Attenuation of the antinociceptive action of the selective kappa-opioid receptor agonist, U-50,488H by ICS-205-930

The antinociceptive action of s.c. administered U-50,488H was antagonized by s.c. administered ICS-205-930, a selective 5-HT3 receptor antagonist. To characterize the site of interaction, U-50,488H and ICS-205-930 were administered either intracerebroventricularly (i.c.v.) or intrathecally (i.t.). When U-50,488H was administered i.c.v., its antinociception action was antagonized by ICS-205-930 given either i.c.v. or i.t., increasing the ED50 values of U-50,488H by approximately twofold from 48 to 98 and 90 nmol/mouse, respectively. However, when U-50,488H was administered i.t., its antinociception action was not antagonized by ICS-205-930 given either i.c.v. or i.t. These findings suggest that i.c.v., but not i.t. administered U-50,488H may release serotonin both supraspinally and spinally to interact with 5-HT3 receptors to produce antinociception.     

Disability of development of tolerance to morphine and U-50,488H, a selective kappa-opioid receptor agonist, in neuropathic pain model mice

We examined the analgesic and anti-allodynic effects of morphine and U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide methanesulfonate salt), a selective kappa-opioid receptor agonist, and the development of tolerance to their effects in neuropathic pain model mice induced by sciatic nerve ligation (SNL). In the tail-pinch method, morphine at 10 mg/kg, s.c. produced a weak analgesic effect in SNL mice; however, U-50,488H at 5 mg/kg, s.c. produced an analgesic effect equipotent to that in normal mice. In contrast, morphine produced an adequate analgesic effect when given either intracerebroventricularly (i.c.v.) or intrathecally (i.t.), but U-50,488H only produced analgesia when given i.t. Repeated administration of morphine (either i.c.v. or i.t.) or U-50,488H (either s.c. or i.t.), did not induce tolerance to the effect. In the static allodynia test with an application of von Frey filaments, both compounds given s.c. suppressed the allodynic effect, but in the dynamic allodynia test involving lightly stroking the plantar surface with a cotton bud, only U-50,488H produced an anti-allodynic effect. Repeated administrations of both compounds did not develop tolerance to these anti-allodynic effects. Thus, U-50,488H was found to be a highly effective at blocking hyperalgesia and allodynia in nerve injury, and these findings suggest that kappa-opioid receptor agonists are attractive pharmacological targets for the control of patients with neuropathic pain.     

Role of spinal κ opioid receptors in the blockade of the development of antinociceptive tolerance to morphine

The site of action of the k opioid receptor agonist, U-50,488H in suppressing the development of tolerance to morphine antinociception was examined by local application, either intrathecal (i.t., spinal) or intracerebroventricular (i.c.v., supraspinal) in mice. Mice given morphine s.c., i.c.v. or i.t. daily developed toleunce regardless of the route. Co-administration of U-50.488H i.p. at a subanalgcsic dose suppressed the development of tolerance to s.c and i.t. administered morphine without affecting the antinociceptive effect of morphine. U-50.488K did not influence the development of tolerance to i.c.v. administered morphine. The antinociceptive effect of s.c. administered morphine was not affected by co-administration of U-50,488H given i.t. or i.c.v.: however, the development of tolerance to morphine was suppressed by i.t. but not i.c.v. administered U-50.488H. The suppressive effect of U-50.488H on the development of tolerance to morphine was abolished by pretreatment with nor-binaltorphiminc (nor-BNI) given i.p. or i.t. Intraccrebroventricularly administered nor-BNI failed to abolish the effect of U-50.488H. We suggest that U-50.488H suppresses the development of tolerance to morphine at the spinal level by interacting with κ opioid receptors in this area.     

5-HT3 receptor antagonists inhibit the response of kappa opioid receptors in the morphine-induced Straub tail [corrected

We used the morphine-induced Straub tail to examine the actions of a 5-HT₃ receptor antagonist and κ opioid receptor agonist. The κ opioid receptor agonist, U-50,488H (4–16 mg/kg i.p.), produced a dose-related inhibition of the tail elevation induced by morphine (10 mg/kg s.c.) in ICR male mice. ICS-205-930 (3 and 10 mg/kg i.p.) and zacopride (0.3 and 1 mg/kg i.p.), 5-HT₃ receptor antagonists, attenuated the inhibitory effect of U-50,488H in a dose-dependent manner. ICS-205-930 and zacopride did not inhibit the morphine-induced Straub tail. These observations suggest that the actions of κ opioid receptors may be modulated by 5-HT³ receptors in the morphine-induced Straub tail.     

Abstinence from U-50,488H, a kappa-opiate receptor agonist, decreases the binding of [3H]DPAT to 5-HT1A receptors in the hypothalamus of the rat.

The effect of trans-( ± )-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzene-acetamide methane sulfonate (U-50,488H), a κ-opiate agonist-induced tolerance and abstinence on 5-HT_1A receptors was determined in regions of the brain and spinal cord of the rat. The administration of U-50,488H (25 mg/kg, i.p., twice daily) to male Sprague-Dawley rats for 4 days resulted in the development of almost complete tolerance to its analgesic and hypothermic effects. On day 5, the animals were divided into tolerant and abstinent groups and sacrificed. The brain and spinal cord were excised from all groups of rats and the brain was dissected into 6 regions, namely, amygdala, hypothalamus, striatum, midbrain, pons + medulla and cortex. The 5-HT_1A receptors were characterized by using [³H]8-hydroxy-2-(di-n-propylamino)tetralin ([³H]DPAT) as the ligand. The binding constants (B_max and K_dvalues) of [³H]DPAT in regions of the brain and spinal cord of rats tolerant to U-50,488H and vehicle did not differ. However, the B_max value of [³H]DPAT in the hypothalamus of U-50,488H-abstinent rats was decreased but the K_d value did not change. In the other regions of the brain and spinal cord of U-50,488H-abstinent rats, the B_max and K_d values of [³H]DPAT were unaffected. Subcutaneous administration of DPAT produced hypothermic response in vehicle- and U-50,488H-treated rats. The intensity of this effect was more marked in U-50,488H-abstinent group. It is concluded that 5-HT_1A receptors are down-regulated in the hypothalamus of U-50,488H-abstinent rats but the hypothermic response to 5-HT_1A agonist is intensified.     

Effect of repeated administration of U-50,488H, a kappa opioid receptor agonist, on central 5-HT1 and 5-HT2 receptors in the rat

The effect of repeated administration of U-50,488H, a kappa-opioid receptor agonist, on the development of tolerance to its analgesic effect and on the 5-HT1 and 5-HT2 receptors in the cerebral cortex and spinal cord of the rat were determined. Male Sprague-Dawley rats were injected twice daily with U-50,488H, (25 mg/kg, i.p.) or its vehicle for 4 days. The assessment of tolerance to the analgesic effect and biochemical determinations were made on day 5. Repeated administration of U-50,488H resulted in the development of tolerance to its analgesic effect. The 5-HT1 and 5-HT2 receptors were characterized by using 3H-5-hydroxytryptamine (3H-5-HT) and 3H-spiperone as the ligands and unlabeled 5-hydroxytryptamine (5-HT) and ketanserin, respectively, to determine the nonspecific binding. In the spinal cord 3H-5-HT bound to 5-HT1 receptors at a single high-affinity site with a Bmax value of 41.3 +/- 9.6 fmol/mg protein and a Kd value of 22.6 +/- 7.0 nmol/l. 3H-Spiperone bound to 5-HT2 receptors in the spinal cord with a Bmax value of 16.1 +/- 3.8 fmol/mg protein and a Kd value of 0.36 +/- 0.15 nmol/l. Repeated administration of U-50,488H to rats did not affect spinal cord 5-HT1 and 5-HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blockade of morphine reward through the activation of κ-opioid receptors in mice

The effects of systemic (s.c.) treatment with the κ-agonists U-50,488H and E-2078 (a stable dynorphin analog) on the morphine-induced place preference were examined in mice. Morphine (s.c.) caused a dose-related preference for the drug-associated place; the effects at doses of 3 and 5 mg/kg were significant. On the other hand, U-50,488H or E-2078 produced a dose-related conditioned place aversion. Both U-50,488H (1 mg/kg, s.c.) and E-2078 (0.1 mg/kg, s.c.) induced a slight, nonsignificant place aversion. Pretreatment with U-50,488H (1 mg/kg) abolished the morphine (3 mg/kg)-induced place preference. The morphine-induced place preference was also significantly decreased by pretreatment with E-2078 (0.1 mg/kg). The inhibitory effects of the κ-agonists were antagonized by the κ-antagonist nor-binaltorphimine (nor-BNI; 3 mg/kg, s.c.). In contrast, pretreatment with U-50,488H did not affect the place preference induced by the dopamine (DA) receptor agonist apomorphine (1 mg/kg, s.c.). In addition, morphine (3 mg/kg, s.c.) significantly increased the levels of the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the limbic forebrain (nucleus accumbens and olfactory tubercle) but not in the striatum, implying that activation of the mesolimbic DA system may play an important role in the morphine-induced place preference in mice. Pretreatment with U-50,488H significantly reduced the morphine-induced elevation of DA metabolites in the limbic forebrain. These results suggest that κ-agonists suppress the morphine-induced place preference, and that activation of κ-opioid receptors could suppress the reinforcing effects of morphine which may be induced by enhanced DA transmission in the mesolimbic DA system.     

Interaction between the cardiovascular effects of clonidine and the kappa-opioid agonist U-50,488H in the anterior hypothalamic area of the rat brain

In thiobutabarbitone-anaesthetized rats, microinjection of clonidine (1-40 nmol) into the anterior hypothalamic area (AHy) produced dose-dependent reductions in mean arterial blood pressure and heart rate. Microinjection of the kappa-opioid agonist U-50,488H (3 and 10 nmol) did not modify these parameters. Simultaneous co-administration of clonidine (4 nmol) and U-50,488H (10 nmol) into the AHy resulted in significant potentiation of the clonidine-induced hypotension and marked attenuation of the bradycardia. A lower dose of U-50,488H (3 nmol) co-administered with clonidine (4 nmol) did not influence the cardiovascular responses to clonidine. These findings suggest that AHy neurons involved in the cardiovascular responses to clonidine may be modulated by kappa-opioid receptor stimulation.     

Schild (apparent pA2) analysis of a kappa-opioid antagonist in Planaria

Previous investigators have provided radioimmunological and immunocytochemical evidence for an enkephalinergic (opioid) system in Planaria and described naloxone-sensitive qualitative behavioral responses to κ-opioid receptor agonists. We report the application of Schild-analysis to the antagonism of a selective κ agonist (U-50,488H) by a selective κ antagonist (nor-BNI) in a quantitative in vivo endpoint. The results provide further evidence of a κ-opioid-like receptor in planarians.     

Effects of morphine in rats treated chronically with U-50,488 H, a kappa opioid receptor agonist

The pharmacological effects of morphine, namely analgesic, hyperthermic and cataleptic effects, were assessed in rats rendered tolerant to U-50,488H, a kappa opioid receptor agonist. Male Sprague-Dawley rats were injected intraperitoneally with U-50,488H (25 mg/kg) twice a day for four days. The rats which served as controls were injected similarly with the vehicle. Chronic administration of U-50,488H resulted in the development of tolerance to its analgesic and hypothermic effects, but not to its diuretic effect. The development of tolerance to the pharmacological effects of U-50,488H was associated with decreased binding of [3H]ethylketocyclazocine [( 3H]EKC) to brain and spinal cord membranes. The decreased binding of [3H]EKC in U-50,488H-treated rats was due to changes in the Bmax value; the Kd values remained unaltered. Intraperitoneal administration of morphine (8 mg/kg) to rats produced analgesia (as determined by the tail-flick test) and hyperthermia. A dose of 50 mg/kg of morphine produced cataleptic response. The intensity of analgesic, hyperthermic and cataleptic effects of morphine were unaltered in rats tolerant to U-50,488H. The development of tolerance to analgesic and hypothermic effects of U-50,488H were associated with down-regulation of brain and spinal cord kappa opioid receptors. Finally, U-50,488H does not confer cross-tolerance to morphine, a predominantly mu opioid receptor agonist.     

A selective kappa-opioid agonist, U-50,488H, blocks the development of tolerance to morphine analgesia in rats

The development of tolerance to morphine analgesia was completely blocked by the coadministration of a selective kappa-opioid agonist, U-50,488H at doses of 3.2 or 10 mg/kg i.p. These doses of U-50,488H exerted no analgesic effect by themselves and did not affect the analgesia induced by 10 mg/kg of morphine. The analgesic effect of morphine was restored when 10 mg/kg of U-50,488H was coinjected in morphine-tolerant rats. These findings suggest that activation of the kappa-opioid system prevents the development of tolerance to morphine analgesia.     

Differential effects of two kappa-opiate agonists, U-50,488H and U-69,593, on the binding of 3H-(3-MeHis2) thyrotropin-releasing hormone to rat spinal cord and amygdala membranes.

The effect of delta- and kappa-opiate receptor agonists on the binding of 3H-(3-MeHis2) thyrotropin-releasing hormone (3H-MeTRH) to membranes of the spinal cord and amygdala of male Sprague-Dawley rats was determined in an effort to further understand interactions between opiates and TRH receptors. The agonists used were D-Ala2-MePhe4-Gly-ol5-enkephalin (DAMGO, mu-receptor), cyclic D-penicillamine2-D-penicillamine5-enkephalin (DPDPE, delta-receptor), cyclic D-penicillamine2-L-penicillamine5-enkephalin (DPLPE, delta-receptor), D-Ala2-D-Leu5-enkephalin (delta-receptor), U-50,488H and U-69,593 (kappa-receptor). 3H-MeTRH bound to amygdala and spinal cord membranes at a single site with Bmax values of 35.7 +/- 5.4 and 15.8 +/- 2.6 fmol/mg protein, and Kd values of 6.3 +/- 1.1 and 5.2 +/- 0.7 nmol/l, respectively. The competition experiments were carried out at a concentration of 2 nmol/l 3H-MeTRH. The concentration of opiate ranged from 10(-9) to 10(-4) mol/l. DAMGO, DPDPE and DPLPE had no effect on the binding of 3H-MeTRH to amygdala or spinal cord membranes. The two highly selective kappa-agonists differed in their interaction with TRH receptors. Whereas U-69,593 did not modify the binding of 3H-MeTRH, U-50,488H significantly inhibited the binding of 3H-MeTRH to both spinal cord and amygdala membranes. U-50,488H has been found to be 10 times more potent than U-69,593 at the central kappa-opiate receptors and may explain their differential action at the TRH receptors. It is concluded that mu- and delta-opiate agonists do not interact with brain and spinal cord TRH receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Beta-lactam antibiotic prevents tolerance to the hypothermic effect of a kappa opioid receptor agonist

Beta-lactam antibiotics are the only clinically approved drugs which directly increase glutamate uptake. They activate the glutamate transporter subtype 1 (GLT-1), the protein responsible for 90% of glutamate uptake in the mammalian brain. The capacity of GLT-1 to clear extracellular glutamate suggests that glutamate transporter activators be explored for therapeutic approaches to clinical conditions caused by increased glutamatergic transmission. One of the most common drug effects mediated by increased glutamatergic signaling is opioid tolerance. Therefore, we tested the hypothesis that a beta-lactam antibiotic (ceftriaxone), by increasing glutamate uptake, prevents tolerance to hypothermia induced by a kappa opioid receptor agonist (U-50,488H). A single injection of U-50,488H (20mg/kg, s.c.) caused significant hypothermia in rats. Tolerance to the hypothermic effect of U50,488H was induced by injecting U50,488H (20mg/kg) twice daily for 7days. Pretreatment with ceftriaxone (200mg/kg, i.p.) for 7days did not alter the acute hypothermic response to U50,488H (20mg/kg) but did prevent tolerance to U50,488H-induced hypothermia. Central administration of dl-threo-beta-benzyloxyaspartic acid (TBOA) (0.2mumol, i.c.v.), a glutamate transporter inhibitor, abolished the effect of ceftriaxone. These results identify a functional interaction between ceftriaxone and U50,488H in vivo and provide pharmacological evidence that a beta-lactam antibiotic abolishes tolerance to hypothermia induced by a kappa opioid receptor agonist.     

Contralateral but not systemic administration of the kappa-opioid agonist U-50,488H induces anti-nociception in acute hindpaw inflammation in rats

1. The anti-nociceptive effects of contralateral administration of kappa-opioid agonist U-50,488H were investigated in rats. 2. Inflammation was induced by unilateral injection of 1% carrageenan into the right hindpaw. Prior to carrageenan injection, U-50,488H or saline was administered into the left hindpaw. Withdrawal responses to mechanical and heat stimulation and oedema levels were evaluated at 3, 6 and 24 h post-carrageenan injection. 3. The results showed that the inflammatory effect of 1% carrageenan peaked after 6 h with bilateral decreases in withdrawal latencies and ipsilateral oedema formation. 4. Contralateral treatment with 0.01, 0.05, 0.3 and 2 mg of U-50,488H attenuated nociceptive reflexes to mechanical stimulation on the inflamed side at 6 h. The anti-nociceptive effect of contralateral treatment was dose-dependent at 3 and 24 h. The hindpaw withdrawal latencies to heat stimulation were prolonged at 3 and 24 h after contralateral treatment with 0.3 mg U-50,488H. No effect on inflammatory oedema formation was observed, except for a decrease at 3 h after treatment with 2 mg of U-50,488H. 5. Sciatic nerve denervation on the contralateral side abolished the anti-nociceptive effects of U-50,488H (0.3 and 2 mg). In contrast, contralateral injection of 1 mg morphine prolonged paw latencies in denervated rats. 6. Both co-administration of the peripherally selective opioid antagonist naloxone methiodide with 0.3 mg U-50,488H, and alternatively, systemic administration of 0.3 mg U-50,488H reversed the anti-nociceptive effects induced by contralateral injection of U-50,488H. 7. Taken together, our findings indicate that the contralateral administration of U-50,488H attenuates nociceptive behaviour resulting from acute inflammation. The effect is mediated via peripheral neuronal kappa-opioid receptors and, possibly, spinal cord mechanisms, suggesting a new treatment approach for acute inflammatory conditions.     

Effect of the kappa-receptor agonist, U-50,488H, on cerebral ischemia-induced impairment of working memory assessed in rats by a three-panel runway task.

The effect of U-50,488H, a selective kappa-receptor agonist, on memory functions in an animal model of cerebral ischemia was investigated by use of a three-panel runway task. A 5-min period of ischemia caused a significant increase in the number of errors (pushes made on the two incorrect panels of the three panel-gates at four choice points) in a working memory task but it did not impair a reference memory task. U-50,488H at 10 and 32 mg/kg, administered i.p. immediately after blood flow restoration significantly reduced the increase in errors expected to occur in a working memory task assessed 24 h after 5 min of ischemia. This protective effect of U-50,488H on amnesia in the ischemic rat was antagonized by the kappa-receptor antagonist, MR-2266. We conclude that U-50,488H prevents the impairment of working memory following transient forebrain ischemia, an event mediated by the activation of the kappa-opioid receptor.     

Binding characteristics of [3H]SCH 23390 in spinal cord and discrete brain regions of kappa-opiate tolerant-dependent and abstinent rats.

The effects of chronic administration of U-50,488H, a highly selective kappa-opiate receptor agonist, and its subsequent withdrawal were determined. The binding characteristics of [3H]SCH 23390 to dopamine D1 receptors were investigated on membranes of rat spinal cord and in discrete brain regions. Male Sprague-Dawley rats received U-50,488H (25 mg/kg) intraperitoneally twice a day for 4 days. Animals serving as controls received only vehicle. Two different treatment schedules were used. In one, rats were injected with U-40,588H on day 5 and were sacrificed 1 h later (tolerant-dependent rats). In another, the rats were sacrificed 16 h after the last injection of U-50,488H (abstinent rats). Chronic administration of U-50,488H resulted in the development of tolerance to its analgesic effect, as demonstrated by the decreased response to a challenge dose of U-50,488H compared to vehicle-injected rats. The binding characteristics (Bmax and Kd values) of [3H]SCH 23390 were unaffected in spinal cord and other regions of brain of tolerant-dependent rats. In U-50,488H-abstinent rats, Bmax values of [3H]SCH 23390 were increased in hypothalamic and striatal membranes, but Kd values were unaffected. These results suggest that, in U-50,488H-abstinent rats, dopamine D1 receptors are up-regulated in hypothalamus and striatum.     

U-50, 488, saline and naltrexone discrimination in U-50, 488-treated pigeons

Pigeons treated with 10.0mg/kg/day of U-50,488 discriminated among intramuscular (i.m.) injections of U-50,488 (10mg/kg), saline, and naltrexone (0.178mg/kg), while responding under a fixed-ratio 20 schedule of food presentation. Training compounds occasioned responding on the appropriate keys with pigeons responding >/=90% on the naltrexone key at doses larger than 0.032mg/kg of naltrexone, >/=90% on the U-50,488 key at doses larger than 3.2mg/kg of U-50,488, and >/=90% on the saline key after saline. Several opioid agonists and antagonists were studied for their discriminative stimulus effects. None of the compounds substituted completely (>/=90%) for either training compound in all pigeons (n = 5); however, bremazocine substituted completely for U-50,488 in three out of five pigeons. Compounds with opioid antagonist actions under other conditions substituted for naltrexone in some subjects: levallorphan, two out of five; nalbuphine, one out of five; nalorphine, two out of five; and quadazocine, three out of four. Morphine did not substitute for naltrexone or U-50,488 in any of the subjects. When U-50,488 treatment was terminated and subjects were studied daily after injections of saline, responding occurred predominantly on the saline key; the absence of naltrexone key responding after termination of U-50,488 treatment suggests that this dosing regimen was not adequate for the development of dependence, or that the discriminative stimulus effects of abstinence-induced withdrawal were qualitatively different from the discriminative stimulus effects of naltrexone under these conditions.     

Down-regulation of central receptors for thyrotropin-releasing hormone in kappa opiate agonist-induced abstinence in the rat.

The effect of U-50,488H, a selective kappa opiate agonist, on tolerance-dependence and abstinence on the TRH receptors of the spinal cord and discrete regions of the brain of male Sprague-Dawley rats was determined. Rats were injected intraperitoneally twice daily with 25 mg/kg of U-50,488H for 4 days. Rats serving as controls were injected with the vehicle. On day 5, rats which were labeled as tolerant to U-50,488H were injected with U-50,488H (25 mg/kg) and sacrificed 1 hr later, whereas those labeled as abstinent were sacrificed without any injection. The above procedure has been previously shown to produce a high degree of tolerance to the analgesic and hypothermic effects of U-50,488H. The spinal cord and regions of the brain (hippocampus, cortex, midbrain, hypothalamus, corpus striatum, pons and medulla, and amygdala) were isolated for binding studies. The ligand [3H]MeTRH was used for TRH receptors. The binding constants, Bmax and Kd values, of [3H]MeTRH to bind to membranes prepared from various regions of the brain and spinal cord of rats tolerant-dependent on U-50,488H were unaffected. However, in rats abstinent to U-50,488H, the binding of [3H]MeTRH to membranes of the hypothalamus, and pons and medulla, was decreased. The decreased binding of [3H]MeTRH to hypothalamic membranes was due to changes in Bmax value, while in pons and medulla it was due to an increase in the Kd value.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kappa opioid agonists produce anxiolytic-like behavior on the elevated plus-maze

The selectivek agonist U-50,488H was evaluated on the elevated plus-maze test of anxiety. U-50,488H was administered intraperitoneally to male Sprague-Dawley rats 20 min before testing, first in an open field apparatus, then followed immediately on the elevated plus-maze. No significant change in spontaneous locomotor activity was measured in the open field apparatus, suggesting that U-50,488H was devoid of sedative effects in the dose range tested (0.1–1000 µg/kg, IP). Doses between 10 and 1000 µg/kg produced significant increases in elevated plus-maze behavior that were consistent with anxiolytic actions for U-50,488H. These anxiolytic-like effects were antagonized by naloxone (2.0 mg/kg, IP), suggesting an opioid receptor site of action. In addition, we tested thek ₁-selective U-50,488H-derivative, U-69,593 (100 µg/kg, IP), which was also shown to mimic the anxiolytic-like effects produced by U-50,488H. These results suggest that low doses of the selectivek ₁ agonists U-50,488H and U-69,593 are endowed with anxiolytic properties in rodents and that thek opioid system may be involved in the behavioral response to anxiety.