The effect of opioid agonists and antagonists on gastrointestinal motility in mice selected for high and low swim stress-induced analgesia.

BACKGROUND: The opioid system in the gastrointestinal (GI) tract plays an important physiological role, but is also responsible for the side effect of opioid drugs, including troublesome constipation in chronic pain treatment. The aim of this study was to characterize and validate a new mouse model to study the effects of opioid agonists and antagonists in the GI tract. METHODS: Six-week-old male Swiss-Webster mice, divergently bred for high (HA) and low (LA) swim stress-induced analgesia (SSIA), were used in the study. To assess the influence of opioid agonists (morphine and loperamide) and antagonists (naloxone hydrochloride, NLX and naloxone methiodide, NLXM) on GI motility, whole GI transit (whole GIT) and upper GIT assays were conducted. To evaluate the expression of opioid receptors in the ileum and colon of HA and LA mice, immune staining was performed. KEY RESULTS: The effect of morphine was more pronounced in HA line, whereas loperamide exerted a stronger effect in LA mice. Furthermore, NLX and NLXM differentially abolished the inhibitory action of the central and peripheral opioid system on whole and upper GIT in HA and LA mice. The differences in GI motility between HA and LA mice coexisted with parallel changes in the expression of opioid receptors in the ileum and colon. CONCLUSIONS & INFERENCES: Differences in the activity of the endogenous opioid system are responsible for the vulnerability to changes in GI motility during treatment with opioids. Our findings validate the HA/LA model for further studies on opioids in the GI tract.

Comparison of polypropylene versus polyester mesh in the Lichtenstein hernia repair with respect to chronic pain and discomfort.

BACKGROUND: Inguinal hernias are the most common operative procedure performed by general surgeons, and tension-free mesh techniques have revolutionized the procedure. While hernia recurrence rates have decreased, chronic postoperative pain has become recognized more widely. New mesh products offer the potential to decrease pain without compromising recurrence rates. Polyester mesh is a softer material than traditional polypropylene and may offer the benefit of causing less postoperative pain and improved quality of life. METHODS: Prospective, single-blind, randomized controlled trial involving 78 patients assigned to receive Lichtenstein type repair with either polyester (n = 39) or polypropylene (n = 39) mesh. Attempt was made to identify ilioinguinal, iliohypogastric, and genitofemoral nerves intraoperatively and document their handling. Patients were interviewed and examined preoperatively and postoperatively at 2 weeks and 3 months. Inguinal Pain Questionnaire (IPQ) and VAS scores were obtained and analyzed using two sample t test for continuous variables and Chi-square test for categorical variables. RESULTS: VAS scores at 3 months were 0.46 for the polyester group versus 0.56 for the polypropylene group (P = 0.6727). At 3 months, 82.3% of the polyester and 76.4% of the polypropylene group had VAS = 0 (P = 0.5486). There was no significant difference between the two groups' VAS scores at 3 months. IPQ did not show any difference between the two groups with the exception of "catching or pulling" being reported in 34.3% of polyester and 5.7% of polypropylene groups (P = 0.0028). CONCLUSIONS: Polyester mesh does not decrease the amount of chronic pain at 3 months. Outcomes with polyester mesh are comparable to polypropylene mesh for Lichtenstein inguinal hernia repair with regards to postoperative pain and quality of life. The sample size in this study was small and limits the significance of the results. Further studies are needed to find the optimal mesh for inguinal hernia repair.

[Alström-syndrome: a missed diagnosis with consequences]. / Alström-Syndrom: Eine verkannte Diagnose mit Konsequenzen.

BACKGROUND: Alström-syndrome (OMIM: 203 800) is a rare disease with autosomal recessive inheritance. Characteristic features are retinal degeneration, truncal obesity, diabetes mellitus and sensorineural hearing loss. Further variable symptoms include chronic hepatitis and asthma. CASE REPORT: A patient with asthma associated with retinal degeneration is presented. The investigations demonstrated truncated obesity, sensorineural deafness and impaired glucose tolerance and Alstrom-syndrome was diagnosed. She received hearing aids, diabetes training and is regularly reinvestigated for further manifestations of Alström-syndrome.

Tamoxifen side effects, age-related macular degeneration (AMD) or cancer associated retinopathy (CAR)?

PURPOSE: Differential diagnosis of maculopathies can be difficult but is important if patients also suffer from other diseases such as breast cancer treated with antiestrogens. The main possible diagnoses, especially in the elderly, are age-related macular degeneration, tamoxifen and cancer-associated retinopathy (CAR). METHODS: We describe an 84-year-old patient with breast and colon cancer, who complained of a decrease in visual acuity after treatment with low-dose antiestrogens. She underwent a general ophthalmological investigation, perimetry and electroretinographic examination with multifocal (m-ERG) and flash-electroretinogram (flash-ERG). RESULTS: Visual acuity was reduced to 1/50 and 0.3. The ophthalmological examination was normal, except for extensive bilateral maculopathy with shining crystalline deposits, central and peripheral visual field defects, slightly affected scotopic and photopic potentials in the flash-ERG, and an abnormal m-ERG. CONCLUSIONS: The findings are expected with age-related macular degeneration with crystalline drusen, but also with CAR. Even if the single and total dosage of antiestrogens given to the patient is sufficient to cause tamoxifen retinopathy, this diagnosis can be excluded because, in tamoxifen retinopathy unlike in the case presented here, the deposits are not distributed in all retinal layers.

Antidepressant-type effect of the NK3 tachykinin receptor agonist aminosenktide in mouse lines differing in endogenous opioid system activity.

The influence of the tachykinin NK3 receptor agonist, aminosenktide on the immobility in the forced swimming test was studied in mouse lines selectively bred for divergent magnitudes of stress-induced analgesia. The high analgesia (HA) line is known to display enhanced, and the low analgesia (LA) line displays reduced activity of the opioid system. Aminosenktide at doses of 125 microg/kg or 250 microg/kg intraperitoneally (IP) reduced, in naltrexone-reversible manner, the immobility more of opioid receptor-dense HA than of unselected mice, but was ineffective in the opioid receptor-deficient LA line. The effect of aminosenktide was quite similar to the antiimmobility action of desipramine (10 mg/kg IP), a prototypic antidepressant agent. None of the compounds increased animals' locomotion as found with an open field test; therefore their antiimmobility effect cannot be attributed to a change in general motility. The results claim that aminosenktide causes an antidepressant effect, and endogenous opioids are involved in this process.

Acoustic startle and open-field behavior in mice bred for magnitude of swim analgesia.

Acoustic startle response (ASR) and open-field activity was examined in the 46th generation of mice that have been selectively bred for high analgesia (HA) and for low analgesia (LA) induced by 3-min swimming in 20 degrees C water. These lines were earlier found to differ in brain opioid receptor density and in the expression of opioid-mediated phenomena, as analgesic sensitivity to opiates and reversibility of swim stress-induced analgesia (SSIA) by naloxone. For comparison, a randomly bred control (C) line was used. To measure the amplitude of ASR, the mice were exposed to 110-dB acoustic stimuli in a Coulbourn apparatus. In saline-injected mice, the ASR force was found significantly lower in the LA than in the HA, as well in the C line, but did not differ between the two last lines. Naltrexone hydrochloride (10 mg/kg IP 30 min before ASR testing) augmented the startle in the opioid receptor-dense HA line, but had no effect in the opioid receptor-deficient LA line, as well in the C line; therefore, the ASR magnitude in naltrexone-injected HA mice was significantly higher compared to the C line. HA mice displayed less activity in an open-field test; that is, they remained immobile longer in the center of the field, and thereafter performed less ambulation and less rearing against the wall compared to the LA line. Naltrexone failed to modify the open-field activity in any line. The results confirm that the pattern of ASR depends on the genetic makeup of the animals. The higher amplitude of ASR, taken together with the lower open-field activity of HA mice, can be interpreted in terms of higher anxiety level, compared to the LA line. It is suggested that the higher ASR in HA mice relies on a nonopioid mechanism, which is tonically inhibited by the opioid system.

[Reading ability and need for reading aids, inadequate management of a nursing home population]. / Lesefähigkeit und Hilfsmittelbedarf, Unterversorgung in einer Altenheimpopulation.

INTRODUCTION: In our society people are getting older and often become handicapped and immobile. Reading then is one of their main passtime and very important for their social integration and independence. PATIENTS AND METHODS: Seventy-seven (6 males, 71 females) randomly chosen elderly people (age ranged from 77 to 94 years, mean: 85.5 years) staying in nursing homes were examined concerning their reading ability of newspaper print with their own reading equipment. Exclusion criteria were extensive organic diseases and impaired mental ability, such as dementia. Relevant anamnestic data, including ophthalmologic, family and social history were ascertained by questionnaire. Special attention was given to visual acuity for near distance, reading ability, motivation and personal reading aids. Further questions dealt with general diseases, medication, social contacts inside and outside the nursing homes and the former occupation of the patient. If reading of newspaper print with individual glasses was impossible, the effect of magnification was evaluated and the magnification factor was determined (Zeiss reading charts). RESULTS: Thirty-eight people (45%) were unable to read with their own reading glasses. 91% of them regained reading ability by magnification, they had inadequate visual aids. 77% of this group had a magnification requirement of 1 to 3 times, 14% needed 10 to 25 times of magnification and 9% more than 25 times. Only one person had an electronic magnifying reading system (CCTV). CONCLUSION: Reading aids of elderly people very frequently are insufficient. Magnification can be helpful in most cases and various magnification systems are available. With this support elderly people could regain their quality of life, their independence and socialization. Nursing costs could also be reduced.

Alterations of brain monoamine levels in pigs exposed to acute immobilization stress.

Concentrations of noradrenaline (NA), adrenaline (A), dopamine (DA) and 5-hydroxytryptamine (5-HT), as well as DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and the main 5HT metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), were measured using the HPLC technique in 15 brain areas of control and immobilized Duroc pigs. The animals were immobilized for 5, 15, 30 and 60 min in a prone position. Control pigs displayed patterns of regional distribution of brain monoamines similar to those described in other species, especially rats and dogs. However, absolute values of noradrenaline and adrenaline in the hypothalamus were much higher than in other species. Also, in most structures, the DOPAC/DA ratio was relatively high, in comparison to a relatively low HVA/DA ratio, which suggests a species-related difference in the turnover of dopamine. The most conspicuous changes produced by immobilization stress consisted of a substantial decrease in the hypothalamic levels of noradrenaline and adrenaline. Dopamine and 5-HT turnover was affected in the hippocampus (cornu Ammonis), and in the raphe nuclei. These structures are proposed to play a major role in the responsiveness of pigs to acute stress conditions.

Analgesia in selectively bred mice exposed to cold in helium/oxygen atmosphere.

In order to evaluate the stressing role of swim hypothermia in producing swim stress-induced analgesia (SSIA), we examined whether a mere decrease in the animals' core temperature without swimming would be sufficient to elicit analgesia. The subjects were Swiss-Webster mice selectively bred for 37 and 40 generations for divergent magnitudes of SSIA. High (HA) and low analgesia (LA) mice were exposed for 15 min to temperatures in the range between -5 and +20 degrees C in 79% He/21% O2 (Heliox) atmosphere. The Heliox exposure produced ambient temperature-dependent hypothermia and analgesia, as assessed with a hot-plate test (56 degrees C). The post-Heliox analgesia was of much higher magnitude in HA than in LA mice. The steeper slope of regression of the magnitude of analgesia upon hypothermia in HA mice indicates that these mice are far more sensitive to the analgesic effect of hypothermia than LA mice. Naltrexone HCl (10 mg/kg i.p.) attenuated analgesia in ambient temperature-dependent manner in HA, but not in LA mice. In view of the apparent similarity of Heliox-induced analgesia and SSIA we suggest that hypothermia is a powerful component of swim stress to induce SSIA in the mouse.

Mu and delta opioid receptor analgesia, binding density, and mRNA levels in mice selectively bred for high and low analgesia.

The present study examined mu and delta opioid analgesia, receptor binding, and receptor mRNA levels in lines of mice from two selective breeding projects of relevance to opioid analgesia. Large differences were observed in the analgesic potency of [d-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO), [d-Pen2,5]enkephalin (DPDPE), and [d-Ala2]deltorphin II (DELT), selective mu, delta1, and delta2 opioid receptor agonists, respectively, in mice selectively bred for high (HA) and low (LA) swim stress-induced analgesia (SIA). HAR and LAR mice, selectively bred for high and low levorphanol analgesia, respectively, display equally large differences in their analgesic sensitivity to DAMGO, modest differences in sensitivity to DPDPE, and no differences in sensitivity to DELT. These sizable genotypic differences in analgesic potency were accompanied by HA/LA and HAR/LAR differences in whole-brain homogenate [3H]DPDPE and/or [3H]DELT, but paradoxically not [3H]DAMGO, binding. Solution hybridization of mRNA extracts encoding mu (MOR-1) or delta (DOR-1) opioid receptors indicated some regional differences in gene expression between high and low lines. Surprisingly, differences in these in vitro markers were often in the direction of LAR>HAR. The present data indicate that selection for either SSIA or levorphanol analgesia produces differential effects on mu and delta opioid analgesia that are accompanied by alterations on in vitro assays, the significance of which remains to be determined. The data are discussed with regard to the utility of in vitro biological markers and genetic models of analgesia.

Acute morphine dependence in mice selectively-bred for high and low analgesia.

Acute morphine dependence was compared in mice selectively-bred for high (HA) and low (LA) swim stress-induced analgesia and high (HAR) and low (LAR) levorphanol analgesia by counting the number of naloxone-precipitated jumps. Whereas LAR mice displayed greater acute morphine dependence than HAR mice, HA and LA mice did not differ. No genotypic differences were observed in non-dependent mice, discounting possible differences in basal naloxone sensitivity and/or opioid peptide levels. Thus, the two selection projects, while both producing lines exhibiting highly divergent sensitivity to morphine analgesia, have not had analogous effects on all opioid measures, supporting the notion of independent genetic mediation of opioid analgesia and dependence. Further, these data suggest that analgesic sensitivity may not predict sensitivity to morphine dependence.

Cone and rod function in cone degenerations.

Progressive cone dystrophy (CD) is usually marked in the initial stages by reduced visual acuity, color vision deficiency and alterations in the photopic electroretinogram, while morphological alterations can be very mild; in some forms rods are affected in a later stage as well. We examined 40 patients with progressive cone dystrophy to determine the extent of functional losses in the cone system with psychophysical tests. A great variety of visual acuity and fundus alterations was found. Myopia was present in 74% of the patients. An autosomal dominant pattern of inheritance predominated (32%). No prevalence of gender was found. The age of onset ranged between 10 and 30 yr. All patients had progression of their symptoms. The total error score in color arrangement tests, the saturated Farnsworth Panel D-15 and the Farnsworth-Munsell 100-hue test, was pathologic with a predominance of confusions along the tritan and scotopic axis. Especially if visual acuity was below 0.5, color vision defects increased, but color vision defects were also found in patients with normal visual acuity. A general decrease of sensitivity in all three cone mechanisms was observed in measurements of spectral sensitivity. Moreover, cone-cone interaction as tested by transient tritanopia measurements was usually disturbed. In the dark adaptation function the threshold of the cone branch was usually elevated. These tests provide a good means to ascertain the correct diagnosis in early stages of the disease and to monitor progression in patients suffering from cone dystrophy.

Metabolic correlates of selection for swim stress-induced analgesia in laboratory mice.

The upper limits of metabolic rates and the links between maximal and resting metabolic rates in vertebrates have recently received a lot of attention, mainly due to their possible relationship to the evolution of endothermy. We measured peak metabolic rates during 3 min swimming in 20 degrees C water (Vo2swim), maximal metabolic rate (Vo2max) in -2.5 degrees C Helox, and basal metabolic rate (BMR) in two lines of mice selected for high (HA) and low (LA) swim stress-induced analgesia (SSIA). We found that exercise combined with heat loss used for producing SSIA also acted as a selection agent, resulting in a 15% HA/LA line difference in Vo2swim. Core body temperature of HA mice (characterized by lower Vo2swim) was also on average 3.2 degrees C lower than that of LA mice. Furthermore, Vo2max of HA mice was lower than that of LA mice by 8% and accompanied by larger hypothermia. Thus mice with exceptionally high (or low) Vo2max tended to have exceptionally high (or low) Vo2swim, resulting in a positive correlation between Vo2swim and Vo2max. All these suggest that selection for SSIA produced genetically correlated responses in both Vo2swim and Vo2max. However, we did not observe HA/LA differences in BMR. Hence, changes in resting and maximum metabolic rates are not necessarily correlated. We hypothesize that the lack of such a correlation was partially due to the modulation of metabolic responses by SSIA.

["Oligocone" trichromasy, a rare form of incomplete achromatopsia]. / Die "Oligocone"-Trichromasie, eine Sonderform der inkompletten Achromatopsie.

PATIENTS AND METHODS: An 11-year-old girl presented because of reduced visual acuity while color vision was almost normal. Besides a general ophthalmological examination, special psychophysical tests, such as perimetry, color vision tests using pseudoisochromatic plates, arrangement tests, the Nagel anomaloscope and spectral sensitivity measurement, and electrophysiological tests (electroretinogram and electrooculogram) were conducted. RESULTS: The tests yielded the following: congenital nystagm, normal results at ophthalmoscopy, best visual acuity of 0.1 monocular and 0.2 binocular. Perimetry revealed a relatively central scotoma. All color vision tests showed only mild dysfunction of the blue-sensitive cones. Findings at photopic electroretinogram were almost completely lacking. There was no sign of progression in the last 6 years. CONCLUSION: Differential diagnosis includes all diseases associated with congenital nystagm, such as aniridia, diseases of the optic nerve, albinism and all forms of hereditary cone dysfunction, cone dystrophies and complete and incomplete congenital stationary monochromatism. In the present case the findings are most congruent with oligocone trichromasy.

Differential sensitivity of mice bred for stress-induced analgesia to morphine and ACEA-1011 in the formalin test.

The antinociceptive effect of morphine, an opioid receptor agonist, and ACEA-1011, a novel NMDA receptor/glycine site antagonist, was examined in the formalin test in mice selectively bred for high (HA) and low (LA) swim stress-induced analgesia (SSIA). A subcutaneous (SC) injection of formalin produced a biphasic nociceptive response in both lines. HA mice spent more time licking the injected paw than the LA mice in both phases of the formalin test. Morphine was equally potent in the early phase in both lines, but it was more potent in HA mice than in LA mice in the tonic late phase of the formalin test. Similarly, ACEA-1011 produced an equally potent antinociceptive effect in the early phase in both lines; however, the compound was more potent in LA mice than in HA mice in the tonic late phase of the formalin test. These data suggest that in HA mice antinociception in the tonic late phase of the formalin test is mediated largely by an opioid-mediated mechanism, whereas in the opioid-deficient LA line at least a nonopioid-mediated mechanism involving the NMDA receptor is also implicated.

The genetics of pain and pain inhibition.

The present review summarizes the current state of knowledge about the genetics of pain-related phenomena and illustrates the scope and power of genetic approaches to the study of pain. We focus on work performed in our laboratories in Jastrzebiec, Poland; Portland, OR; and Los Angeles, which we feel demonstrates the continuing usefulness of classical genetic approaches, especially when used in combination with newly available molecular genetic techniques.