Second-order schedules of intravenous drug self-administration in rhesus monkeys.

Lever-pressing behavior was generated and maintained in 3 rhesus monkeys by intravenous infusions of morphine or cocaine under a second-order schedule of reinforcement. Under this schedule, every tenth lever-press response (FR 10) during a fixed interval of time produced a 2 sec stimulus light. The first FR 10 completed after a 60 min interval had elapsed produced the stimulus light and an intravenous infusion of morphine or cocaine. The stimulus light remained on for the duration of the drug infusion (50-60 sec). Sessions of morphine or cocaine presentation, each with distinct stimulus light conditions, alternated on a daily basis. Under this schedule, single doses of morphine from 0.125 to 1.0 mg/kg maintained high overall response rates (maximum of 40 Rs/min) in the pattern characteristic of fixed interval (FI) schedules of reinforcement. There was no functional relationship between the response-rates and the doses of morphine tested. The simultaneous infusion of naloxone (0.125 mg/kg/) with morphine (0.25 mg/kg) markedly decreased response rates. However, the infusion of the same dose of naloxone five min after the presentation of morphine failed to suppress self-administration behavior. Naloxone had no effects on cocaine-reinforced responding.     

Brain acetylcholine in morphine pellet implanted rats given naloxone

Adult male rats were implanted with intraventricular (ivt.) brain cannulae for injection of 5 g of acetylseco-hemicholinium-3 (acetylseco HC-3) as a means of studying acetylcholine (ACh) utilization during morphine withdrawal. Animals were made dependent by implanting s.c. two 75 mg morphine base pellets 24 hrs apart. On the 4th day animals were given 10 mg/kg of naloxone i.p. and/or 5 g acetylseco HC-3 ivt. and sacrificed by decapitation at various times. The brains were removed and assayed for ACh using a pyrolysis gas Chromatographie procedure. Total brain ACh before or after acetylseco-HC-3 was not altered at 5, 30, 60 and 120 but was decreased at 10 min after naloxone. These results are in sharp contrast to our previous data of enhanced brain ACh utilization in withdrawn rats made dependent to morphine by several weeks of twice daily injections. It is apparent that short term morphine pellet administration does not produce the marked neurochemical and behavioral changes of long term morphine injections.Supported in part by grant DA 00830, USPHS.     

Influence of tiagabine on the antinociceptive action of morphine, metamizole and indomethacin in mice

The influence of tiagabine at a dose of 3.2 mg/kg (single administration) and at a dose of 1.2 mg/kg (multiple administration - 10 days) on the antinociceptive effect of morphine (10 mg/kg), metamizole (500 mg/kg) and indomethacin (10 mg/kg - single dose and 1.4 mg/kg - multiple doses) was investigated in mice using the hot-plate and tail-flick tests. All drugs were injected intraperitoneally. Tiagabine was administered to mice 30 min before the analgesic drugs. Measurement of the reaction to a noxious stimulus was performed 60, 90 and 120 min after administration of tiagabine. The study was further conducted for 10 days with repeated drug doses. Tiagabine and morphine administered in single doses demonstrate an additive antinociceptive effect in the hot-plate test and a slightly synergistic effect in the tail-flick test. A single administration of tiagabine slightly increased the antinoceptive action of metamizole and indomethacin in both tests, but that effect is less pronounced than the antinociceptive action of tiagabine alone. Repeated administration of tiagabine with morphine abolishes the tolerance to morphine analgesia. Both single and repeated administration of tiagabine alone exerted the antinociceptive effect in the hot-plate test.     

Brain reward deficits accompany naloxone-precipitated withdrawal from acute opioid dependence

Single injections with morphine can induce a state of acute opioid dependence in humans and animals, typically measured as precipitated withdrawal when an antagonist such as naloxone is administered 4-24 h after morphine. Repeated treatment with morphine results in a progressive shift in potency of naloxone to produce such acute withdrawal signs. The current study examined alterations in brain reward thresholds after acute and repeated treatment with morphine (5.6 mg/kg) using a discrete-trial current-intensity brain-stimulation reward procedure. Rats with stimulation electrodes aimed at the medial forebrain bundle at the level of the lateral hypothalamus were tested in twice daily sessions separated by 4 h. Separate groups of rats received treatment with morphine immediately after the first daily test session, and one of several doses of naloxone (0.10, 0.33, 1.0 mg/kg) 4 h later and immediately before the second session; these morphine and naloxone treatments were repeated for four consecutive days (Morphine-Repeat NAL). Additional groups examined the independent contribution of repeated morphine or repeated naloxone. One control group (Morphine-Vehicle) received morphine on all four treatment days, but vehicle before the second test session. A second group (Morphine-Single NAL) also received morphine on all four treatment days, but received 1.0 mg/kg only once after the final morphine pretreatment. A final control group received no morphine at all but received the 1.0-mg/kg dose of naloxone four times (Vehicle-Repeat NAL) before the second daily test session. Repeated naloxone alone (Vehicle-Repeat NAL) produced no changes in brain reward thresholds. Repeated morphine alone (Morphine-Vehicle) failed to alter reward thresholds measured 4 h postmorphine, but produced a slight increase in thresholds in the test sessions that occurred before morphine treatment on Days 3 and 4 (and hence 23.5 h after the previous day's morphine injection). This suggested the development of a modest spontaneous withdrawal-induced reward deficit measurable at 23.5 but not 4 h postmorphine. Naloxone dose-dependently increased brain reward thresholds 4 h after a single morphine pretreatment, with a further shift to the left in the naloxone dose-effect function resulting from repeated morphine and naloxone administration (Morphine-Repeat NAL). However, when the highest dose of naloxone was tested only after the final morphine pretreatment (Morphine-Single NAL), its potency was no different than when administered after the first morphine pretreatment. The results indicate that neuroadaptation within brain reward circuitry results in significant reward deficits after a single morphine pretreatment, and this deficit increases rapidly with repeated morphine and naloxone-induced withdrawal experience.     

Repeated experience with naloxone facilitates acute morphine withdrawal: potential role for conditioning processes in acute opioid dependence

Single injections with morphine can induce a state of acute opioid dependence in humans and animals, typically measured as precipitated withdrawal when an antagonist such as naloxone is administered 4-24 h after morphine. Repeated treatment with morphine at 24-h intervals can result in a progressive shift in potency of naloxone to produce such acute withdrawal signs, including suppression of operant responding for food reward. The current study characterized fully both morphine and naloxone dose-effect functions in an effort to establish the relative contributions of repeated morphine vs. repeated naloxone (Nal) experience to these potency shifts. Rats trained on an FR15 schedule for food received four vehicle or morphine injections (0.56-5.6 mg/kg sc), spaced 24 h apart. Four hours after each morphine pretreatment (Repeat Nal), or 4 h after the fourth and final morphine pretreatment only (Single Nal), a cumulative dose-effect function for naloxone-induced suppression of responding was determined. Vehicle-pretreated (Morphine Naive) rats showed little change in the naloxone dose effect function even after four cumulative dose-effect determinations. By contrast, a progressive increase in naloxone potency was observed following successive pretreatments with morphine under Repeat Nal conditions, and the magnitude of naloxone potency shift was morphine dose dependent. At a morphine dose of 5.6 mg/kg, repeated naloxone experience in the presence of morphine was not an absolute requirement to produce an increase in naloxone potency across days, but repeated naloxone could potentiate the magnitude of the observed shift, indicating both experience-independent and experience-dependent processes at work. At lower doses of morphine (1.0 and 3.3 mg/kg) no shift in naloxone potency was observed across days of morphine treatment in the absence of repeated naloxone experience (Single Nal conditions), indicating an increasing contribution of naloxone experience-dependent processes as dose of morphine was decreased. It is argued that these experience-dependent processes in the progressive shift of naloxone potency observed in the current study may reflect an important role of conditioning in the early development of opioid dependence.     

Conditioning processes contribute to severity of naloxone-precipitated withdrawal from acute opioid dependence

Rationale Single injections with morphine can induce a state of acute opioid dependence in humans and animals, typically measured as precipitated withdrawal when an antagonist such as naloxone is administered 4–24 h after morphine. Repeated treatment with morphine results in further increases in naloxone potency, and prior work has shown that this progressive shift in naloxone potency requires repeated naloxone experience under some but not all experimental conditions.Objective The current study sought to further characterize the experimental conditions that support naloxone experience-dependent and experience-independent potentiation of precipitated suppression of operant responding in morphine pretreated rats, and to assess more directly whether conditioning mechanisms may contribute to the former process.Methods Rats trained on an FR15 schedule for food received a total of five vehicle or morphine injections (5.6 mg/kg SC) at 4, 8, or 22 h prior to an operant session in which a cumulative dose-effect function for naloxone-induced suppression of responding was determined. Separate groups of animals at each interval between morphine and naloxone received cumulative naloxone dosing after all morphine pretreatments (NAL ALL DAYS) or after just the first and last morphine pretreatment (NAL FIRST/LAST). Additional groups of rats at the 4 h MOR–NAL interval received most of their naloxone cumulative dose-effect experience in either the home cage or in the operant context with levers retracted.Results Vehicle-pretreated (Morphine-Naive) rats showed little change in the naloxone dose-effect function even after five cumulative dose-effect determinations. With a single morphine pretreatment, naloxone potency was increased at 4 or 8 h post-morphine, but not at 22 h. With repeated morphine treatment, all MOR–NAL intervals resulted in significant shifts in naloxone potency across treatment days even when naloxone was administered only after the first and last morphine pretreatment. However, much greater shifts in naloxone potency were observed at 4-h and 8-h intervals when naloxone was administered on all treatment days. At the 22 h MOR–NAL interval, there was no further potentiation in naloxone potency with additional naloxone experience provided on the intermediate days. Finally, when the repeated naloxone experience occurred in the home cage at the 4-h interval, naloxone potency was identical to that seen after limited naloxone experience (NAL FIRST/LAST), and significantly less than naloxone potency in groups receiving repeated naloxone experience in the operant context.Conclusions The results suggest that conditioned withdrawal mechanisms may play a significant role in the initial development of opioid dependence.     

Discriminative response control by naloxone in morphine pretreated rats

In an operant procedure using a lever press response 12 male, hooded rats were trained to discriminate 1.25 mg/kg naloxone from a saline injection. On certain days, according to a counterbalanced training schedule, naloxone was administered 8 h after 40 mg/kg morphine and 10 min prior to a trial in which food was available on an FR10 schedule from one of two levers in a dual lever operant chamber. On other days saline was administered 10 min prior to a trial in which food was made available by pressing the other lever. After criterion performance for acquisition of the discrimination had been reached, tests were carried out to determine its nature. Discrimination of naloxone was dose-dependent and was significantly diminished when naloxone was administered 36 h after morphine. Partial generalization of cyclazocine with naloxone was observed. Spontaneous withdrawal from morphine, tested during trials preceeded by an injection of saline instead of naloxone at various time intervals after morphine, did not generalize with the naloxone discriminative stimulus.     

Detection of antagonist activity for narcotic analgesics in mouse hot-plate test.

On the assumption that by the use of the hot-plate procedure the antagonist properties of narcotic analgesics could be detected, the effect of morphine, pentazocine, nalorphine and naloxone were investigated. The latency of paw-licking and jumping-off were determined and compared. The agonist, morphine, at doses of 0.025, 0.05 and 0.1 mmole/kg injected IP significantly increased paw-lick and jump-off latency above that seen in saline controls. The mixed agonist-antagonist, pentazocine, at doses of 0.048, 0.096 and 0.192 mmole/kg and nalorphine, an antagonist with some agonist activity, at doses of 0.032, 0.064 and 0.128 mmole/kg significantly increased the latency of paw-licking, but did not significantly change the jump-off latency. At a dose of 0.016 mmole/kg naloxone treated mice jumped from the hot-plate significantly sooner than controls but no effects of naloxone on paw-licking latency were observed. These results suggest that agonist properties are involved in the paw-lick response and that antagonistic properties determine jumping-off behavior.     

Ethopharmacological analysis of naloxone-precipitated morphine withdrawal syndrome in rats: a newly-developed “etho-score”

The intensity of opiate withdrawal syndrome in rats is usually quantified on the basis of selected physical signs or global scores. However, the selection criteria of signs and scores have not been subjected to an ethological discussion, hence they appear to be somewhat arbitrary. The objectives of this study were thus: i) to analyse the rat's behaviour during the nalox-one-precipitated morphine withdrawal syndrome, ii) to evaluate the validity of classic methods, and iii) to design a new etho-score. Ten rats were implanted with morphine pellets (75 mg×2, SC), all receiving different naloxone doses following a within-subject design (0, 0.01, 0.05, 0.1, 0.5, 1 mg/kg SC). Twenty unexperienced rats and 20 with placebo pellets were injected with either saline or naloxone. Behaviour was videotaped and later analysed by computer-based ethological techniques. The ethogram encompassed 16 patterns displayed by rats during morphine withdrawal. Frequency, duration and latency of each pattern was measured, and a cluster analysis allowed discerning the structure of behaviour. Several physical signs and the Gellert-Holtzman score were also evaluated. The data revealed that writhing responses linearly changed in a dose-related fashion, and mastication was also enhanced after naloxone. Wet-dog shakes and jumping changed following an U-shaped curve. Significant changes in weight loss were found to be dose-dependent, and highly correlated to diarrhea. Learning effects were found to reliably affect exploration, writhing responses and some physical signs. The Gellert-Holtzman score was gradually enhanced after naloxone, being affected by learning as well. Naloxone affected lying and self-care responses in placebo rats. To sum up, the data indicated that: i) classic signs are useful, although most of them are disrupted by high naloxone or affected by learning effects, ii) the Gellert-Holtzman score was validated in this study, and iii) mastication and weight loss are good indicators of naloxone-precipitated morphine withdrawal, representing the basis of an etho-score which is herein proposed.     

Effects of ethylketazocine and morphine alone and in combination with naloxone on schedule-controlled behavior in pigeons

The behavioral effects of morphine and ethylketazocine were compared in pigeons responding under multiple fixed-interval, fixed-ratio schedules of food presentation. Both morphine and ethylketazocine produced dose-related decreases in rates of responding maintained under either schedule. Maximal effects of morphine were observed about 15–45 min after injection and typically lasted the entire session (about 60 min). Effects of ethylketazocine had a faster onset (maximal effects were observed within 15 min after injection), and shorter duration (effects diminished within the session). Ethylketazocine and morphine had similar potencies. Dose-effect curves for both drugs were shifted to a similar degree by naloxone.     

Time-dependent codeine hypoalgesia and hyperalgesia in domestic fowl.

Recent research demonstrated that codeine produced hypoalgesia and morphine produced hyperalgesia against a noxious thermal stimulus in young domestic fowl. The bidirectional effects of these opiate agonists on nociception are inconsistent with the notion that codeine's algesic effects result through in vivo demethylation of codeine to yield morphine. In Experiment 1, the temporal pattern (15,30,60 and 120 min) of codeine (30 mg/kg) effects on thermal nociception and respiration were examined in 15-day-old cockerels. Codeine produced a time-dependent biphasic response: hypoalgesia at 15 min and hyperalgesia at 60 and 120 min. Respiration was depressed by codeine at all test intervals. To assess for opioid specificity, Experiment 2 examined the action of naloxone (5 mg/kg) on the temporal pattern (15 and 60 min) of codeine effects (30 mg/kg) on thermal nociception and respiration. Bidirectional codeine algesic effects were observed at the 15- and 60-min test intervals. Naloxone increased the codeine jump latency scores at the 15-min interval and decreased codeine jump latency scores at the 60-min interval. These results suggest that codeine engages opposed nonopioid-mediated hypoalgesic and opioid-mediated hyperalgesic nociceptive systems in this animal model. Codeine depressed respiration at both the 15- and 60-min test intervals and this respiratory depression was reversed by naloxone. These findings support the notion that codeine respiratory effects are mediated by opioid system activity.     

Naloxone increases carbon dioxide stimulated respiration in the rabbit

1. The effects were studied of morphine and naloxone on the respiratory minute volume and the minute volume stimulated by carbon dioxide in the anaesthetized rabbit. 2. The respiratory minute volume is reduced by morphine (2 mg/kg) to about 60% of control. The effect of morphine is abolished by naloxone (5 mg/kg); the minute volume depressed by morphine transiently becomes larger after naloxone than prior to morphine. Also the minute volume stimulated by carbon dioxide becomes larger after naloxone than that prior to the period of depression produced by morphine. 3. Naloxone (0.5 mg and 5 mg/kg i.v.) enhances the sensitivity of respiration to carbon dioxide by about 21% and 28%, respectively. 0.5 mg/kg naloxone itself had no influence, 5 mg/kg for about 5 min increases basal respiratory minute volume. 4.It is assumed that endogenous opiates modulate respiration and, like exogenously administered opiates, reduce the sensitivity of respiration to carbon dioxide. 5. The hypothesis is discussed that endogenous opiates are involved in regulation of biological functions which are known to be inhibited by opiates and which belong to the "protective system" postulated by O. Schaumann.     

Opioid dependence in myenteric neurons innervating the circular muscle of guinea-pig ileum

Summary Guinea-pigs were treated with morphine for 6–8 days by subcutaneous implantation of pellets, each containing a mixture of morphine base (120 mg) and morphine hydrochloride (35 mg). Each guinea-pig received a single pellet. Mechanical activity of the circular muscle was recorded in vitro in preparations comprising the circular muscle and myenteric plexus. Exposure to morphine was maintained by addition of 1 M morphine to the organ baths. After 90 min, morphine was withdrawn, either by repeatedly washing tissues in morphine-free Krebs' solution , or by addition of naloxone to reduce the occupancy of the opioid receptors by morphine. Withdrawal of morphine resulted in markedly enhanced contractile activity compared with that in circular muscle-myenteric plexus preparations from untreated control guinea-pigs. The withdrawal contractions were abolished by tetrodotoxin (600 nM) and greatly reduced by hyoscine (1 M), indicating that they resulted from action potential discharge in myenteric neurons that release acetylcholine onto the circular muscle. Activation of the cholinergic excitatory motor neurons was not secondary to synaptic activation by cholinergic interneurons, because hexamethonium (100 M) did not affect withdrawal contractions. The withdrawal response may therefore arise in the cholinergic excitatory motor neurons themselves, or in neurons that activate them via noncholinergic mechanisms. Send offprint requests to S. Johnson at the above address     

Reversal of morphine-induced catalepsy in the rat by narcotic antagonists and their quaternary derivatives

The effects of the pure narcotic antagonists, naloxone and naltrexone, and their quaternary derivatives, methylnaloxone and methylnaltrexone, were examined in reversing the catalepsy induced by morphine in rats. Morphine, 20 mg/kg, induced rigid catalepsy which attained a peak effect (as manifested by duration of catalepsy) at 60-120 min and progressively declined thereafter. Both naloxone and naltrexone, administered subcutaneously 40 min after the injection of morphine, dose-dependently reduced the duration of the catalepsy at doses of 10-30 micrograms/kg. Methylnaloxone also completely reversed the catalepsy at doses of 1-10 mg/kg, when given subcutaneously. In contrast, the subcutaneous administration of methylnaltrexone only partially reversed the catalepsy at doses up to 56 mg/kg 60-90 min post-morphine. The extent of the reversal of catalepsy produced by methylnaltrexone tended to increase with time. Methylnaltrexone, administered into the cerebral ventricles 70 min after the injection of morphine, completely suppressed the catalepsy with an ED50 of approx. 1 microgram/kg when tested at 90 min after morphine. These results indicate that opiate-induced catalepsy is predominantly mediated at sites within the central nervous system. Methylnaltrexone is about 10,000 times more potent in reversing catalepsy when administered centrally than when administered peripherally. Thus, methylnaltrexone may be useful in defining sites of opiate action and in therapeutically blocking undesirable peripheral effects of opiate analgesics.     

Effects of methionine-enkephalin and morphine on spontaneous locomotor activity: Antagonism by naloxone

Methionine-enkephalin (MEK), a postulated endogenous ligand for the opiate receptors, when administered intracerebroventricularly (ICV) in a dose of 1.75 μmoles/kg) of morphine sulfate had no effect on motor activity. Higher doses (7.0 μmoles/kg) of both MEK and morphine produced profound depression in motor activity; the decrease was significant from 6 to 30 min after their administration. Subcutaneous administration of naloxone (1 mg/kg) did not alter the motor activity. However, administration of naloxone (1 mg/kg) 2 min prior to MEK (7.0 μmole//kg) administration completely blocked the effect of the latter for 15 min while antagonizing the effect of 7.0 μmoles/kg of morphine for 10 min. At 30 min after 7.0 μmoles/kg of either MEK or morphine administration, the motor activity in these groups was identical with that of the naloxone treated group. Methionine-enkephalin in doses of 0.2 and 0.4 μmole/kg had no effect on motor activity for 1 hr observation period. A significant increase in motor activity was recorded 45 and 60 min after 0.2 μmole/kg of morphine sulfate, whereas 0.4 μmole/kg dose of morphine showed significant increase in motor activity only at 60 min after its administration. Furthermore, 0.2 μmole/kg of morphine produced a greater increase in motor activity compared with 0.4 μmole/kg dose at 45 and 60 min after administration. It is concluded that morphine and MEK produce differential effects on mouse spontaneous motor activity with respect to time and dose and that naloxone can inhibit the effects of MEK more effectively than that of morphine on motor activity.     

Is there any Cross-Antagonism between μ-Opioid and α2-Adrenergic Receptors in the Rat Spinal Cord?

Abstract: A functional connection, evidenced by synergism and cross-tolerance, seems to exist between the μ-opioid and the α₂-adrenergic receptors in the superficial dorsal horn of the rat spinal cord. In this study possible cross-antagonism between these systems was studied by intrathecal administration of morphine 2.5 μg or dexmedetomidine 1.25 μg 15 min. after subcutaneous injection of naloxone 1.0 mg/kg or atipamezole 3.0 mg/kg in the morphine group and 4.0 mg/kg or 1.0 mg/kg in the dexmedetomidine group, respectively. No cross-antagonism of the antinociceptive effect was seen either in the tail flick or in the hot plate test at 15, 30, 45 and 60 min. from the pretreatment.     

Naloxone-induced analgesia and morphine supersensitivity effects are contingent upon prior exposure to analgesic testing

Repeated administration of naloxone have been found to result in the development of analgesia. Pretreatment with naloxone can also produce supersensitivity to morphine. This study examined whether the development of these phenomena is affected by exposure to pain (hotplate testing) during opiate blockade. During acquisition, two experimental groups of rats received identical treatment with respect to repeated naloxone injections (5 mg/kg) and the environment in which the injections were administered. A contingent group (NAL-C) received hot-plate testing under the influence of naloxone, while a noncontingent group (NAL-NC) experienced hot-plate testing and naloxone separated by an interval of 24 h. At test, NAL-C rats manifested naloxone-induced analgesia (NIA) whereas the NAL-NC animals did not. The NAL-C rats also showed supersensitivity to the analgesic effects of morphine (3 mg/kg) and to the cataleptic effects of morphine (17.5 mg/kg) while the NAL-NC rats did not differ from saline controls. Thus, both NIA and morphine supersensitivity were completely dependent on testing in the drug state during acquisition; mere exposure to an identical regime of naloxone injections was insufficient to produce these phenomena.     

Behavioral effects of naloxone and nalorphine preceding and following morphine maintenance in the rhesus monkey

The effects of morphine, naloxone, and nalorphine on responding maintained under a variable-interval schedule of food presentation were assessed in rhesus monkeys before and after successive periods of daily morphine maintenance (15.0 mg/kg/day SC). Withdrawal from morphine dependence was accomplished gradually following the first two maintenance periods and abruptly following the third period. Schedule-controlled responding was disrupted when morphine maintenance was abruptly discontinued but not when the maintenance dosage was gradually reduced to zero. Tolerance to the acute effects of IV morphine on responding developed during morphine maintenance and dissipated after daily injections were discontinued. The effects of IV naloxone and IV nalorphine following each period of morphine maintenance were generally similar to their effects in initial determinations. These data indicate that tolerance-producing regimens of repeated daily injections with morphine do not necessarily produce enduring changes in the effects of opiate antagonists on schedule-controlled behavior. Additionally, gradual withdrawal from morphine maintenance can minimize the behavioral disruptions that attend abrupt abstinence.     

The effect of morphine and naloxone on the interaction of afferent signals of differing modalities in the spinal cord

The effect of the electrical nerve stimulation with low (2-4 V, 100 Hz, 5 min) and high (45 V, 1 Hz, 1 min) intensity on the nociceptive responses in the ventrolateral tracts was studied in unanesthetized rats with the transsected spinal cord. Both kinds of stimulation reduced nociceptive responses but the effect of low-intensity stimulations was diminished when they were repeated and was absent over 24 hours after spinalization. The effect of low-intensity stimulation was abolished by naloxone (0.1 and 1 mg/kg) and was reduced during the antinociceptive effect of morphine (1 and 4 mg/kg). The effect of high-intensity stimulation was preserved over 24 hours after spinalization and after repeated stimulations. It was not changed by naloxone and morphine.     

Acute opiate withdrawal in rats undernourished during infancy: impact of the undernutrition method

Acute morphine withdrawal was assessed in adult rats following early postnatal undernutrition produced by two different methods (Large Litter procedure-20 pups/litter and Modified Slob procedure-rats cross-fostered on days 2, 4, and 6 to nonlactating dams for 24-hour periods). Response rates were first stabilized on a FR16 operant schedule. A single dose of morphine (20 mg/kg) was then administered, followed 4 h later by a single injection of naloxone (2.5 mg/kg). Males reared in large litters showed little behavioral disruption after morphine, suggesting either insensitivity to the opiate or the rapid development of tolerance. After naloxone. Modified Slob males displayed milder withdrawal than those in the well-nourished control or large litter groups. Thus the method of undernutrition influenced morphine's action and expression of withdrawal. A clear sex difference was also evident, females appearing to be generally less sensitive to the opiate- and naloxone-induced withdrawal than males. Body temperature underwent a characteristic elevation following morphine and a depression following naloxone across all groups, but undernutrition did not affect these responses. Hence, behavior proved to be the more sensitive measure for revealing differences in opiate dependence and withdrawal following early life undernutrition, under the test conditions employed.