On the selectivity of intravenous mu- and kappa-opioids between nociceptive and non-nociceptive reflexes in the spinalized rat.

1. In electrophysiological experiments in spinalized, alpha-chloralose anaesthetized rats, opioids and anaesthetics were tested intravenously (i.v.) on the responses of individual motoneurones to alternating noxious (heat or pinch) and non-noxious (tap or vibration) stimuli. 2. On cells that were sensitive to low doses of mu-opioids, both fentanyl (0.5-4 micrograms kg-1 i.v.) and morphine (0.5 mg kg-1 i.v.) selectivity reduced reflexes to noxious stimuli to a greater degree than the higher doses required to reduce nociceptive reflexes (fentanyl 8 micrograms kg-1 i.v.; morphine 1-8 mg kg-1 i.v.) depressed non-nociceptive reflexes to a similar degree. 3. A similar spectrum of selectivity was seen with U-50,488 (0.5-16 mg kg-1 i.v.) although statistically significant selective depression of reflexes was only evident at the lowest dose tested (0.5 mg kg-1 i.v.). All effects of U-50,488 were readily reversed by low doses of the opioid antagonist, naloxone (10-100 micrograms kg-1 i.v.). 4. The dissociative anaesthetic/PCP ligand ketamine (0.5-4 mg kg-1 i.v.) was similar in having selective actions at low doses on sensitive cells but non-selective actions when higher doses were required. In contrast, the general anaesthetics methohexitone (4 mg kg-1 i.v.) and alphadolone/alphaxalone (1 mg kg-1 i.v.) were consistently non-selective between reflexes to noxious and non-noxious stimuli. alpha-Chloralose (20-40 mg kg-1 i.v.) had very little effect on reflexes to any of the synaptic inputs tested.     

Local administration of mu or kappa opioid agonists attenuates capsaicin-induced thermal hyperalgesia via peripheral opioid receptors in rats

Rationale: By acting on peripheral opioid receptors, opioid agonists can attenuate nociceptive responses induced by a variety of agents. Objectives: This study was conducted to characterize capsaicin-induced thermal hyperalgesia in rats and to evaluate the hypothesis that local administration of either mu or kappa opioid agonists (fentanyl and U50,488, respectively) can attenuate capsaicin-induced nociception. Methods: Capsaicin was administered s.c. in the tail of rats to evoke a nociceptive response, which was measured by the warm-water tail-withdrawal procedure. Either fentanyl or U50,488 was co-administered with capsaicin in the tail to evaluate local antinociceptive effects. In addition, the local antagonism study was performed to confirm the site of action of both opioid agonists. Results: Capsaicin (0.3–10 μg) dose dependently produced thermal hyperalgesia manifested as reduced tail-withdrawal latencies in 45°C water. Co-administration of either fentanyl (0.32–3.2 μg) or U50,488 (10–100 μg) with capsaicin (3 μg) attenuated capsaicin-induced hyperalgesia in a dose-dependent manner. Furthermore, this local antinociception was antagonized by small doses (10–100 μg) of an opioid antagonist, quadazocine, applied s.c. in the tail. However, the locally effective doses of quadazocine, when applied s.c. in the back (i.e., around the scapular region), did not antagonize either fentanyl or U50,488. Conclusions: In this experimental pain model, activation of peripheral mu or kappa opioid receptors can attenuate capsaicin-induced thermal hyperalgesia in rats. It supports the notion that peripheral antinociception can be achieved by local administration of analgesics into the injured tissue without producing central side effects. Received: 10 May 1999 / Final version: 18 August 1999     

Interactions between mu and kappa opioid agonists in the rat drug discrimination procedure

The present study was designed to explore the nature of the interaction between mu and kappa opioid agonists in the rat drug discrimination procedure. In rats trained to discriminate the kappa agonist U50,488 (5.6 mg/kg) from water, the other kappa agonist bremazocine substituted completely for the U50,488 training stimulus, and the additional kappa agonist tifluadom substituted in three of five of rats tested. In contrast, the mu agonists morphine, fentanyl, and buprenorphine produced primarily vehicle-appropriate responding. When morphine, fentanyl, and buprenorphine were combined with the training dose of U50,488, all three mu agonists reduced U50,488-appropriate responding. In rats trained to discriminate the mu agonist morphine (10.0 mg/kg) from saline, the other mu agonists morphine and buprenorphine all substituted in a dose-dependent manner for the morphine training stimulus, whereas U50,488, bremazocine, and tifluadom produced primarily vehicle-appropriate responding. When combined with the training dose of morphine, bremazocine antagonized morphine's discriminative stimulus effects, whereas U50,488 and tifluadom had no effect. The barbiturate pentobarbital neither substituted for, nor antagonized, the discriminative stimulus effects of either U50,488 or morphine. These results suggest that mu agonists and kappa agonists produce interacting effects in the drug discrimination procedure in rats.     

Effect of mu and kappa opioid receptor agonists on rat plasma corticosterone levels

The effect of several mu and kappa opioid receptor agonists on rat plasma corticosterone levels, measured using radioimmunoassay, was investigated. The mu agonists, morphine and fentanyl, and the kappa agonists, U-50,488, tifluadom and bremazocine, all produced dose-related increases in rat plasma corticosterone levels. The effects of both fentanyl and U-50,488 were reversed by naloxone, indicating an action at opioid receptors. Pretreatment of the rats with the irreversible, mu-selective antagonist, beta-funaltrexamine, reduced the effect of fentanyl, but not that of U-50,488, indicating that both mu and kappa opioid receptors are involved in mediating this effect.     

Mu, but not kappa, opioid agonists induce contractions of the canine small intestine ex vivo

The proposed kappa opioid receptor agonists ethylketocyclazocine (EK), nalorphine, bremazocine and U-50,488H were evaluated for their ability to produce contractions of isolated, vascularly perfused canine small intestinal segments. Responses to these agonists were compared to those of morphine and phenazocine, a mu benzomorphan. Morphine (0.04-25 micrograms) and phenazocine (0.01-3.0 micrograms) both produced naloxone-reversible contractions, suggesting that the responses were mediated largely by mu opioid receptors. In contrast, the proposed kappa agonists were ineffective in producing intestinal stimulation, with only EK (1-100 micrograms) showing minimal but significant activity at very high doses. We suggest that the effects of EK may be mediated through mu opioid receptors and that kappa receptors appear not to be involved in the contractile response of the dog small intestine to opioids.     

Spinal antinociceptive actions and naloxone reversibility of intravenous mu- and kappa-opioids in spinalized rats: potency mismatch with values reported for spinal administration

1. The relative spinal effectiveness of mu- and kappa-opioids has been assessed by their intravenous potencies on nociceptive responses (heat and/or pinch) of single motoneurones recorded in alpha-chloralose anaesthetized, spinalized rats. 2. The depressant actions of both mu- and kappa-opioids were reversed by low intravenous doses of naloxone (10 to 100 micrograms kg-1). When tested at a dose of 1 microgram kg-1 i.v., naloxone antagonized the effects of the mu-agonist morphine but had no effect on the kappa-opioid U-50,488. This provides further support for the theory that the actions of mu- and kappa-ligands were mediated at different subclasses of opioid receptor but highlights the difficulties in using antagonists with poor receptor selectivity to differentiate between mu- and kappa-receptor-mediated effects in vivo. 3. The molar potency rations of fentanyl: morphine:U-50,488: tifluadom for thermal and mechanical nociceptive responses were 620: 1.0:0.74:5.7 and 520:1.0:0.56:7.7 respectively. These potency ratios, as well as the absolute potencies, agree well with those reported in several behavioural studies in which systemic administration of agonists was used in non-thermal tests. 4. The agonist potency values obtained in this study contrast with those reported for local spinal administration. By this route, the potency of lipophilic opioids (e.g. fentanyl, U-50,488 and tifluadom) relative to hydrophilic opioids (e.g. morphine) is much reduced, implying that activity of intrathecally administered opioids is more dependent on the physico-chemical properties of the agonists used than on the relative abundance in the spinal cord of functional opioid receptors of the mu- and kappa-subtypes. This conclusion indicates that the results with locally applied opioids should not be used to assess spinal opioid receptor function.     

Spinal antinociceptive actions of mu- and kappa-opioids: the importance of stimulus intensity in determining ''selectivity'' between reflexes to different modalities of noxious stimulus.

1. In electrophysiological experiments in spinalized rats, mu- and kappa-opioids were tested intravenously on the responses of single motoneurones to electronically controlled, alternating noxious heat and noxious pinch stimuli. The effects of mu- and kappa-opioids were compared with those of the general anaesthetic alpha-chloralose and the dissociative anaesthetic/PCP ligand ketamine. 2. The kappa-opioids U-50,488 (0.5-16 mgkg-1 i.v.) and tifluadom (0.05-1.6 mgkg-1 i.v.) had very similar actions to the mu-opioid fentanyl (0.5-16 micrograms kg-1 i.v.). Thus all three agonists reduced thermal and mechanical nociceptive reflexes in parallel and in a dose-dependent manner, but only so long as neuronal responses to the alternating stimuli elicited similar excitability levels in the neurone under study. Ketamine (0.5-16 mgkg-1 i.v.) had similar actions to the opioids whereas alpha-chloralose (20 mgkg-1 i.v.) had very little effect on neuronal responsiveness. 3. Apparently 'selective' depressions by both mu- and kappa-opioids could be orchestrated by a deliberate mismatch of the intensities of alternating noxious heat and pinch stimuli; as measured by neuronal firing rate, the weaker of the responses to either type of stimulus was invariably reduced to a greater degree. 4. Similar 'selectivity' could be demonstrated for both mu- and kappa-ligands when the weaker and stronger responses were of the same modality, being applied by the same pincher device but with alternating applied force. 5. It is concluded that the 'selective' spinal actions of kappa-opioids seen in non-thermal over thermal behavioural models of nociception is likely to be related to the relative intensities, rather than the modalities, of the noxious stimuli used. The validity of the interpretation of results obtained in such behavioural studies is discussed.     

Subgroups among mu-opioid receptor agonists distinguished by ATP-sensitive K+ channel-acting drugs.

1. We evaluated the effects of the i.c.v. administration of different K+ channel blockers (gliquidone, 4-aminopyridine and tetraethylammonium) and an opener of K+ channels (cromakalim) on the antinociception induced by several mu-opioid receptor agonists in a tail flick test in mice. 2. The s.c. administration of all agonists of mu-opioid receptors tested (morphine, 1-16 mg kg-1; metadone, 1-6 mg kg-1; buprenorphine, 0.04-0.64 mg kg-1; fentanyl, 0.02-0.32 mg kg-1 and levorphanol, 0.2-3.2 mg kg-1) elicited a dose-dependent antinociceptive effect. 3. The ATP-sensitive K+ channel blocker, gliquidone (0.06-16 micrograms per mouse, i.c.v.) antagonized the antinociception induced by buprenorphine, morphine and metadone. In contrast, gliquidone (0.25-160 micrograms per mouse) did not modify the antinociceptive effects of fentanyl and levorphanol. 4. Cromakalim (4-64 micrograms per mouse, i.c.v.), an opener of ATP-sensitive K+ channels, enhanced the antinociception produced by buprenorphine, morphine, and methadone, and did not significantly modify the antinociceptive effects of fentanyl and levorphanol. 5. The i.c.v. administration of the K+ channel blockers tetraethylammonium (10 micrograms per mouse) or 4-aminopyridine (25 ng per mouse) did not significantly modify the antinociception induced by any mu-opioid receptor agonist tested. 6. These results suggest that the opening of ATP-sensitive K+ channels is involved in the antinociceptive effect of morphine, buprenorphine and methadone, but not in that of fentanyl or levorphanol. Consequently, we suggest that at least two subgroups can be distinguished among mu-opioid receptor agonists, each inducing antinociception through different effector mechanisms.     

Pharmacological characterization of an operant discrimination among two doses of morphine and saline in pigeons

A cumulative dose, multiple-trial test procedure was developed in eight pigeons trained to discriminate among saline, 1.8mg/kg morphine, and 10mg/kg morphine. Initially, single-trial tests were used to evaluate stimulus effects of acute doses of morphine. Next, the test procedure was altered so that cumulative doses were tested within a single session. Results from cumulative-dose tests of morphine were consistent with those from single-trial tests. The cumulative-dose test procedure was then used to characterize the high-dose and low-dose morphine training stimuli. The mu agonists etorphine, fentanyl, methadone and morphine dose-dependently evoked both low-dose and high-dose morphine-like effects, with a similar potency order (etorphine > fentanyl > methadone = morphine). In contrast, nalbuphine evoked only low-dose effects, consistent with low efficacy mu agonist activity. The kappa opiate U50,488H evoked saline-key responses, whereas the non-opiate ketamine evoked saline-key responses in the majority of pigeons, but high-dose and/or low-dose responding in others. Naltrexone dose-dependently antagonized both low-dose and high-dose stimulus effects of morphine, but not its rate-decreasing effects. Apparent pA(2) values for naltrexone were 7.2 for low-dose stimulus effects of morphine, and 7.4 for high-dose effects. These characteristics suggest that stimulus effects of both low and high training doses of morphine are mediated by common, presumably mu opioid, receptor populations.     

Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation

If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine,l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine,l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists. In addition, the lack of cross-tolerance between morphine and the kappa agonists examined demonstrate that this behavioral preparation is a useful tool for differentiating the effects of compounds acting at different opioid receptor types.     

Discriminative stimulus effects of the 5HT1A agonist 8-OH-DPAT: attenuation by mu but not by kappa opioids

The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT_1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The ratedecreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT_1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.     

Food hoarding and ingestion in the deer mouse, Peromyscus maniculatus: selective responses to mu and kappa opiate agonists

The feeding behavior of the deer mouse, Peromyscus maniculatus, includes food hoarding as well as ingestion. Administration of the prototypical mu opiate agonist, morphine sulfate, 1-20 mg/kg, produced over three hours a significant dose-dependent stimulation of hoarding by free feeding deer mice. The specific kappa opiate agonist, U-50,488H, 0.10-10 mg/kg, markedly increased ingestion without having any augmentatory effects on hoarding. The mixed mu and kappa opiate agonist, ketocyclazocine hydrochloride, 1-10 mg/kg, as well as various combinations of morphine sulfate and U-50,488H, augmented both hoarding and ingestion. Food restriction for 24 hr caused a significant, naloxone (1.0 mg/kg) reversible, increase in food intake. Food deprivation also modified the hoarding and ingestion responses of the deer mice to the mu and kappa opiate agonists, reducing the relative amounts of food that were hoarded. These results indicate that mu and kappa opioid systems are differentially involved in the mediation of various aspects of feeding. This also suggests that environmental factors, such as food restriction, can modify the relative roles of mu and kappa opioid systems in the expression of feeding behavior.     

Kappa antagonist properties of buprenorphine in the shock titration procedure

Buprenorphine produced a dose-dependent antagonism of the selective kappa opioid agonist U50,488 in squirrel monkeys responding under the shock titration procedure. In one group of four monkeys, 0.003-0.01 mg/kg buprenorphine produced dose-dependent rightward shifts in the individual U50,488 dose-effect curves and increased the A50 value for U50,488 more than 2-fold in each monkey. Furthermore, 0.01 mg/kg buprenorphine antagonized a maximally effective dose of U50,488 in these monkeys. Buprenorphine (0.01-0.1 mg/kg) also produced rightward shifts in the group U50,488 dose-effect curve for a second group of three monkeys. Buprenorphine's antagonism of U50,488 was probably not a consequence of any mu opioid antagonist properties of buprenorphine in this procedure since (1) buprenorphine produced an inconsistent antagonism of the selective mu agonist fentanyl, and (2) the selective mu antagonist beta-funaltrexamine did not antagonize U50,488. These results support the hypothesis that buprenorphine has kappa antagonist activity in the shock titration procedure.     

Sex and day-night differences in opiate-induced responses of insular wild deer mice, Peromyscus maniculatus triangularis

We examined the effects of mu and kappa opiate agonists on the day- and night-time nociceptive, locomotory and ingestive behaviors of an island population of wild male and female deer mice, Peromyscus maniculatus triangularis. The prototypical mu opiate agonist, morphine, had significant analgesic and locomotory effects, which were blocked by naloxone, and the specific delta opiate antagonist, ICI 154,129, respectively. The specific kappa opiate agonist, U-50,488, had significant analgesic actions and inhibitory effects on locomotor activity, as well as stimulating feeding. Significant day-night variations occurred in the analgesic and activity responses, with the mu and kappa opiate agonists having significantly greater effects at night. There were also prominent sex differences in responses; male deer mice displaying significantly greater levels of mu and kappa opiate-induced analgesia and alterations in activity than female animals. These sex differences in opiate-induced effects were most pronounced at night, female deer mice displaying reduced day-night rhythms of responsiveness. These results demonstrate the existence of significant day-night rhythms and sex differences in the mu and kappa opiate behavioral responses of a wild population of rodents.     

The discriminative stimulus properties of U50,488 and morphine are not shared by fedotozine

Fedotozine is a kappa opioid receptor agonist having antinociceptive properties but devoid of diuretic effects. The aim of the study was to evaluate the discriminative stimulus effects of fedotozine at doses previously reported to produce maximal effects in in vivo assays measuring kappa-mediated analgesia. By using a two-lever drug discrimination task, two groups of rats were trained to discriminate either a 3 mg/kg i.p. dose of the kappa opioid agonist, U50,488, or a 5 mg/kg i.p. dose of the mu opioid agonist, morphine, from saline. Once trained, rats were used to conduct tests of stimulus generalization with morphine, U50,488 and fedotozine along with another kappa agonist, CI-977, and another mu agonist, fentanyl. The stimulus effect of U50,488 was shared by CI-977 but not by morphine. Conversely, the stimulus effect of morphine was shared by fentanyl but not by U50,488. Fedotozine (1–10 mg/kg) failed to substitute to either U50,488 or morphine. These results indicate that, when administered at doses fully effective in producing antinociception, the interoceptive stimulus effects of fedotozine, if any, can be distinguished from those produced by U50,488 and morphine.     

Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation

The effects of various mu and kappa opioid agonists were evaluated in three squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation before, during and after a regimen of chronic morphine administration. Initially, dose-effect curves for the mu opioid agonists morphine and l-methadone, the kappa opioid agonists U50,488 and tifluadom, the mixed mu/kappa opioid agonist ethylketocyclazocine, and the non-opioid compound pentobarbital were determined in non-tolerant squirrel monkeys. Subsequently, monkeys were administered up to 3.0 mg/kg of morphine twice daily for 8-9 weeks, which resulted in a 1/2 to 3/4 log unit shift to the right of the morphine dose-effect curve relative to its prechronic position. During the chronic morphine regimen, the l-methadone dose-effect curve shifted to the right approximately 3/4 log unit, while the U50,488 and pentobarbital dose-effect curves did not change. In contrast, the ethylketocyclazocine and tifluadom dose-effect curves shifted to the left approximately 1/4 and 3/4 log unit, respectively. The lack of cross-tolerance between mu and kappa agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of mu and kappa agonists. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with kappa agonist activity during the regimen of chronic morphine administration suggests that morphine tolerance modulates their     

Kappa opioid receptor-mediated depression of activity evoked in convergent dorsal horn cells by thermal and non-thermal noxious stimulation

The response of convergent dorsal horn cells to tonic and phasic noxious heating and to noxious pinching was studied before and after topical application of a solution (30 nmol) of the kappa agonist U-50,488H to the dorsal surface of the spinal cord. U-50,488H depressed the discharge of convergent units evoked by thermal and mechanical nociceptive stimuli. The opiate antagonist WIN 44,441-3 reversed the effect of U-50,488H. It is concluded that kappa opioids are effective in preventing the depolarization of convergent dorsal horn neurons evoked by either thermal or non-thermal noxious stimuli.     

Effects of the delta opioid agonist BW373U86 in pigeons trained to discriminate fentanyl,bremazocine and water in a three-choice drug discrimination procedure

The delta opioid agonist BW373U86 was examined alone and in combination with mu agonists in pigeons trained to discriminate the mu agonist fentanyl (0.056 mg/kg), the kappa agonist bremazocine (0.017 mg/kg), and distilled water in a three-choice drug discrimination procedure. BW373U86 (0.01–10 mg/kg) produced a dose-dependent increase in fentanyl-appropriate responding and complete generalization to fentanyl in four of five subjects. BW373U86 did not elicit bremazocine-appropriate responding in any of the subjects. Fentanyl-appropriate responding elicited by BW373U86 was antagonized by the delta selective antagonist naltrindole (0.1–10 mg/kg) but not by the mu selective antagonist naloxone (0.1–30.0 mg/kg). When BW373U86 was administered in combination with the mu agonists fentanyl, morphine and nalbuphine, a low dose of BW373U86 (0.01 mg/kg) that elicited primarily water-appropriate responding when administered alone did not produce a significant change in the ED₅₀ values for fentanyl, morphine or nalbuphine. Higher doses of BW373U86 (0.1–1.0 mg/kg) increased levels of fentanyl-appropriate responding elicited by low doses of fentanyl, morphine and nalbuphine to levels similar to those produced by BW373U86 alone. These results indicate that BW373U86 shares discriminative stimulus properties with the mu agonist fentanyl in pigeons, possibly by acting at delta opioid receptors. However, BW373U86 does not potentiate the discriminative stimulus effects of mu agonists or share discriminative stimulus effects with the kappa agonist bremazocine.     

Developmental responses to opioids reveals a lack of effect on stress-induced corticosterone levels in neonatal rats.

The neonate has an unusual capacity for survival and the possibility exists that mechanisms for controlling stress responses may differ in the developing animal. In adults both endogenous and exogenous opioids can modulate the corticosterone responses to stress. We have studied this effect in neonatal rats and found that opioid modulation is absent in early postnatal development. Neonatal rats of either sex were injected with morphine (5-50 mg kg-1), fentanyl (10-100 micrograms kg-1), buprenorphine (0.1-30 mg kg-1) or naloxone (0.1-10 mg kg-1) and plasma corticosterone measured fluorimetrically 15 or 20 min later. In addition naloxone reversibility studies (1 mg kg-1, co-administered) were carried out for the opioid agonists. In adult rats, elevations in plasma corticosterone caused by injection stress were potentiated by morphine, fentanyl and buprenorphine. In neonates, though injection stress-induced rises in plasma corticosterone were absent at 10 days, elevations were observed at 21 days and later. However, significant potentiation of this corticosterone response by fentanyl was absent at 21 days and at later ages (30 and 40 days) for morphine and buprenorphine. The potentiating effect of all three agonists did not become fully effective until day 45. In addition, in animals acclimatized to injection stress by 7 day injection pretreatment, fentanyl did not significantly alter corticosterone levels in 30 day old neonates. High doses of naloxone (10 mg kg-1) significantly increased the corticosterone response to injection stress in adult rats but this effect was absent in 30 day old animals.(ABSTRACT TRUNCATED AT 250 WORDS)