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PubMed2004

Serum hyaluronan and hyaluronidase: very early markers of toxic liver injury.

BACKGROUND: Dimethylnitrosamine (DMN), a potent hepatotoxin, administered to rats, provides a convenient model for toxic liver injury. Indicators of early liver injury are important clinically, for surveillance, for screening new drugs that are potentially hepatotoxic and for identifying drugs that protect against liver injury. Both cirrhosis and wound healing culminate in deposition of fibrous connective tissue and scarring. Increased hyaluronan (HA) occurs in the earliest stage of wound healing. Hyaluronidase, the enzyme that degrades hyaluronan, is also elevated whenever rapid turnover of hyaluronan occurs. We test the hypothesis that elevated levels of circulating hyaluronan and hyaluronidase could provide indicators of very early liver damage. METHODS: Dimethylnitrosamine was administered to adult male albino rats by intraperitoneal injections for 7 consecutive days. RESULTS: Increased serum hyaluronan levels observed on day 2 reached a maximum on day 4. Hyaluronidase was elevated on the first day and reached a maximum on day 2 that was 30-times control levels. Hyaluronan-specific staining in liver sections was maximal on day 7, occurring predominantly in portal triads and in sinusoidal spaces. Individual hepatocytes were slightly enlarged and contained intracellular hyaluronan, which was not evident in control sections. Though circulating hyaluronan levels had decreased after day 4, continued hyaluronan staining persisted in liver sections through day 21. Conventional indicators of liver injury, such as serum aminotransferase enzymes, did not reach a peak until day 7. Conventional gross and histopathological changes, including severe centrilobular congestion and hemorrhagic necrosis, were observed only after day 7. Both hyaluronan and hyaluronidase are indicators of very early liver damage in the dimethylnitrosamine-treated rat, occurring well before conventional indicators appear, or before overt histopathologic changes of liver damage can be seen. However, levels are increased only transiently, indicating that serial assays are necessary. CONCLUSIONS: Measures of circulating hyaluronidase activity may be used to assess liver damage.

Alanine Transaminase↗
PubMed2005

Effects of R-102444 and its active metabolite R-96544, selective 5-HT2A receptor antagonists, on experimental acute and chronic pancreatitis: Additional evidence for possible involvement of 5-HT2A receptors in the development of experimental pancreatitis.

The effects of R-102444 ((2R, 4R)-4-lauroyloxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride) and its active metabolite R-96544 ((2R, 4R)-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-4-hydroxy-1-methylpyrrolidine hydrochloride), potent and selective 5-hydroxytryptamine 2A (5-HT2A) receptor antagonists, on development of pancreatitis were investigated in experimental models of acute and chronic pancreatitis. Rat acute pancreatitis was induced by caerulein (20 microg/kg) intraperitoneal injection and by pancreatic duct ligation. In both the models, serum amylase and lipase activities were markedly increased. R-102444 dose-dependently reduced these enzyme activities at a dose range of 10 to 100 mg/kg (p.o.) for the caerulein model and 0.3 to 10 mg/kg (p.o.) for the ligation model. In a mouse model of acute pancreatitis induced by a choline-deficient, ethionine (0.5%)-supplemented diet, subcutaneous administration of R-96544 (10-100 mg/kg, bid) reduced serum amylase activity. Histological analysis showed that R-96544 dose-dependently attenuated pancreatic necrosis, inflammation and vacuolization. The effect of R-102444 was further examined in male Wistar Bonn/Kobori rats (4-9 months of age) which spontaneously show pancreatic fibrosis and parenchymal destruction compatible with human chronic pancreatitis. In Wistar Bonn/Kobori rats (from 3 to 9 months of age) fed a diet containing 0.017% and 0.17% of R-102444, pancreatic weight, pancreatic protein and amylase content were higher compared to those in non-treated pancreatitis control rats. Histological analysis showed that R-102444 suppressed parenchymal destruction and replacement with adipose tissue, indicating inhibition of pancreatic atrophy. These results clearly indicate that R-102444 and R-96544 inhibit the progression of acute and chronic pancreatitis and support the contention of possible involvement of 5-HT2A receptors in the progression of experimental pancreatitis.

Acute Disease↗
PubMed2004

Apnea and bradycardia due to anaphylaxis to tobacco glycoprotein in the infant rabbit.

Prenatal and postnatal exposure to cigarette smoke is associated with an increased incidence of the sudden infant death syndrome, although the cause(s) for this is unknown. Tobacco glycoprotein (TGP), a group of proteins purified from cured tobacco leaves and present in cigarette smoke, have been shown to cause anaphylaxis in excised hearts and lungs of adult rabbits that were neonatally sensitized to TGP and later rechallenged. We sought to determine whether anaphylaxis occurred in live infant rabbits who were neonatally sensitized to TGP. At the age of 1 day, 12 animals were sensitized to TGP (0.1mg in 0.25 cc alum) via intraperitoneal injection (i.p.i.) followed by a booster ipi at the age of 30 days (TGP-S). Seven animals received i.p.i. of antigen-free alum only (controls). All animals underwent an intravenous TGP challenge at age 42+/-2 days. Heart rate (HR) and respiratory rate (RR) were recorded for 2 min prior to and 5 min after the challenge. Baseline HR (approximately 260) and RR (approximately 120) were similar in all animals. Seven TGP-S animals developed apnea (1.9-4.7s) within 60s of the challenge while none of the controls did. The TGP-S also became bradycardic (the lowest HR over 50 consecutive beats), with the HR decreasing from 260 to 220 vs the controls, whose HR remained constant (approximately 250). We conclude that some rabbits neonatally sensitized to TGP develop apnea and bradycardia upon further intravenous TGP challenge. These studies suggest that cigarette smoke exposure may be associated with a higher rate of SIDS via an anaphylactic mechanism.

Anaphylaxis↗
PubMed2006

Contribution of calpains to photoreceptor cell death in N-methyl-N-nitrosourea-treated rats.

The purpose of the present study was to determine if proteolysis by the calcium-dependent enzyme calpains (EC 3.4.22.17) contributed to retinal cell death in a rat model of photoreceptor degeneration induced by intraperitoneal injection of N-methyl-N-nitrosourea (MNU). Retinal degeneration was evaluated by H&E staining, and cell death was determined by TUNEL assay. Total calcium in retina was measured by atomic absorption spectrophotometry. Activation of calpains was determined by casein zymography and immunoblotting. Proteolysis of alpha-spectrin and p35 (regulator of Cdk5) were evaluated by immunoblotting. Calpain inhibitor SNJ-1945 was orally administrated to MNU-treated rats to test drug efficacy. MNU decreased the thickness of photoreceptor cell layer, composed of the outer nuclear layer (ONL) and outer segment (OS). Numerous cells in the ONL showed positive TUNEL staining. Total calcium was increased in retina after MNU. Activation of calpains and calpain-specific proteolysis of alpha-spectrin were observed after MNU injection. Oral administration of SNJ-1945 to MNU-treated rats showed a significant protective effect against photoreceptor cell loss, confirming involvement of calpains in photoreceptor degeneration. Conversion of p35 to p25 was well correlated with calpain activation, suggesting prolonged activation of Cdk5/p25 as a possible downstream mechanism for MNU-induced photoreceptor cell death. SNJ-1945 reduced photoreceptor cells death, even though MNU is one of the most severe models of photoreceptor cell degeneration. Oral calpain inhibitor SNJ-1945 may be a candidate for testing as a medication against retinal degeneration in retinitis pigmentosa.

Animals↗
PubMed2006

Protein isolate from the herb, Phyllanthus niruri L. (Euphorbiaceae), plays hepatoprotective role against carbon tetrachloride induced liver damage via its antioxidant properties.

Phyllanthus niruri L. (Euphorbiaceae) (P. niruri) is a well-known hepatoprotective herbal plant. In the present study, hepatoprotective potential of the protein isolate of P. niruri was investigated against carbon tetrachloride (CCl(4)) induced liver damage in vivo. Protein isolate of P. niruri was intraperitoneally injected in mice either prior to (preventive) or after the induction of toxicity (curative). Levels of different liver marker enzymes in serum and different anti-oxidant enzymes, as well as lipid peroxidation products and glutathione (GSH) in liver homogenates were measured in normal, control (toxicity induced) and protein isolate treated mice. Administration of CCl(4) increased the serum glutamate pyruvate transaminase (GPT) and alkaline phosphatase (ALP) levels of mice sera along with increased lipid peroxidation and reduced levels of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in the liver. Treatment with the protein isolate of P. niruri significantly altered these changes to almost normal. The protein isolate also showed protective properties as was evidenced in histopathological studies. Results suggest that the protein isolate of P. niruri protects liver tissues against oxidative damage and somehow helps stimulating repair mechanism present in liver. It could be used as an effective hepatoprotector against CCl(4) induced liver damage.

Animals↗
PubMed2005

Pro-oxidant activity of aluminum in the rat hippocampus: gene expression of antioxidant enzymes after melatonin administration.

Aluminum (Al)-induced pro-oxidant activity and the protective role of exogenous melatonin, as well as the mRNA levels of some antioxidant enzymes, were determined in the hippocampi of rats following administration of Al and/or melatonin. Two groups of male rats were intraperitoneally injected with Al (as Al lactate) or melatonin only, at doses of 7 and 10 mg/kg/day, respectively, for 11 weeks. During this period, a third group of animals received Al (7 mg/kg/day) plus melatonin (10 mg/kg/day). At the end of the treatment, hippocampus was removed and processed to examine the following oxidative stress markers: glutathione transferase (GST), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as protein content. Gene expression of Cu-ZnSOD, MnSOD, GPx, and CAT was evaluated by real-time RT-PCR. On the other hand, Al, Fe, Mn, Cu, and Zn concentrations in hippocampus were also determined. The results show that Al exposure promotes oxidative stress in the rat hippocampus, with an increase in Al concentrations. The biochemical changes observed in this tissue indicate that Al acts as pro-oxidant agent, while melatonin exerts antioxidant action by increasing the mRNA levels of the antioxidant enzymes evaluated. The protective effects of melatonin, together with its low toxicity and its capacity to increase mRNA levels of antioxidant enzymes, suggest that this hormone might be administered as a potential supplement in the treatment of neurological disorders in which oxidative stress is involved.

Aluminum Compounds↗
PubMed2005

Effects of cyclophosphamide on the immune system and disease resistance of Asian catfish Clarias batrachus.

Cyclophosphamide (CYP), a multifunctional alkylating agent is known as a potent immunosuppressor in endotherms. Here, an experiment was conducted in an ectothermic Asian catfish species, Clarias batrachus to investigate its effect on non-specific and specific immunity as well as disease resistance against a common bacterial pathogen challenge. CYP was intraperitoneally injected for 3 consecutive days at a rate of 200 mgkg(-1) body weight. After 72 h post-injection, control and CYP-treated fish were screened for superoxide production through nitroblue tetrazolium (NBT) assay, myeloperoxidase (MPO) activity, packed cell volume (PCV) and total protein, lysozyme, alternative complement activity (ACH50) and natural haemagglutinin titre as a measure of non-specific immunity level as well as disease resistance against Aeromonas hydrophila challenge to vaccinated and unvaccinated fish. To study the effect on specific immunity, CYP was injected thrice at an interval of 7 days after bacterin injection and serum antibody titre was measured by bacterial agglutination titre assay. The results showed a significant (P<0.05) decrease in NBT and MPO activities, and percent survival against A. hydrophila challenge (both in unvaccinated and vaccinated fish) in CYP-treated fish, when compared to control fish. The above results support the immunosuppressive action of CYP in freshwater catfish, C. batrachus. The neutrophil activities, as measured through superoxide production and myeloperoxidase levels, might be important contributors during A. hydrophila infection and that treatment with CYP reduces phagocytic killing power and inhibits resistance against aeromoniasis.

Aeromonas hydrophila↗
PubMed2006

Multiple human mesenteric arterial grafts from the same donor to study human chronic vascular rejection in humanized SCID/beige mice.

BACKGROUND: Chronic vascular rejection (CVR) is a major problem in clinical transplantation. Studies in experimental animals have been important to understand some of its mechanisms, but they are hampered by the difficulty of extrapolating the results into clinical practice. METHODS: We created a new experimental model for the study of human CVR by grafting multiple human mesenteric arteries from the same human donor into different SCID/beige mice in the infrarenal aortic position. Twenty-seven different mice were successfully grafted with a human artery from 6 donors. One week later, 23 of the mice received an intraperitoneal injection of 40 million human spleen cells, either from the same donor (autologous) or from another donor (allogeneic). RESULTS: In 81% of the mice an immune reconstitution was obtained, shown by the presence of human T, B and NK cells and IgG in circulating blood. At the time of sacrifice, 5 weeks after the arterial transplantation, a typical CVR with infiltration of human immune cells and deposit of human immunoglobulin was observed in the reconstituted mice that received allogeneic cells, whereas only minor lesions were noted in autologous combinations. No CVR was observed without injection of human splenocytes. We did not observe lymphoma or graft-vs-host reactions during the experiment. CONCLUSIONS: We show that it is feasible to graft multiple human arteries from the same donor into SCID/beige mice, and that a specific and typical CVR is observed after reconstitution with allogeneic spleen cells. Our method allows for pre-clinical testing of new therapeutics in controlled series.

Anastomosis, Surgical↗
PubMed2005

The cochlear targets of cisplatin: an electrophysiological and morphological time-sequence study.

Cisplatin ototoxicity has at least three major targets in the cochlea: the stria vascularis, the organ of Corti, and the spiral ganglion. This study aims to differentiate between these three targets. In particular, we address the question of whether the effects at the level of the organ of Corti and spiral ganglion are mutually dependent or whether they develop in parallel. This question was approached by studying the ototoxic effects while they develop electrophysiologically and comparing these to earlier presented histological data [Van Ruijven et al., 2004. Hear. Res. 197, 44-54]. Guinea pigs were treated with intraperitoneal injections of cisplatin at a dose of 2 mg/kg/day for either 4, 6, or 8 consecutive days. This time sequence has not revealed any evidence of one ototoxic process triggering another. Therefore, we have to stay with the conclusion of Van Ruijven et al. (2004) that both processes run in parallel.

Action Potentials↗
PubMed2005

Hydroxyethylstarch microcapsules: a preliminary study for tumor immunotherapy application.

The objective of this work was to prepare microcapsules which would allow protection and slow release of antigens used for melanoma immunotherapy treatment. Hydroxyethylstarch (HES) microcapsules were prepared using interfacial cross-linking with terephthaloyl chloride (TC). They were characterized with respect to morphology (microscopy) and size (in the 4-15 microm range). Bovine serum albumin (BSA) was used as model protein for loading and release studies. Microcapsules were loaded with solutions at different protein concentrations (0.5-5%). The maximum loading efficiency (20%) was observed with the concentration of 2.5%, which allowed a loading capacity near 100%. Confocal laser scanning microscopy (CLSM) visualization showed that BSA was entrapped within the microcapsules and not only associated to their outer surface. BSA-release studies showed a 20% BSA release within 30 min while 80% remained entrapped in the microcapsules for 4 days. Microcapsules were degraded by alpha-amylase and addition of esterase to alpha-amylase enhanced slightly their degradation. In vitro studies on melanoma cells showed that HES microcapsules were non-toxic. Preliminary in vivo studies demonstrated that microcapsules were biodegradable after intraperitoneal injection (i.p.). The observation of peritoneal wash showed a complete degradation within 7 days, indicating a possible application as an in vivo drug delivery system especially to enhance the presentation of antigens.

Animals↗
PubMed2004

The effect of oral 5-HTP administration on 5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats.

5-Hydroxytryptophan (5-HTP), which is the rate-limiting precursor in serotonin (5-hydroxytryptamine (5-HT)) biosynthesis, is used as an oral supplement to enhance serotonin levels in humans. To evaluate its effects on serotonin levels and localization, 5-hydroxytryptophan was administered to Sprague-Dawley rats either orally or via intraperitoneal injection. 5-Hydroxytryptophan-immunoreactivity was co-localized with serotonin-immunoreactivity in the serotonergic dorsal raphe nucleus of control animals and this was not changed in animals given 5-hydroxytryptophan. Oral 5-HTP administration increased the intensity of both 5-HTP and serotonin immunoreactivity in raphe neurons. However, 5-HTP treatment also caused ectopic 5-hydroxytryptophan-immunoreactivity and serotonin-immunoreactivity in normally dopaminergic neurons of the substantia nigra par compacta. Serotonin-immunoreactivity was confined to neurons that also displayed amino acid decarboxylase immunoreactivity, but in a small percentage of substantia nigra neurons, serotonin immunoreactivity was not co-localized with tyrosine hydroxylase-immunoreactivity. The intensity of the immunoreactivity to serotonin and 5-hydroxytryptophan in the substantia nigra was maximal within 2h of 5-hydroxytryptophan administration and returned to control levels by 24h. This time course mirrored changes in HPLC measurements of 5-hydroxytryptophan, serotonin, and the metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the urine. 5-Hydroxytryptophan administration did not cause ectopic appearance of either serotonin or 5-hydroxytryptophan in the noradrenergic locus coeruleus. These results suggest that a single oral dose of 5-HTP increases the 5-HTP and serotonin content of serotonergic neurons and causes the transient ectopic appearance of serotonin in some normally non-serotonergic neurons.

5-Hydroxytryptophan↗
PubMedDate not supplied

Early treadmill exercise decreases intrastriatal hemorrhage-induced neuronal cell death and increases cell proliferation in the dentate gyrus of streptozotocin-induced hyperglycemic rats.

Intracerebral hemorrhage (ICH) is a severe complication in diabetic patients. Currently, physical exercise is recommended as a behavioral intervention to promote functional recovery in brain diseases, including ICH. Recently, hyperglycemia is known to aggravate brain injury in experimental ICH. Here, we examined the effect of treadmill exercise on the intrastriatal hemorrhage-induced neuronal cell death and cell proliferation in the dentate gyrus of hyperglycemic rats. Hyperglycemia was induced by the intraperitoneal injection of 50 mg/kg streptozotocin (STZ). Intrastriatal hemorrhage was induced by the infusion of 0.2 U collagenase into the striatum using stereotaxic instrument. Rats in the exercise groups were forced to run on a treadmill for 30 min daily for 10 days. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Cell proliferation was assessed by the 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry. Our data showed that in rats started treadmill exercise 24 h after ICH induction, the size of lesion induced by hemorrhage and the number of apoptotic cells were decreased significantly. The number of proliferating cells in the dentate gyrus was significantly decreased in hyperglycemic rats. Treadmill exercise markedly enhanced cell proliferation in the dentate gyrus of hyperglycemic rats. The data suggest that treadmill exercise may provide therapeutic value to ICH patients with hyperglycemia by suppressing neuronal apoptosis and increasing cell proliferation.

Animals↗
PubMed2006

Pyridoxine does not prevent hyperbaric oxygen-induced seizures in rats.

Normobaric supplemental oxygen can prolong seizures not caused by hyperbaric oxygen therapy. In addition, hyperbaric oxygen therapy can cause seizures. The mechanism of hyperbaric oxygen-induced seizures is unknown. We hypothesized that pretreatment with pyridoxine may delay the onset of hyperbaric oxygen-induced seizures, recognizing that pyridoxine is already an antidote for some epileptogenic poisons such as isoniazid and monomethylhydrazine. Therefore, rats were pretreated with intraperitoneal injections of pyridoxine at 48, 24, and 2 h before undergoing hyperbaric oxygen (HBO) treatment at 3 atmospheres absolute with 100% oxygen and were compared to a control group of HBO-treated rats for time to onset of seizures. There was no difference in onset of seizure time between the pyridoxine-treated group of rats and the control rats. Supplemental pyridoxine pretreatment did not alter the time to onset of seizures during HBO treatment in this study.

Animals↗
PubMed2004

Antidiabetic and antihyperlipidaemic effect of alcoholic Syzigium cumini seeds in alloxan induced diabetic albino rats.

Syzigium cumini, commonly known as 'jamun', is widely used in different parts of India for the treatment of diabetes mellitus. The present study was designed to evaluate the antidiabetic and antihyperlipidaemic effect of an alcoholic extract of Syzigium cumini seeds (JSEt) in alloxan diabetic rats. Diabetes was induced by single intraperitoneal injection of alloxan (150 mg kg(-1) body weight). Oral administration of alcoholic JSEt to diabetic rats at a dose of 100 mg kg(-1) body weight resulted in a significant reduction in blood glucose and urine sugar and lipids in serum and tissues in alloxan diabetic rats. The extract also increases total haemoglobin. The extract brought back all the parameters to normal levels. The effect of alcoholic JSEt was similar to that of insulin. Thus, our investigation clearly shows that alcoholic JSEt has both antidiabetic and antihyperlipidaemic effects.

Alloxan↗
PubMed2005

Antidiabetic effects of extracts from Psidium guajava.

During a screening of medicinal plants for inhibition of protein tyrosine phosphatase1B (PTP1B), an extract from Psidium guajava (Myrtaceae) leaves exhibited significant inhibitory effect on PTP1B. Thus, its antidiabetic effect on Lepr(db)/Lepr(db) mice was evaluated. Significant blood glucose lowering effects of the extract were observed after intraperitoneal injection of the extract at a dose of 10mg/kg in both 1- and 3-month-old Lepr(db)/Lepr(db) mice. In addition, histological analysis of the liver from the butanol-soluble fraction treated Lepr(db)/Lepr(db) mice revealed a significant decrease in the number of lipid droplets compared to the control mice. Taken together, it was suggested that the extract from Psidium guajava leaves possesses antidiabetic effect in type 2 diabetic mice model and these effect is, at least in part, mediated via the inhibition of PTP1B.

Age Factors↗
PubMed2005

Enhancement of peritoneal macrophage phagocytic activity against Leishmania major by garlic (Allium sativum) treatment.

It has been shown that garlic (Allium sativum) extract modulates immune responses. Macrophage activation is required to establish control of the intracellular infection and progressive disease of leishmaniasis. In this study, we consider the effect of a garlic extract and a fraction isolated from it on the engulfment and destruction of Leishmania major by resident peritoneal macrophages of Balb/c mice. In regard to this study, the infiltration of macrophages in the peritoneal cavity after garlic treatment and the rate of amastigotes per macrophage were determined. The results show that a single dose of 20 mg/kg garlic extract intraperitoneally (i.p.) alters the number of peritoneal macrophages for at least 2 weeks. Intraperitoneal injection of garlic extract (20 mg/kg) or its protein fraction (0.04 mg/kg) augments parasite engulfment and destruction of intracellular amastigotes by macrophages.

Animals↗
PubMed2004

Involvement of natural killer cells in PolyI:C-induced liver injury.

BACKGROUND/AIMS: The roles of T cells, natural killer T cells (NKT) and macrophages in autoimmune hepatitis have been well documented. However, the roles of natural killer (NK) cells in liver injury remain obscure. Here we examined the effect of Polyinosinic: polycytidylic acid (PolyI:C)-activated NK cells on liver injury. METHODS: Mice were intraperitoneally injected with PolyI:C at a dose of 20mug/g body wt. The percentage and absolute number of NK cells in the liver were analyzed with flow cytometry. Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) assay and H-E staining were used to evaluate the liver injury. RESULTS: Following PolyI:C injection, NK cells accumulation and activation occurred in the liver. Meanwhile, slight elevation of ALT/AST in the serum, mild inflammation and focal necrosis in the liver were also observed. Depletion of NK cells markedly attenuated PolyI:C-induced liver injury. Neutralization of endogenous Interleukin-12 produced by Kupffer cells abrogated the accumulation of NK cells in the liver and subsequent liver injury. The liver injury was also alleviated by neutralization of vascular cell adhesive molecule-1. CONCLUSIONS: These findings suggest that PolyI:C preferentially recruits and activates hepatic NK cells, which may be responsible for the mild hepatitis.

Alanine Transaminase↗
PubMed2006

Targeting pain-suppressed behaviors in preclinical assays of pain and analgesia: effects of morphine on acetic acid-suppressed feeding in C57BL/6J mice.

UNLABELLED: Pain increases the rate, frequency, or intensity of some behaviors (eg, withdrawal responses) and suppresses other behaviors (eg, feeding). Our laboratories are developing assays to test analgesic drug candidates using measurements of pain-suppressed rather than pain-elicited behaviors. Such assays may model important aspects of clinical pain and provide a means for distinguishing true analgesics from drugs that produce motor impairment. The present study compared effects of the mu opioid analgesic morphine and the nonanalgesic neuroleptic haloperidol on intraperitoneal acetic acid-induced writhing (a pain-elicited behavior) and suppression of feeding behavior (a pain-suppressed behavior). In feeding studies, C57BL/6J mice were given access to a dish containing 8 mL Ensure(trade mark) liquid food (0-100% in water) during daily sessions (7.5-120 min). Levels of consumption were dependent on both Ensure concentration and session duration. Intraperitoneal injection of acetic acid (0.10-0.56%) produced a time- and concentration-dependent decrease in Ensure consumption. Morphine (1 mg/kg) prevented both acid-induced writhing and acid-induced suppression of feeding, whereas the dopamine antagonist haloperidol inhibited writhing without preventing acid-induced suppression of feeding. The effects of morphine were time-dependent, selective for acid-suppressed feeding, and naltrexone-reversible. These results suggest that assays of pain-suppressed behaviors may complement assays of pain-elicited behaviors in preclinical studies of candidate analgesics. PERSPECTIVE: This paper presents a new preclinical strategy for assessing pain and analgesia in mice that is congruent with current methods of pain assessment in the clinic. This strategy may therefore be a useful complement to more traditional procedures for assessing pain and analgesia.

Acetic Acid↗