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Pairs of male and female rats were injected with either tertiary naltrexone (NTX) which readily crosses the blood-brain barrier, or quaternary naltrexone (QNTX) which does not, to determine the importance of central opioid systems in the elaboration of juvenile social behavior. In the first experiment, only intraperitoneal injections of NTX (1.0 mg/kg) suppressed the frequency of wrestling pins. Peripheral injections of QNTX (10.0 mg/kg) were without effect. In a second experiment, QNTX (2.0, 4.0, or 8.0 micrograms/4.0 microliters) was injected directly into the lateral ventricles. Intracerebroventricular injection of the moderate dose reliably reduced frequency of pinning while the higher dose was severely incapacitating and the low dose was without effect. The results of these two experiments confirm an important role for brain opioid systems in the control of juvenile social interaction.

The effects of handling stimuli and stress odors on species-specific defensive behavior and pain sensitivity were examined in rats. Animals not adapted to handling had longer jump latencies on the hot plate test of pain sensitivity than those with extensive handling experience. In a postshock freezing test, naltrexone enhanced defensive freezing relative to saline controls in nonadapted animals. However, naltrexone produced no such effect in rats that were adapted to handling. These two studies indicate that the handling procedure triggered an endogenous opioid analgesic response in rats not adapted to handling. Experiment 3 showed that a similar naltrexone-reversible opioid analgesia can be triggered by stress odors. Naltrexone, when compared to saline, enhanced postshock freezing in the presence of conspecific stress odors, but not in their absence. In Experiment 4, stress odors and nonadapted handling were able to activate defensive freezing directly, when tested in compound but not in isolation. The studies are consistent with the view that stress odors and handling stimuli are danger signals that activate endogenous opioid analgesia as well as defensive behavior, suggesting that analgesia is a component of the rat's defensive behavior system.

The effects of 16-Me cyprenorphine (M80) on the antinociception produced by reexposing rats to a chamber associated with footshock (1 mA, 0.75 sec) 24 hr earlier was assessed with the formalin test. In Experiment 1, intracerebroventricular administration of M80 dose-dependently (0.5-8 micrograms) reversed conditional analgesia. Experiment 2 demonstrated that M80 (5 micrograms) had no effect on baseline pain sensitivity, but completely reversed conditional analgesia. Experiment 3 demonstrated that 0.25 micrograms DAGO, 3.5 micrograms DPDPE, and 28 micrograms U50,488H all produced equivalent levels of antinociception on the formalin test. The 5 micrograms dose of M80 completely reversed the antinociception produced by DPDPE but did not influence that produced by DAGO or U50,488H. These data suggest, that at the doses employed, M80 is a selective delta-opioid receptor antagonist and that delta-receptors are involved in conditional fear-induced analgesia.

Three opioid agonists ([D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAGO), [D-Pen2,D-Pen5]enkephalin (DPDPE) and U50488H) were tested independently for their ability to produce analgesia in the formalin test. These agonists were chosen based upon their ability to act selectively at mu, delta and kappa opioid receptor types respectively. Rats received one intracerebroventricular (i.c.v.) injection of an agonist 20 min after subcutaneous injection of 15% formalin into a rear paw. Formalin injection produces continuous pain that results in two stereotypic behaviors, paw licking and paw lifting. Ten minutes after i.c.v. injection rats were observed for an 8 min period and scored for formalin-induced behavior. All agonists produced analgesia as indicated by a dose-dependent attenuation of formalin-induced behavior. At the doses tested, the rank order of analgesic efficacy was DAGO greater than DPDPE greater than U50488H. We suggest that centrally located mu, delta and kappa opioid receptors can each modulate the perception of this clinically relevant form of continuous pain. Additionally, the highest dose of DPDPE tested significantly increased rearing whereas DAGO and U50488H failed to affect rearing.

The acquisition of morphine analgesic tolerance was investigated in neonatal rats. Morphine was found to produce a potent analgesia, as measured by latency to retract a hindpaw from a 52 degree C hotplate, in rat pups as young as 1 day of age. Morphine analgesic tolerance, however, did not develop in rats until the third week of life. Rats given the same daily morphine regimen starting at 15 days of age or older showed rapid tolerance development. The data from four experiments indicate that experience with morphine prior to this age (Day 15) does not impact on the analgesic efficacy of the drug. Similarly, when morphine treatment was discontinued and the rats given a naloxone challenge, withdrawal symptoms were not observed in very young rats. Opiate withdrawal was first detected in rats that started their daily morphine treatment at 30 days of age and were then challenged with naloxone at 52 days of age. Therefore, two correlates of opiate addiction, tolerance and withdrawal, appear to be relatively late-developing phenomena in the rat.

The cerebellar vermis has extensive anatomical connections with many brain stem and forebrain structures which have been implicated in emotional or affective behavior. Previous reports indicate that lesions of the vermis in a variety of experimental animals result in altered emotional behavior. The studies reported here attempted to clarify the nature of the change in emotional behavior following vermal lesions in rats by testing the animals in a variety of fear-eliciting situations. As compared with controls, vermal-lesioned rats froze less in the presence of a cat and showed fewer signs of fear in an open field. However, their responses to footshock did not differ fundamentally from controls. They recovered more quickly than controls from the neophobic response to a novel taste but showed robust taste-aversion learning. The results are discussed in terms of the role of the cerebellum in the modulation of fear-related behaviors and in terms of similarities and differences with the effects of amygdala lesions. The results expand the body of data implicating the cerebellum in the modulation of complex motivational behavior.

In three experiments we examined the analgesic potency of kappa opioid receptor agonists in 2- and 16-day-old rats. Ethylketocyclazocine (1-50 mg/kg) produced similar dose- and time-dependent increases in the latency to retract a hind paw from a noxious thermal stimulus in rats of both ages. Bremazocine (0.001-10 mg/kg), a kappa agonist with reported antagonist activity at mu receptors, was also effective in producing analgesia in 2-day-old rats. The dose-effect relationship for bremazocine was nonmonotonic. Bremazocine analgesia (0.1 mg/kg) was reversed by both naltrexone and MR2266, a putative kappa opioid antagonist. These results are discussed in terms of the functional integrity of a kappa analgesic system in the developing rat.

Rats received unsignaled shocks in an observation chamber, with different groups varying with respect to time between shocks. Twenty-four hours later the rats were returned to the observation chamber for a test of conditioning to contextual stimuli. The freezing response served as the dependent variable. In Experiment 1 we found that distributed shock trials (60 s) resulted in more context conditioning than did massed trials (3 s or 16 s). Experiment 2 replicated this intertrial interval (ITI) effect when total time in the context was equated for the massed and distributed groups. The observed beneficial effect of distributed practice for conditional stimuli arises because of decreased contextual conditioning with longer ITIs (e.g., Gibbon & Balsam, 1981; Rescorla & Wagner, 1972). Although the basic effect of enhanced performance with longer ITIs is consistent with Wagner's rehearsal model (e.g., 1978), three findings argue against such an account. First, posttrial stimulation did not reduce the benefit obtained from distributed trials (Experiment 3). Second, intertrial distractors did not improve performance of the animals subjected to massed trials (Experiment 4). And third, the ITI effect was not eliminated when conditioning was brought to its asymptote (Experiment 5). The overall pattern of data is consistent with an opponent-process account suggesting that in addition to supporting conditioning, the unconditional stimulus (US) activates a B-state capable of reducing the impact of the next US and that this B-state lasts longer than 16s but decays before 60 s.

When rats are placed in a context with mild electric shock (1 mA/0.75 s), the environmental cues alone can provoke an immobile crouching behavior termed freezing. Freezing response is a Pavlovian conditional response provoked by stimuli that come to be associated with shock. Previous research has shown that peripheral injection of opioid antagonists can enhance this response. Two experiments were conducted to determine if peripheral and/or central opioid mechanisms are involved in this enhancement of freezing by employing quaternary naltrexone (QNTX), an opioid antagonist which does not readily penetrate the 'blood-brain barrier'. QNTX (5 and 10 micrograms/rat) administered i.c.v. prior to shock significantly enhanced freezing 24 h later, whereas i.p. injected QNTX, at doses as high as 20 mg/kg, had no effect. These results suggest that the enhancement of conditional freezing produced by QNTX is mediated by central, not peripheral, opioid mechanisms.

Earlier research has demonstrated that opioid involvement in drinking is primarily mediated centrally [8,10]. Drinking is attenuated by the centrally and peripherally active opioid antagonists naloxone and naltrexone in doses as low as 1.0 mg/kg, but not by the quaternary forms of these antagonists [4]. Peripherally administered quaternary forms of these antagonists fail to suppress drinking in doses as high as 10 mg/kg. We generated dose-response curves for centrally and peripherally administered SR58002C, a "newer" quaternary opioid antagonist purported to have high peripheral selectivity, on drinking in 23.5 hr water deprived rats. SR58002C was administered both intracerebroventricularly (ICV, 0, 10, 40 and 80 micrograms/rat) and intraperitoneally (IP, 0, 10, 40 and 80 mg/kg). Doses of SR58002C above 10 mg/kg IP or 10 micrograms ICV significantly reduced drinking in comparison to controls. However, SR58002C appears to be less potent than quaternary naltrexone in suppressing drinking after ICV administration.

Rats were exposed to three shocks, spaced 20 s apart, at two different levels of severity, low (.75 s, 1 mA) and high (3 s, 4 mA). Both shock levels produced a similar suppression of the recuperative behavior elicited by an injection of formalin into a rat's hind paw. Naloxone fully reversed the analgesia produced by the low-severity shock but only partially reversed the analgesia produced by the high-severity shock (Experiment 1). Hypophysectomy did not alter the level of analgesia (Experiment 2). When the rats were tested in a chamber different from the one they were shocked in, both analgesias were totally reversed (Experiment 3). However, imposing a delay between shock and analgesia testing did not reduce analgesia (Experiment 4). These results suggest that analgesia is not directly elicited by the shock but by apparatus stimuli associated with shock. Further support for this position was obtained when it was found that a Pavlovian extinction procedure could completely eliminate analgesia (Experiment 5). In all of the experiments, the freezing response, one of the rat's species-specific defense reactions, was monitored simultaneously with recuperative behavior. A parallel was found between analgesia and this defensive response, a result suggesting that an animal's endogenous analgesic systems may be activated along with the animal's defensive motivational system. The results point to the critical nature of associative variables in the control of endogenous analgesic systems. They also suggest that shock severity is a determinant of analgesia's sensitivity to naloxone.

Earlier research has demonstrated that when rats are placed in a context associated with mild electric shock (1 mA/0.75 sec), environmental cues alone can produce conditional analgesia that suppresses pain sensitivity on the formalin test. This analgesia appears to be mediated by endogenous opioids since it is reversed by the centrally active opioid antagonists naloxone and naltrexone. Two experiments attempted to determine if peripheral or central opioids mediate this analgesia by employing quaternary naltrexone (QNTX), an antagonist which does not readily penetrate the blood-brain barrier at moderate doses. Intracerebroventricularly administered QNTX (10 micrograms) significantly reversed conditional analgesia, whereas intraperitoneally injected QNTX did not affect formalin-induced behavior. These results suggest that the conditional analgesia produced by our procedures is mediated by central, not peripheral, opioid mechanism(s).

The freezing behavior of the rat that occurs following painful electric shock was found to increase when the animal was pretreated with the opiate antagonist naloxone. Freezing was a positive linear function of drug dose and shock intensity (Experiment 2). Naloxone pretreatment enhanced freezing only when the animal was given two or three shocks but did not affect freezing when the animal was given only one shock or not shocked at all (Experiments 3, 4, and 5). Naloxone must be present during shock, nor just during the observation period, in order to increase freezing (Experiment 6). These results suggest that when an animal is shocked, it releases endogenous analgesics (endorphins) that make a subsequent shock less aversive. Naloxone, by blocking the endorphin system, makes the shock more aversive than it would normally be.