Thermoregulatory, motor, behavioural, and nociceptive responses of rats to 3 long-acting neuroleptics

We investigated physiological effects of intramuscular injections of the following 3 long-acting neuroleptics commonly used in wildlife management: haloperidol (0.05, 0.1, and 0.5 mg/kg body mass), zuclopenthixol acetate (0.5, 1, and 5 mg/kg), and perphenazine enanthate (1, 3, and 10 mg/kg), in a rat model. Body temperature and cage activity were measured by intra-abdominal telemeters. Nociceptive responses were assessed by challenges to noxious heat and pressure. Haloperidol (0.5 mg/kg) produced a significant nocturnal hypothermia (p < 0.05) and decreased nighttime cage activity and food intake. Zuclopenthixol (5 mg/kg) significantly decreased nighttime body temperature and cage activity and, at 1 mg/kg and 5 mg/kg, significantly decreased food intake 5-17 h after injection (p < 0.05). Perphenazine (10 mg/kg) significantly decreased nighttime body temperature and cage activity and, at all doses, significantly decreased food intake 5-17 h after injection (p < 0.05). Significant analgesic activity was evident in rats given 5 mg/kg zuclopenthixol up to 40 h after injection, and 10 mg/kg perphenazine from 48 to 96 h after injection (p < 0.0001). Zuclopenthixol (5 mg/kg) and perphenazine (10 mg/kg) had significant antihyperalgesic activities at 16 h postinjection and 24-48 h postinjection, respectively (p < 0.0001). Haloperidol had no significant antinociceptive activity at doses tested. Motor function was impaired in rats given 0.5 mg/kg haloperidol, 5 mg/kg zuclopenthixol and 10 mg/kg perphenazine. Effects of long-acting neuroleptics on body temperature, feeding, and activity were short-lasted and should not preclude their use in wildlife. Antinociceptive actions were longer-lasting, but were nonspecific, and we recommend additional analgesics for painful procedures during wildlife management.     

Evaluation of the anti-inflammatory and antinociceptive properties of p-cymene in mice

We attempted to identify the antinociceptive and anti-inflammatory actions of the monoterpene p-cymene. Firstly, behavioural screening was carried out to verify the influence of p-cymene [25, 50, and 100 mg/kg intraperitoneal (i.p.)] on the central nervous system (CNS) activity. The antinociceptive activity of p-cymene was evaluated by the acetic acid-induced writhing response, formalin, and hot-plate test, respectively. The leukocyte migration induced by injection of carrageenan was used to assess the anti-inflammatory activity. p-Cymene showed depressant activity on CNS after 4 h of treatment and also a possible action on the autonomous nervous system (ANS), mainly at the dose of 100 mg/kg (i.p.). It was found that p-cymene (50 and 100 mg/kg, i.p.) significantly (p < 0.05) reduced the writhing responses induced by acetic acid. p-Cymene also decreased the licking time in the first and second phase, respectively, of the formalin test. The results of the hot-plate test showed that all doses of p-cymene increased significantly the latency time of the response to the thermal stimulus in both licking and jumping parameters. In addition, there was a significantly (p < 0.05) decreased leukocyte migration at all doses of p-cymene. The experimental data demonstrate that p-cymene possesses antinociceptive and anti-inflammatory activities.     

Effect of chronic intermittent exposure to AM radiofrequency field on responses to various types of noxious stimuli in growing rats

There are several reports of altered pain sensation after exposure (from a few minutes to hours in single or repeated doses for 2-3 weeks) to electromagnetic fields (EMF) in adults. The commonly utilized noxious stimulus is radiant heat. The nociceptive responses are known to be influenced by characteristics of stimulus, organism, and environment. We studied the pattern of nociceptive responses to various noxious stimuli in growing rats exposed to radiofrequency field (73.5 MHz amplitude modulated, 16 Hz power density 1.33 mw/cm(2), SAR = 0.4 w/kg) for 45 d (2 h/d). Threshold current for stimulation of nociceptive afferents to mediate motor response of tail (TF), vocalization during stimulus (VD), and vocalization after discharge (VA); the withdrawal latency of tail (TFL) and hind paw (HPL) to thermal noxious stimulus and tonic pain responses were recorded in every rat. The TFL was not affected, HPL was decreased (p < 0.01), and the thresholds of TF and VD were not affected, while, that of VA was significantly decreased. The tonic pain rating was decreased (p < 0.01). A decrease in the threshold of VA (p < 0.01) is indicative of an increase in the emotional component of the response to the phasic pain, whereas a decrease in the pain rating indicates analgesia in response to the tonic pain. The results of our study suggest that chronic (45 d), intermittent (2 h/d) amplitude modulated RF field exposure to the peripubertal rat increases the emotional component of phasic pain over a basal eaualgesic state, while late response to tonic pain is decreased. The data suggest that amplitude modulated RF field differentially affects the mechanisms involved in the processing of various noxious stimuli.     

Antinociceptive effect induced by intraperitoneal administration of vitamin K2 (menatetrenone) in ICR mice

The antinociceptive effect of vitamin K2 (menatetrenone) in mice was examined using tail-flick and formalin test. Menatetrenone at doses of 10, 50 and 100 mg/kg, i.p. produced a dose-dependent and significant inhibition of the tail-flick response in mice. Menatetrenone (50 and 100 mg/kg, i.p.) had no significant effect on the duration of the first phase of the formalin-induced flinching. However, menatetrenone (100 mg/kg, i.p.) significantly inhibited the second phase of the formalin-induced flinching. I.p. administration of menatetrenone (100 mg/kg) significantly reduced the duration of nociceptive responses induced by i.t. injection of bradykinin, but not of substance P, prostaglandin E2 or N-methyl-D-aspartate (NMDA). These present data suggest that i.p. pretreatment with menatetrenone produced dose-dependent antinociceptive effect in mice. This effect may be, at least in part, mediated by the inhibition of bradykinin dependent nociceptive transmission in the spinal cord.     

4-Amino-5-vinyl-3(2H)-pyridazinones and analogues as potent antinociceptive agents: Synthesis, SARs, and preliminary studies on the mechanism of action

A series of 4-amino-5-vinyl-3(2H)-pyridazinones and analogues were synthesized and their antinociceptive effect was evaluated in the mouse abdominal constriction model. Several of the novel compounds showed ED(50) values in the range 6-20mg/kg/sc and demonstrated to be able to completely protect all the treated animals from the effect of the noxious stimulus at 30 mg/kg/sc. SAR studies confirmed the essential role played by an amino or substituted amino function at position 4 and by a vinyl group at position 5 of the diazine system.     

Antinociceptive activity of metapramine in mice. Relationship with its pharmacokinetic properties.

The antinociceptive effect of acutely and chronically (every brain elimination half-life time) administered metapramine, a tricyclic antidepressant without anticholinergic or cardiotoxic effects, was studied in three different pain tests. In the hot plate test, its action was more potent when jumping was used as a pain parameter (acute ED50 = 19 +/- 3 mg/kg, i.p.) than when pain was assessed by licking of forepaws (only 20 mg/kg, i.p. was weakly active). Five chronic doses of 15 mg/kg were as active in the tail-flick test as an acute dose of 20 mg/kg (only active dose). Metapramine was more effective in the PBQ-induced writhing test after acute (ED50 = 9.9 +/- 0.1 mg/kg, i.p.) and chronic administration. A significant linear correlation was found between the effect in this test and plasma and overall brain levels of metapramine. No correlation was observed with levels of its three desmethylated metabolites. The usefullness of using a well-defined pattern of administration based on pharmacokinetic parameters and the involvement of monoaminergic mechanisms and of some metabolites of metapramine are discussed.     

Persistent pain model reveals sex difference in morphine potency

Central or systemic administration of agonists directed at the mu or delta opiate receptors generally produce a greater degree of analgesia in males than in females. To date, most studies examining sex-based differences in opioid analgesia have used acute noxious stimuli (i.e., tail-flick and hot plate test); thus the potential dimorphic response of centrally acting opiates in the alleviation of persistent inflammatory pain is not well established. In the present study, right hind paw withdrawal latency (PWL) to radiant thermal stimuli was measured in intact male and cycling female Sprague-Dawley rats before and after unilateral hind paw injection of the inflammatory agent complete Freund's adjuvant (CFA). Control animals received intraplantar injection of saline. Twenty four hours after CFA or saline injection, animals received either saline or morphine bisulfate (0.5-15 mg/kg sc). Separate groups of control or inflamed animals were tested on their responsiveness to morphine at 7, 14, and 21 days post-CFA or saline. No sex differences were noted for baseline PWLs, and females displayed slightly less thermal hyperalgesia at 24 h post-CFA. At all morphine doses administered, both the antihyperalgesic effects of morphine in the inflamed animals and the antinociceptive effects of morphine in control animals were significantly greater in males compared with females. Similarly, in males, the antihyperalgesic effects of morphine increased significantly at 7-21 days post-CFA; no significant shift in morphine potency was noted for females. These studies demonstrate sex-based differences in the effects of morphine on thermal hyperalgesia in a model of persistent inflammatory pain.     

Study of the antinociceptive effect of tetrahydropapaveroline derivatives. Interaction with opioids

The antinociceptive effect of racemic tetrahydropapaveroline (THP), of its two R(+)- and S(−) enantiomers, of 1-2-dehydro-THP and of 1-carboxy-THP was assessed using different pain tests in mice. None of these drugs possessed a significant activity in the hot-plate and tail-flick tests. However, after i.p. injection, they reduced the number of abdominal writhes induced by phenylbenzoquinone, with ED₅₀ values of 51 ± 7, 73 ± 9 and 79 ± 7 mg/kg for the most potent compounds: 1,2-dehydro-THP, ±THP and -THP, respectively. This activity was not antagonized by naloxone (1 mg/Kg, S.c.). However combination of inactive doses of these three compounds (32 mg/Kg, I.p.) and of morphine (0.5 mg/Kg, S.c.) led to a significant antinociceptive effect (83 to 85 % of reduction of the number of writhes). This synergistic potentiation confirmed with the combination of ±THP (16 mg/Kg, I.p.) and morphine (0.5 mg/Kg, S.c.) was totally inhibited by naloxone (1 mg/Kg, S.c.). These results, although excluding a direct agonistic effect of THP derivatives on opiate receptors, suggest an indirect interaction of these drugs with the endogenous opioid system.     

Stress-Induced Antinociception in Fish Reversed by Naloxone

Pain perception in non-mammalian vertebrates such as fish is a controversial issue. We demonstrate that, in the fish Leporinus macrocephalus, an imposed restraint can modulate the behavioral response to a noxious stimulus, specifically the subcutaneous injection of 3% formaldehyde. In the first experiment, formaldehyde was applied immediately after 3 or 5 min of the restraint. Inhibition of the increase in locomotor activity in response to formaldehyde was observed, which suggests a possible restraint-induced antinociception. In the second experiment, the noxious stimulus was applied 0, 5, 10 and 15 min after the restraint, and both 3 and 5 min of restraint promoted short-term antinociception of approximately 5 min. In experiments 3 and 4, an intraperitoneal injection of naloxone (30 mg.kg⁻¹) was administered 30 min prior to the restraint. The 3- minute restraint-induced antinociception was blocked by pretreatment with naloxone, but the corresponding 5-minute response was not. One possible explanation for this result is that an opioid and a non-preferential μ–opioid and/or non-opioid mechanism participate in this response modulation. Furthermore, we observed that both the 3- and 5- minutes restraint were severely stressful events for the organism, promoting marked increases in serum cortisol levels. These data indicate that the response to a noxious stimulus can be modulated by an environmental stressor in fish, as is the case in mammals. To our knowledge, this study is the first evidence for the existence of an endogenous antinociceptive system that is activated by an acute standardized stress in fish. Additionally, it characterizes the antinociceptive response induced by stress in terms of its time course and the opioid mediation, providing information for understanding the evolution of nociception modulation.     

Evaluation of intramuscular ketoprofen and butorphanol as analgesics in chain dogfish (Scyliorhinus retifer)

The mediation of nociception with analgesic medications has not been well documented in elasmobranchs. The purpose of this study was to determine effective analgesic doses of the opioid agonist‐antagonist, butorphanol, and the non‐steroidal anti‐inflammatory drug, ketoprofen, in an elasmobranch. This was evaluated by repetitively assessing minimum anesthetic concentrations of the immersion anesthetic, tricaine methanesulfonate (MS‐222), required to prevent response to noxious stimuli in chain dogfish (Scyliorhinus retifer) when administered multiple doses of each of the analgesics (0.25, 0.5, 1.0, 2.5, and 5.0 mg/kg butorphanol and 1.0, 1.5, 2.0, and 4.0 mg/kg ketoprofen). Baseline concentrations of MS‐222 required to prevent a response to a noxious stimulus were determined for each animal and served as the controls. Although individual animals displayed a reduction in MS‐222 concentration with various doses of both analgesics, no statistically significant difference was noted between control animals and animals given analgesics. It is plausible that unique elasmobranch anatomy, lack of appropriate medication dose or timing of administration, and other physiological factors not yet identified may have contributed to the lack of apparent efficacy of the analgesics evaluated in this study. Zoo Biol 0:1–10, 2006. © 2006 Wiley‐Liss, Inc.     

Pharmacological analysis of inhomogeneous static magnetic field-induced antinociceptive action in the mouse

The effect of inhomogeneous, 2-754 mT static magnetic field (SMF) on visceral pain elicited by intraperitoneal injection of 0.6% acetic acid (writhing test) was studied in the mouse. Exposure of mice to static magnetic field (permanent NdFeB N50 grade 10 mm x 10 mm cylindrical magnets with alternating poles) during the nociceptive stimulus (0-30 min) resulted in inhibition of pain reaction: the number of writhings decreased from 9 +/- 2, 32 +/- 4 and 30 +/- 3 to 2 +/- 0.03, 15 +/- 1.6, and 14 +/- 1.6, respectively, measured in 0-5th, 6-20th, and 21-30th min following the acetic acid challenge. The pain reaction during the total observation period was reduced by 57% (P < 0.005). The analgesic action induced by SMF was inhibited by subcutaneous administration of naloxone (1 and 0.2 mg kg(-1)), irreversible micro-opioid receptor antagonist beta-funaltrexamine (20 mg kg(-1)) and delta-opioid receptor antagonist naltrindole (0.5 mg kg(-1)), but the kappa-opioid receptor antagonist norbinaltorphimine (20 mg kg(-1)) failed to affect the SMF-induced antinociception. In contrast to the subcutaneous administration, the intracerebroventricularly injected naloxone (10 microg mouse(-1)) did not antagonize the antinociceptive effect of SMF. The results suggest that acute exposure of mice to static magnetic field results in an opioid-mediated analgesic action in the writhing test in the mouse. The antinociceptive effect is likely to be mediated by micro and (to a lesser extent) delta-opioid receptors.     

Effect of diphenylhydramine on the Tyr-MIF-1 antinociception in rats.

Tyr-MIF-1 is a representative of the MIF's family of endogenous peptides. It has been isolated from bovine hypothalamus and human parietal cortex that suggests its involvement in nociception. Tyr-MIF-1 can bind to the mu-receptors as well as to its specific non-opiate receptors in the brain. Data in the literature rise the idea that histamine (HA), a well known nociceptive agent, and Tyr-MIF-1 might have a common pathway in their effects on nociception. We tested that possibility by investigation of the combined action of diphenhydramine (DPH, an H (1) -antagonist) and Tyr-MIF-1 on nociception. The changes in the nociceptive effects were examined in the male Wistar rats by the Randall-Sellito paw-pressure (PP) and the tail-flick (TF) tests. Tyr-MIF-1 in a dose of 1 mg/kg exerted strong naloxone-reversible analgesic effects. DPH (100 microg/kg, i.p.) had an antinociceptive action, too. The co-administration of Tyr-MIF-1 and DPH enhanced the antinociceptive effect, as compared to DPH (PP) and to TYR-MIF-1 alone (TF). These effects were reversed when methylene blue (MB, 500 microg/rat) was applied 1h before the combination. However, naloxone (1 mg/kg, i.p.) only slightly affected the antinociceptive effect of DPH and TYR-MIF-1, compared to that of MB. The results obtained confirmed the hypothesis that cyclic nucleotides are involved in the realization of nociceptive effects of both HA and Tyr-MIF-1.     

The effect of pentobarbital on the antinociceptive action of morphine in morphine-tolerant and non-tolerant rats

The interaction of sodium pentobarbital with morphine sulfate in both morphine-tolerant and non-tolerant rats was investigated using the tail-compression test for analgesia. Male Sprague-Dawley rats (300–350 g) were given pentobarbital (4, 8, or 16 mg/kg) 5 min before morphine (2, 4, 6, or 8 mg/kg). Control animals received two saline injections, or pentobarbital plus saline, or saline plus morphine. All injections were subcutaneous. Prior to the first injection, a baseline nociceptive threshold was determined for each rat by applying a modified micrometer to its tail and increasing the pressure until a squeak was elicited. Test readings were taken every half-hour for 2 hr beginning 30 min after the second injection. For the chronic studies, animals were first made tolerant to morphine by the administration of the narcotic twice a day for 3 days, increasing the dose from 10 to 50 mg/kg/injection. Identical testing procedures were then followed with these rats except that the test dose of morphine given on day 4 was in the range 8–128 mg/kg. It was found that Na pentobarbital, in the subanesthetic doses used, had neither antinociceptive nor hyperalgesic properties. Furthermore, the barbiturate had no effect on the antinociceptive action of morphine in either morphine-tolerant or non-tolerant rats.     

The antinociceptive efficacy of buprenorphine administered through the drinking water of rats

Postoperative pain management in laboratory animals is important for animal welfare and required under law in many countries. Frequent injection of analgesics to rodents after surgery is stressful for the animals and labour-intensive for animal care personnel. An alternative dosing scheme such as administration of analgesics in the drinking water would be desirable. However, the efficacy of a chronic oral analgesic treatment via this route has not yet been documented. This study investigated the antinociceptive efficacy of buprenorphine administered ad libitum via the drinking water of laboratory rats. The antinociceptive efficacy of buprenorphine in drinking water was compared with repeated subcutaneous injections. A comparison was also made between buprenorphine in drinking water and the combination of one single subcutaneous injection of buprenorphine followed by buprenorphine in drinking water. Antinociception was assessed by use of an analgesiometric model measuring the rats' latency time to withdrawal from a noxious heat stimulus applied to the plantar surface of the paw. Results revealed that buprenorphine in drinking water (0.056 mg/mL) induced significant increases in paw withdrawal latency times during a three-day period of administration with a maximal effect at 39 h after the start of buprenorphine administration. One single injection of buprenorphine (0.1 mg/kg s.c.) followed by buprenorphine in the drinking water (0.056 mg/mL) induced an earlier onset of antinociception than buprenorphine in drinking water alone. In contrast, buprenorphine (0.1 mg/kg s.c.) injected every 8 h over a period of three days did not result in significant increases in paw withdrawal latency times. In conclusion, our results suggest that one single subcutaneous injection of buprenorphine followed by buprenorphine in drinking water may be a viable treatment option for the relief of pain in laboratory rats, but at the doses used in this study in pain-free rats it was associated with a decrease in water intake and some behavioural changes.     

Differential effects of isoproterenol injections on the levels of pineal N-acetyltransferase, serum N-acetylserotonin and melatonin

Rats housed under diurnal lighting conditions were either injected with isoproterenol (ISO), 0.5 mg/kg subcutaneous (SC) and sacrificed at different times up to 180 minutes afterwards, or injected with different doses of ISO (0.2 mg/kg to 5.0 mg/kg intraperitoneally (IP] and sacrificed 120 minutes later. Pineal N-acetyltransferase (NATase), serum N-acetylserotonin (NAS) and serum melatonin (MT) levels were determined. It was found that both pineal NATase and serum MT responded to the injection with peak increase at 120 minutes after the injection. This increase in pineal NATase and serum MT levels were also found to be dose-dependent. It was also observed that at 30 minutes after ISO injection, the serum MT level already demonstrated a significant increase which preceeded any increase in the pineal NATase activity. The underlying mechanism for this observation remains undetermined. Unlike serum MT and pineal NATase, there were no changes in serum NAS levels after injections of ISO at all the doses tested or up to 180 minutes after injection of the drug at 0.5 mg/kg dose SC. This suggests that serum NAS level is neither regulated by pineal NATase activity nor is the pineal gland the major source of NAS in circulation. This also indicates that serum NAS level is not influenced by beta-adrenergic stimulation.     

Is there an opiate receptor in the snail Megalobulimus sanctipauli? Action of morphine and naloxone

The effects of morphine sulfate (10, 15 and 20 mg/kg) or saline control (5 mg/kg) on the latency of the anterior body-lifting response to heat (avoidance response) were determined in four groups of snails Megalobulimus sanctipauli (n = 6) individually placed on a metal plate mounted on the surface of a water bath at 52 ± 1°C. The effects of pre-treatment with naloxone hydrochloride (5 mg/kg) or saline (2.5 ml/kg) control on the responses to morphine (15 mg/kg) were determined in two different groups of animals (n = 6). Administration of morphine resulted in an increase in the avoidance behavior latency with maximum effects occuring at 15 mg/kg, 10–15 min after injection. The effects of morphine disappeared within 90–120 min. Saline treatment had no detectable effects on the latency of the response to an aversive stimulus. Naloxone significantly blocked (P < 0.05, Student paired t-test) the increase in avoidance behavior latency. The present results indicate that: 1. morphine has an antinociceptive effect on the response of Megalobulimus sanctipauli to an aversive thermal stimulus; and 2. the morphine-induced “analgesia” may be caused by the stimulation of μ opiate receptors.     

美普他酚及其同分异构体对角叉菜胶引起的炎症大鼠具有抗热痛敏作用

实验以清醒大鼠的缩腿潜伏期为指标,观察了腹腔注射美普他酚及其同分异构体112824和112825对角叉菜胶引起的热痛敏的影响.外周炎症由单侧足底注射角叉菜胶(2 mg/100 μl)引起.注射角叉菜胶3 h后,注射侧后肢局部红肿及热痛过敏反应达到高峰,持续数小时.腹腔注射0.1 mg/kg美普他酚对炎症和非炎症侧后肢的缩腿潜伏期无明显影响(P＞0.05,n=8).腹腔注射1mg/kg和10 mg/kg美普他酚对炎症和非炎症侧后肢产生明显的抗痛敏和抗伤害效应,且对炎症侧缩腿反应的抑制(抗痛敏)作用明显强于非炎症侧(抗伤害)(P＜0.05,n=8～11).预先腹腔注射1.5 mg/kg纳洛酮明显阻断美普他酚引起的抗伤害和抗痛敏效应.腹腔注射美普他酚的同分异构体112824(1 mg/kg)和112825(1.5 ms/kg)可产生与美普他酚类似的抗痛敏作用,该效应可被预先腹腔注射1.5 mg/kg纳洛酮完全阻断.提示美普他酚及其同分异构体具有明显抗伤害和抗痛敏作用,且以后者为强.该作用主要通过mu阿片受体介导.本研究为扩展美普他酚及其同分异构体在临床上的应用提供了依据.     

Toxicity of polycyclic aromatic hydrocarbons. VI. Effects of 1-nitropyrene on serum enzyme levels in rats, and protection against it by beta-naphthoflavone and dimethyl sulfoxide

Male Sprague-Dawley rats were pretreated i.p. with corn oil or DMSO (1.5 ml/kg/day), or with beta-naphthoflavone (BNF, 40 mg/kg/day) in corn oil or DMSO for 3 days. 1-Nitropyrene (1-NP, 150 mg/kg) in DMSO was injected i.p. 24 hr after pretreatment. A significant increase in the levels of several serum enzymes was seen in rats pretreated with corn oil alone 24 hr after 1-NP injection. The increase in enzyme activities was significantly reduced by a 3-day pretreatment with DMSO or BNF.     

Effects of ES52, an enkephalinase inhibitor, on responses of ventrobasal thalamic neurons in rat

The effects of ES52, a highly potent derivative of Thiorphan, an inhibitor of enkephalinase, at doses of 5 and 10 mg/kg IV were studied on the responses to cutaneous stimuli of 18 “nociceptive” (N), 10 “convergent” (NNn) and 4 “non-nociceptive” (Nn) neurons recorded in the ventrobasal (VB) complex of the rat. The responses of neurons exclusively driven by noxious mechanical and thermal stimuli (N neurons) were depressed by 56% by ES52 15 min after the injection of 5 or 10 mg/kg IV. This depressive effect was reversed by naloxone for half the neurons. For the ten neurons driven by both noxious and non-noxious stimuli (convergent NNn neurons), the responses to noxious heat were decreased by 42% at 15 min. By contrast, there was a marked enlargement of their receptive fields to light tactile stimuli, which was not naloxone-reversible. The receptive fields of neurons exclusively driven by non-noxious stimuli (Nn neurons) were also greatly expanded by ES52. These results show that ES52 can depress the responses of VB thalamic neurons to noxious stimuli; the effects on receptive field size underlines the complexity of the endogenous opiate systems.     

Toxicity of aromatic hydrocarbons. VII. Hepatotoxicity of 9-nitrophenanthrene, and protection against it by beta-naphthoflavone

Male Sprague-Dawley rats were treated with a single i.p. injection of DMSO (3.0 ml/kg) or 9-nitrophenanthrene (9-NP, mg/kg) in DMSO. 9-NP produced a significant elevation of serum aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, and gamma-glutamyl transpeptidase (GGTP) levels relative to DMSO-injected rats 24 hr after injection. With the exception of GGTP, the increase in enzyme activities induced by 9-NP was significantly reduced by a 3-day pretreatment with beta-naphthoflavone (BNF; 40 mg/kg/day) in DMSO. The effect of 9-NP on GGTP levels was enhanced by BNF pretreatment.