior in the adult rat.

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.

Prenatal morphine enhances morphine-conditioned place preference in adult rats.

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.

Prenatal naltrexone facilitates male sexual behavior in the rat.

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.