Learning and cross drug effects: Thermic effects of pentobarbital and amphetamine

The effects of environmental cues explicitly paired or unpaired with pentobarbital on the thermic effects of pentobarbital and amphetamine were investigated. Rats received 19 injections of pentobarbital in a distinctive environment and were subsequently tested for the thermic effects of pentobarbital and amphetamine in the distinctive environment, another environment previously associated only with saline, or in the colony room not previously associated with injections. Rats tested in the context of the environmental cues previously associated with pentobarbital were tolerant to the hypothermic effect of pentobarbital, but rats tested in the environment previously associated only with saline or in the colony room were not tolerant. Pentobarbital-experienced rats administered amphetamine in the context of the usual pentobarbital cues exhibited an exaggerated hyperthermic reaction compared to previously drug-naive rats administered amphetamine. Pentobarbital-experienced rats injected with amphetamine in the homeroom exhibited a smaller hyperthermic response than previously drug-naive rats administered amphetamine in the home room. These results demonstrate that an animal's response to a drug can be affected by cues paired and unpaired with drug administration.     

A rapid assessment of stimulus properties of morphine

The difficulty in assessing stimulus properties of drugs becomes apparent when the test drug, like morphine, carries both aversive and reinforcing effects at certain doses. Mice (ICR Crj strain) were trained in a passive avoidance conditioning using a two-compartment shuttle-box. On alternate days, morphine (3.0 mg/kg) was paired with shock in one compartment and saline with shock in the other compartment. A total of 3 morphine/saline pairings were given. Animals were then tested 7 times, one test per day, with saline and different doses of morphine (0.75, 1.12, 1.32, 0.93, 1.50, 3.0 mg/kg) to reveal the stimulus properties of morphine. The preference for the morphine-conditioned safe compartment after morphine injections was used to indicate that the animals associated some “stimulus” or “motivational” properties of morphine with the cues of the safe compartment. The animals discriminated very well between saline and low doses of morphine on the one hand and higher doses of morphine (close to that given during conditioning) on the other. The discontinuity between injections responded to as saline and those responded to as morphine was virtually complete between 1.12 and 1.32 mg/kg of morphine. These findings demonstrate that the present method can be used to establish an association between some stimulus properties of morphine and avoidance of shock. Accordingly, the successful discrimination of the animals between the two compartments revealed some stimulus properties of morphine.     

Long-term perspectives of thyroxine administration in neonatal rats.

Newborn pups were injected with normal saline (group A) and exogenous thyroxine (group B). Elevated T4 and decreased TSH levels from day 7 in group B continued until day 35. T4 and TSH were in normal range by day 42 and were similar to group A. Weight gain was significantly lower in group B. On day 45, half hourly injections (subcutaneous) of TRH were given to half of group A and group B each. Remaining halves were injected with saline. TSH response to TRH was significantly decreased in group B rats. Thus, neonatal hyperthyroidism results in (1) permanent decrease in pituitary reserve of TSH secretion and (2) a permanent imprinting regarding growth and thyroidal development and thus, neonatal period is critical for thyroidal development.     

Pharmacological responses to acute morphine administration in normotensive Wistar-Kyoto and spontaneously hypertensive rats

The effect of acute administration of morphine on analgesia, hyperthermia, hypothermia and catalepsy was determined in spontaneously hypertensive (SH) rats and normotensive Wistar-Kyoto (WKY) rats. A greater analgesic and hyperthermic response to morphine was observed in SH rats than in WKY rats. A dose of morphine (50 mg/kg ip) which produced hypothermia in WKY rats produced pronounced hyperthermia in SH rats. The cataleptic response to morphine was lower in SH rats. The cataleptic response to morphine was lower in SH rats than in WKY rats. The brain and plasma levels of morphine in SH rats were significantly lower as compared to the WKY rats at any dose of morphine used but the ratio of brain to plasma did not differ. It is concluded that SH rats exhibit altered sensitivity to morphine in comparison with their normotensive counterparts.     

Intravenous morphine infusion (IMF) to drug-naive, conscious rats evokes bradycardic, hypotensive effects, but pressor actions are elicited after IMF to rats previously given morphine

Hemodynamic (blood pressure and heart rate) responses of conscious drug-naive rats were studied following intravenous (i.v.) infusion of sterile saline, morphine sulphate, and then naloxone hydrochloride, as well as of other groups previously injected with morphine sulphate. Those groups chronically given morphine sulphate received twice daily injections of morphine sulphate (5 mg/kg, s.c. per injection) for 3 or 6 days before testing with the i.v. infusion of morphine sulphate. Drugs were infused (135 microL/min) through an indwelling femoral venous catheter via a Harvard infusion pump, and blood pressure was recorded from the abdominal aorta via a femoral arterial catheter. Other pretreatment studies were done to determine the receptor mechanisms mediating the blood pressure responses of drug-naive and chronic morphine-treated rats, whereby equimolar doses (0.32 mumol) of specific receptor antagonists were given as a bolus i.v. injection 5 min after saline but before subsequent infusion with morphine sulphate. Intravenous infusion of morphine sulphate (7.5 mg/kg total over 15 min) to drug-native rats caused a transient but precipitous fall in mean arterial pressure and mean heart rate with an associated rise in mean pulse pressure; these effects were blocked in other groups pretreated with atropine. Interestingly, however, rats chronically injected with morphine sulphate for 3 days previously evoked a transient pressor response when subsequently infused i.v. with morphine sulphate, actions that were blocked in other groups when pretreated i.v. with 0.32 mumol of phentolamine, yohimbine, prazosin, or guanethidine. A greater and persistent pressor response occurred following morphine infusion to groups of rats previously injected over 6 days with morphine sulphate, which was associated with tachycardia during the later stages of the 15-min morphine sulphate infusion period. The prolonged pressor and tachycardic responses of this 6-day chronically injected group were completely blocked in another group pretreated i.v. with both phentolamine and propranolol (0.32 mumol). The results suggest that morphine sulphate infusion to conscious, drug-naive rats evokes classical hypotensive effects due to decreases in mean heart rate caused by activation of parasympathetic vagal activity. With 3 or 6 days of chronic morphine sulphate administration beforehand, subsequent i.v. infusion of morphine sulphate evoked pressor actions felt to be caused by a progressive activation of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of repeated nicotine exposure on core temperature and motor activity in male and female rats

Comparatively little is known about the thermoregulatory effects of single and repeated administration of nicotine. Nicotine is a relatively fast acting drug that induces transient changes in core temperature (T_c) of rodents. The development of radio telemetry allows one to detect subtle and rapid changes in T_c that otherwise are difficult to measure with conventional colonic probe techniques. To this end, T_c and motor activity (MA) were monitored by radio telemetry in male and female Sprague-Dawley rats following five daily injections of saline or nicotine tartrate (0.5 mg/kg; sc). The first injection of saline led to a transient increase in T_c that was attributed to the handling and injection procedures. Rats dosed with nicotine for the first time were hypothermic for approximately 2 h after injection. The hypothermia was attributed to an impaired increase in T_c from handling and injection. A transient hyperthermic response began to develop with each successive injection of nicotine. After the fourth injection of nicotine, T_c of male rats increased by 0.5°C above controls; T_c of females increased by 0.25°C above controls after the fifth injection. MA also increased transiently with each injection of saline and nicotine. The MA response of females was significantly greater than the males for the second through fifth injections of nicotine. Overall, the thermoregulatory system develops sensitization with 4–5 repeated injections of nicotine. The mediation of a hyperthermic response to a systemically administered cholinergic agonist is a novel effect. It may aid in understanding the delayed hyperthermic response to organophosphate pesticides. The sensitization of the thermoregulatory system to nicotine may shed light on the neuropharmacological mechanisms of this drug.     

The role of contextual cues on counterirritation in the development process of analgesic tolerance to morphine

Tolerance to morphine analgesia was determined by daily exposing rats either to the same box or different boxes during repeated administration of formalin (2.5%, 0.4 mL/body, sc) and morphine (5 mg/kg, sc). The analgesic effect was determined daily for four consecutive days by exposing rats to either the same box or different boxes, and the process of tolerance development was assessed by a hot plate test (52.5 degrees C). The rats were divided into four groups: one group received formalin and morphine in the same context (Group FM-Same), one group in the different context (Group FM-Diff), one group received saline and morphine in the same context (Group SM-Same), two groups received formalin in the same or different contexts (Groups FS-Same or FS-Diff), and one group received saline in the same context (Group SS-Same). The response latency of Group SM-Same was decreased from Day 2 to a level similar to that of Group SS-Same on Day 4, while that of FM-Same decreased more slowly. The latency of Group FM-Diff maintained the level of Day 2 until Day 4, being significantly longer than that of FM-Same. In the Extinction Phase, all rats received formalin and saline injections in the same box they had been exposed to on Day 1. On the first day, hyperalgesia was evident in Group SM-Same alone. In the Re-test Phase, the rats underwent a second morphine injection, and showed recovery from tolerance. These results indicate that formalin-induced chronic stress pain reduces tolerance development to morphine, and the mutual influence of pain, counterirritation, between formalin and hot-plate, facilitates the effect of contextual cues by inhibiting an associative learning.     

Role of conditioned reinforcers in the initiation, maintenance and extinction of drug-seeking behavior.

The development of a secondary reinforcer as a result of associating a neutral stimulus (buzzer) with intravenous (IV) doses of morpine was studied in rats. Secondary reinforcement developed in the absence of physical dependence and followed the association of the stimulus with either response-contingent or non-contingent injections of morphine. Strength of the conditioned reinforcer, measured in terms of responding on a lever for the stimulus plus infusion of saline solution, was proportional to the unit dosage of morphine employed in pairings of buzzer and drug. When extinction of the lever-press response for IV morphine was conducted (by substituting saline for morphine solution) in the absence of the conditioned reinforcing stimulus, it was seen later that the stimulus could still elicit lever responses, until it too had been present for a sufficient interval of non-reinforced responding. Similarly, extinction of the response for morphine by blocking its action with naloxone in the absence of the stimulus did not eliminate the conditioned reinforcement. Another study showed that a passive, subcutaneous (SC) dose of morphine served to maintain lever-pressing on a contingency of buzzer plus saline infusion. Furthermore, the stimuli resulting from the presence of morphine (after a SC injection) were able to reinstate the lever-responding with only the buzzer-saline contingency when such responses had previously been extinguished. Moreover, it was shown that d-amphetamine could restore responding under the same conditions, and that morphine could also do so for rats in which the primary reinforcer had been d-amphetamine. It is suggested that animal data such as these show that procedures designed for the elimination of human drug-taking behavior must take into account secondary reinforcers as well as the primary reinforcer(s).     

Interaction between the effects of stress and morphine on body temperature in rats

The relation between stress-induced and morphine-induced body temperature changes was examined in rats. Three groups of eight animals thoroughly habituated to handling and rectal probing, and three groups of eight experimentally naive animals were injected intraperitoneally with either 1, 5, or 30 mg/kg morphine sulphate on each of six consecutive days. Differences in temperature readings from the pre-injection baseline showed that on Day 1 of the experiment stress acted to effectively increase the potency of morphine, causing slightly increased hyperthermia at the lowest dose and greatly increased hypothermia at the highest dose. Thus for habituated animals the dose-response curve for morphine was shifted to the right. By Day 6, after repeated morphine injections, all animals showed a hyperthermic response to morphine and the differences between habituated and unhabituated animals had disappeared. These findings were discussed in terms of the interaction between the temperature changes produced by endogenous opioids in stressed animals and the actions of exogenously administered morphine.     

慢性吗啡处理及戒断后大鼠杏仁核中Parvalbumin的表达变化

目的:观察慢性吗啡处理及戒断后大鼠杏仁核中Parvalbumin(PV)的表达变化,为其功能的研究提供形态学依据。方法:将30只健康雄性SD大鼠随机分为吗啡依赖组和生理盐水对照组。吗啡依赖组大鼠腹膜腔注射吗啡,2次/d,起始剂量为5 mg/kg,逐日递增5mg,至第10d为50mg/kg;对照组注射同体积的生理盐水。于末次注射后动物分别存活3h、3 d和14d。用免疫组化方法和相对平均灰度值检测杏仁核内PV的表达。结果:在生理盐水处理组各存活时间点,杏仁核内PV的表达相同。和生理盐水对照组相比,3h时杏仁核内PV的表达明显增加(P<0.05)。第3d时,杏仁核内PV的表达减少,明显低于第3 h组(P<0.05)。至第14d时,PV的表达又开始增加,明显高于第3 d组(P<0.05)。结论:本结果提示慢性吗啡处理及戒断后杏仁核PV的表达具有时相特异性;这种变化在戒断早期可能主要与躯体依赖相关,而戒断晚期主要与精神依赖相关。     

Conditioned place preference from intra-accumbens but not intra-caudate amphetamine injections

Rats received injections of d-amphetamine sulphate (10 micrograms in 0.5 ul) in nucleus accumbens and were placed into one of two (randomly assigned) distinctive environments. The next day the rats were placed into the other environment and received either a saline injection or no treatment. This procedure was repeated six times. When the rats were allowed a free choice between the two environments they showed a significant preference for the one that had been paired with amphetamine. This finding suggests that amphetamine-stimulated release of dopamine in nucleus accumbens can increase the incentive value of neutral stimuli with which it is paired. When the same procedure was carried out with a group of rats that received amphetamine injections in the dorsolateral caudate nucleus, no preference for the side paired with the drug was evident. This suggests that there is functional differentiation between different parts of the dopaminergic terminal system.     

Endothelin receptor antagonists restore morphine analgesia in morphine tolerant rats

Several neurotransmitter mechanisms have been proposed to play a role in the development of morphine tolerance. The present study provides evidence for the first time that endothelin (ET) antagonists can restore morphine analgesia in morphine tolerant rats. Tolerance to morphine was induced by subcutaneous implantation of six morphine pellets during a 7-day period. The degree of tolerance to morphine was measured by determining analgesic response (tail-flick latency) and hyperthermic response to morphine sulfate (8 mg/kg, subcutaneously (s.c.)) in placebo and morphine pellet implanted rats. The maximal tail-flick latency in morphine pellet-vehicle treated rats (7.54 s) was significantly lower (P<0.05) when compared to placebo pellet-vehicle treated rats (10s), indicating that tolerance developed to the analgesic effect of morphine. In separate sets of experiments, ET antagonists, BQ123 (10 microg, intracerebroventricularly (i.c.v.)) and BMS182874 (50 microg, i.c.v.) were administered in placebo and morphine tolerant rats. BQ123 was injected twice daily for 7 days and once on day 8. BMS182874 was administered only on day 8. Morphine (8 mg/kg, s.c.) was administered 30min after BQ123 or BMS182874 administration. It was found that both BQ123 and BMS182874 potentiated morphine analgesia in placebo and morphine tolerant rats. BQ123 potentiated tail-flick latency by 30.0% in placebo tolerant rats and 94.5% in morphine tolerant rats compared to respective controls. BMS182874 potentiated tail-flick latency by 30.2% in placebo tolerant rats and 66.7% in morphine tolerant rats. Morphine-induced hyperthermic effect was also potentiated by BQ123 and BMS182874. The duration of analgesic action was also prolonged by BQ123 and BMS182874. The effect of BMS182874 was less as compared to BQ123. BQ123 and BMS182874 are selective ET(A) receptor antagonists. Therefore, it is concluded that ET(A) receptor antagonists restore morphine analgesia in morphine tolerant rats.     

Chronic deep brain stimulation in the rat nucleus accumbens and its effect on morphine reinforcement.

In order to explore a novel method for the treatment of drug abuse, we evaluated the effect of chronic deep brain stimulation (DBS) of the rat nucleus accumbens (NAc) on morphine reinforcement, using a DBS apparatus and an implant method we developed. Thirty-two adult rats weighing 240-260 g were divided into three groups, which included a DBS group (n = 10, administration of surgery, morphine and DBS), a sham DBS group (n = 12, administration of surgery and morphine) and a control group (n = 10, administration of physiological saline). The DBS electrode was stereotaxically implanted into the core of unilateral NAc and connected to an implantable pulse generator. Then, they were fixed to the rat skull. One week later, the rats in each group were intraperitoneally injected with morphine at an increasing dose (10-60 mg/kg) once daily. The rats in the DBS group were administered a 130-Hz high-frequency stimulation (HFS) once daily. A 900-second conditioned place preference (CPP) paradigm was used for determining the effect of electrical stimulation on morphine reinforcement in rats. The data showed that 7-10 days later, the preference score of the DBS group was significantly lower than that of the sham DBS group. The results suggest that chronic HFS of the rat NAc can block CPP induced by morphine and attenuate morphine reinforcement.     

Short-term tolerance to morphine: effects of diazepam, phenobarbital, and amphetamine

Short-term tolerance to morphine, which can be demonstrated in as little as 3 hours after a single administration of the opiate, was examined in animals chronically pretreated with diazepam, phenobarbital, or amphetamine. Tail-flick latency in mice and changes in plasma corticosterone in rats were the parameters tested in these experiments. Rats primed with either saline or morphine, 10 mg/kg, were injected 3 hours subsequently with morphine, 5 mg/kg. Those primed with saline showed the characteristic plasma corticosterone elevation following morphine, when serial blood samples were examined, whereas those previously treated with morphine did not. Mice were primed with saline or either of two doses of morphine, 30 or 100 mg/kg, 3.5 hours prior to estimation of tail-flick latency and ED50 determinations. Mice primed with either dose of morphine had significantly higher ED50's than those primed with saline. Chronic treatment with diazepam or amphetamine in either species did not significantly alter short-term tolerance development by either parameter. However, with phenobarbital pretreatment, the plasma corticosterone response was attenuated and short-term tolerance to morphine's analgesic effects did not occur. Further studies in morphine-pelleted mice showed that analgesic tolerance occurred similarly in all groups. This suggests that barbiturates may delay the process.     

Corticotropin-releasing hormone (CRH) produces analgesia in a thermal injury model independent of its effect on systemic beta-endorphin and corticosterone

To determine separately the effect of corticotropin-releasing hormone (CRH) on analgesia and on inflammation, rats were assigned to receive CRH 60 microg/kg, CRH 300 microg/kg, morphine 4 mg/kg, or normal saline intravenously 15 min before a burn injury. Two mesh chambers that allowed collection of fluid had been previously implanted subdermally in each rat. The skin overlying the right chamber was subject to thermal injury. The left chamber served as a control. We assessed systemic analgesia, and levels of beta-endorphin and corticosterone in plasma and in chamber fluid before, 1, 4 and 24 h after drug administration. The CRH groups exhibited longer tail flick latencies than the control group (P=0.0001) although the increase in latency was of smaller magnitude than in the morphine group. We did not observe a CRH dose response for analgesia. Plasma corticosterone levels were higher in the CRH 300 microg/kg group than in the normal saline group at 4 h (P=0.03). Levels of beta-endorphin in plasma as well as the levels of corticosterone and beta-endorphin in chambers were similar in the CRH 300 microg/kg group and in the normal saline group (all P values>0.1). Thus, systemically administered CRH produces analgesia in thermal injury independent of its effect on these two markers of local or systemic inflammation.     

Morphine inhibits TRH-induced gastric contractile activity.

This study investigated the effect of centrally and peripherally administered thyrotropin releasing hormone (TRH) on gastric contractile activity of rats 14, 21, 28 and adult (greater than or equal to 50) days (D) of age, and the effect of morphine pretreatment on that response. Rats were anesthetized with urethane, then a tension transducer was implanted on the anterior gastric corpus. Following baseline recording, rats were pretreated with intraperitoneal morphine (2 mg/kg). TRH (5 micrograms) in saline or saline alone (0.6 microliters) was then injected into the cisternum magnum. Additionally, dose response to TRH was examined in 14- and 50-day-old rats. Intracisternal TRH induced a dose-related increase in gastric contractile activity in both 14- and 50-day-old rats. Higher doses of TRH (10 and 30 micrograms) prolonged the response as compared to low doses. Peripheral morphine pretreatment blocked the TRH-induced increase in gastric contractile activity in all age groups although a higher morphine dose (10 mg/kg) was needed to block the effect in 28D rats. Intravenous TRH (5, 10, 30 micrograms) produced an increase in gastric contractile activity in 14D rats which was blocked by vagotomy.     

The role of the pituitary-adrenal axis in the hyperthermia induced by acute peripheral or central (preoptic anterior hypothalamus) administration of morphine to unrestrained rats

The role of the pituitary-adrenal axis in the mediation of morphine-induced hyperthermia of conscious, unrestrained rats was investigated. Rectal (TR) and tail (Tt) temperatures and oxygen uptake rates (VO2) were measured following peripheral or central injection of morphine sulphate (MS) in groups of Sprague-Dawley rats before and after adrenalectomy (adx), hypophysectomy (hyp), or pituitary suppression (via dexamethasone treatment). The hyperthermic TR responses of groups given MS either subcutaneously (5 or 15 mg/kg) or directly into the preoptic anterior hypothalamus (POAH, 1 or 10 micrograms/microL) before adx were not different upon retesting with the same dose of MS 2 weeks later following adx. The hyperthermia with MS was not caused by vasoconstriction or by increases in basal metabolic rate, for Tt rose after the opiate injections whereas oxygen uptake rates (VO2) were reduced. Unexpectedly, the TR following POAH injections of sterile saline (SS) or deionized water after adx increased from those seen before adx. Adx groups supplemented with dexamethasone phosphate (either chronically with 20 micrograms/kg daily for 2 weeks post-adx before retesting with MS or acutely with 250 micrograms/kg 2 h before retesting) showed a hyperthermia to MS (5 mg/kg sc or 1.0 microgram/microL POAH) similar to that seen before adx. However, dexamethasone phosphate (250 micrograms/kg) supplementation to adx rats, that received POAH injections of SS, did reduce the rise in TR. Hyp rats given MS (5 mg/kg, sc) also evoked hyperthermic responses similar to those of non-hyp control groups. The results clearly show that the acute hyperthermia of unrestrained rats induced by either peripheral or central injections of morphine is not caused by activation of the pituitary-adrenal axis.     

Thermoregulatory (core, surface and metabolic) responses of unrestrained rats to repeated POAH injections of beta-endorphin or adrenocorticotropin

Repeated preoptic-anterior hypothalamic (POAH) injections of saline and 10 or 25 micrograms/microliters of beta-endorphin or ACTH were given to groups of male Sprague-Dawley rats. One hr after the fifth injection of beta-endorphin or ACTH, each rat received a POAH injection of naloxone HCl (10 micrograms/microliters). Core (Tre-rectal) and surface (Tt-tail) temperatures, metabolic (VO2) and behavioral responses were recorded 30 min before and 60 min after each drug injection. The initial POAH injection of either dose of beta-endorphin produced a hyperthermia. Peak hyperthermia was reduced in the group given 10 micrograms/microliters of beta-endorphin repeatedly. TtS rose after each beta-endorphin injection but temporally lagged Tre increases. Metabolic rate (VO2) was increased with repeated POAH injections of beta-endorphin. Naloxone reduced the elevated Tre seen with beta-endorphin by increasing Tt's further and reducing VO2. POAH administration of ACTH evoked only a slight hyperthermic Tre response, but elevated TtS and VO2S, due to enhanced grooming and explorative behavior. With repeated ACTH injections, TreS did not change from those on the first day as TtS and VO2 remained enhanced. Naloxone reduced VO2 and TtS of the ACTH-treated rats but TreS still were unchanged. Results suggest that the hyperthermia of unrestrained rats given an acute as opposed to repeated POAH beta-endorphin injections is mediated by different effector mechanisms. With the doses used, the slight and unchanging TreS seen with ACTH occurred because this peptide increased heat production due to locomotor activation yet also exaggerated heat loss by vasodilating the peripheral vasculature.     

Opiate system involvement in the control of LH secretion in diabetic and normoglycemic male rats

The effect of Naltrexone (Nalt), a specific opiate receptor blocker, on LH secretion was studied at frequent intervals during the first hour following treatment. Nalt was injected i.v. by one bolus (1 mg/rat) to diabetic and normoglycemic rats. Blood samples (0.8 ml) were withdrawn at short intervals after injection, through an indwelling cannula. The diabetic rats responded by secretion of LH, which was lower, but not significantly, than that of normal rats, (peak levels 0.74 +/- 0.17 and 0.97 +/- 0.21 ng/ml respectively). After 45 min., LH levels were in the same range as baseline level in the diabetic group; but were still significantly elevated in the control rats. Thus, it can be concluded that in normal rats, as well as in diabetics, LH secretion as a response to Nalt was episodic in spite of Nalt's long half life time. In order to explain the rapid fall in LH levels after Nalt administration, normal rats were injected with a second bolus of Nalt, 2 hours after the first. The second bolus caused only a blunted response of LH secretion. In another experiment, administration of morphine (1 mg/rat) 2 hours after pretreatment with Nalt did not stimulate the prolactin secretion which normally follows morphine treatment. These results indicate that the rapid decrease of LH levels after Nalt treatment in normal rats is not due to absence of the drug in the system. It is suggested that other neural mechanisms, such as the dopaminergic system, are activated during Nalt influence.     

Cross tolerance to etorphine in rats tolerant to morphine-induced antidiuresis

Previously in the analgesic tail flick assay, mice and rats implanted with morphine pellets were shown to be highly tolerant to subcutaneously administered morphine but not to etorphine. The present purpose was to see whether the same differential response would be found to the antidiuretic response of morphine and etorphine in water-loaded rats because the presence of such a differential response would be of value in studying mechanisms of tolerance. Etorphine injected subcutaneously was about 1000x more potent than morphine in producing an antidiuretic response. Following chronic administration of morphine by pellet implantation, where the pellets remained in place during the drug challenge, profound tolerance developed to the antidiuretic effect of both morphine and etorphine. The dose-response curves for both were shifted to the right in non-parallel fashion with decreased slopes and antidiuretic efficacies. The large degree of tolerance developed to the antidiuretic effect of etorphine in morphine pellet implanted rats in contrast to the lack of development of tolerance to etorphine in the tail flick assay indicated that different mechanisms of development of tolerance exist for the two responses.