Agonists at ␦, , and opioid receptors produce interacting effects in rodents and nonhuman primates. To further evaluate the determinants of these interactions, this study examined the effects of mixtures of ␦ ϩ and ␦ ϩ agonists in rhesus monkeys (n ϭ 4 -5) using two behavioral procedures, an assay of schedulecontrolled responding for food reinforcement and an assay of thermal nociception. Results were analyzed using dose-addition analysis. In the assay of schedule-controlled responding, the; the agonists methadone, fentanyl, morphine, and nalbuphine; and the agonists (5␣,7␣,8␤)-(Ϫ)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) and bremazocine all dose dependently decreased rates of food-maintained responding when administered alone. Fixed ratio mixtures of SNC80 ϩ agonists produced additive or subadditive effects, whereas SNC80 ϩ agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas and agonists produced dose-dependent antinociception. SNC80 ϩ agonist mixtures produced superadditive effects manifested as leftward shifts in agonist dose-effect curves. This synergism was antagonized by the ␦-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of agonist antinociception was ␦ receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective agonist bremazocine. These results suggest that ␦ agonists may selectively enhance the antinociceptive effects of agonists in rhesus monkeys. These results also confirm that opioid agonist interactions may depend on the receptor selectivity and relative doses of the agonists and on the experimental endpoint.Biochemical and behavioral evidence indicates the existence of three opioid receptor types, the ␦, , and receptors (Martin et al., 1976;Lord et al., 1977;Evans et al., 1992;Thompson et al., 1993;Yasuda et al., 1993). Agonists selective for ␦, , and receptors produce distinct profiles of physiological and behavioral effects (Gutstein, 2001). In addition, selective ␦, , and agonists may also produce interacting effects. Studies of opioid receptor interactions have been conducted primarily with ␦ and agonists in rodents using assays of antinociception, and results from these studies suggest that the nature of the interaction depends on such variables as the particular agonists used, the relative doses tested, and the behavioral endpoint (Heyman et al., 1989;Jiang et al., 1990;Adams et al., 1993). For example, the peptidic ␦ agonists [D-Pen 2 ,D-Pen 5 ]-enkephalin (DPDPE) and deltorphin II enhanced the effects of some intermediate-efficacy agonists (morphine, normorphine, and codeine), but not of higher efficacy -agonists (PL017, fentanyl, or sufentanil), in an assay of thermal nociception in mice (Heyman et al., 1989;Jiang et al., 1990). In a subsequent study, DPDPE enhanced ...

No abstract

Mu opioid receptor agonists are clinically valuable as analgesics; however, their use is limited by high abuse liability. Kappa opioid agonists also produce antinociception, but they do not produce mu agonist-like abuse-related effects, suggesting that they may enhance the antinociceptive effects and/or attenuate the abuse-related effects of mu agonists. To evaluate this hypothesis, the present study examined interactions between the mu agonist fentanyl and the kappa agonist U69,593 in three behavioral assays in rhesus monkeys. In an assay of schedule-controlled responding, monkeys responded under a fixed-ratio 30 (FR 30) schedule of food presentation. Fentanyl and U69,593 each produced rate-decreasing effects when administered alone, and mixtures of 0.22:1, 0.65:1 and 1.96:1 U69,593/fentanyl usually produced subadditive effects. In an assay of thermal nociception, tail withdrawal latencies were measured from water heated to 50°C. Fentanyl and U69,593 each produced dose-dependent antinociception, and effects were additive for all mixtures. In an assay of drug selfadministration, rhesus monkeys responded for i.v. drug injection, and both dose and FR values were manipulated. Fentanyl maintained self-administration, whereas U69,593 did not. Addition of U69,593 to fentanyl produced a proportion-dependent decrease in both rates of fentanyl selfadministration and behavioral economic measures of the reinforcing efficacy of fentanyl. Taken together, these results suggest that simultaneous activation of mu and kappa receptors, either with a mixture of selective drugs or with a single drug that targets both receptors, may reduce abuse liability without reducing analgesic effects relative to selective mu agonists administered alone.

Interactions between ␦ and opioid agonists in rhesus monkeys vary as a function of the behavioral endpoint. The present study compared interactions between the ␦ agonist SNC80 [(ϩ)-4-[(␣R)-␣-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the agonist heroin in assays of schedule-controlled responding, thermal nociception, and drug self-administration. Both SNC80 (ED 50 ϭ 0.43 mg/kg) and heroin (ED 50 ϭ 0.088 mg/kg) produced a dose-dependent and complete suppression of response rates in the assay of schedule-controlled responding. Heroin also produced thermal antinociception (ED 5°C ϭ 0.18 mg/kg) and maintained drug self-administration under both a fixed ratio schedule [dose-effect curve peak at 0.0032 mg/kg/injection (inj)] and under a food versus heroin concurrent-choice schedule (ED 50 ϭ 0.013 mg/kg/inj), whereas SNC80 did not produce thermal antinociception or maintain self-administration. Fixed ratio mixtures of SNC80 and heroin (1.6:1, 4.7:1, and 14:1 SNC80/heroin) produced additive effects in the assay of schedule-controlled responding and superadditive effects in the assay of thermal nociception. Also, SNC80 did not enhance the reinforcing effects of heroin, indicating that mixtures of SNC80 and heroin produced additive or infra-additive reinforcing effects. These results provide additional evidence to suggest that ␦/ interactions depend on the experimental endpoint and further suggest that ␦ agonists may selectively enhance the antinociceptive effects of agonists while either not affecting or decreasing the sedative and reinforcing effects of agonists.Biochemical and behavioral evidence indicates the existence of three opioid receptor types, the ␦, , and receptors (Martin et al., 1976;Lord et al., 1977;Evans et al., 1992). Agonists selective for ␦, , and receptors produce distinct profiles of physiological and behavioral effects (Gutstein, 2001). In addition, selective ␦, , and agonists may also produce interacting effects. Studies of opioid receptor interactions in rodents and nonhuman primates have been conducted primarily with ␦ and agonists using assays of nociception, and results from these studies suggest that ␦ agonists enhance the antinociceptive effects of agonists and that this interaction depends on such variables as the species studied, the particular agonists used, the relative doses tested, and the behavioral endpoint (Heyman et al., 1989;Adams et al., 1993;Dykstra et al., 2002;Stevenson et al., 2003).Interactions between ␦ and agonists have also been reported for other behavioral endpoints, such as bladder motility, convulsions, Straub tail, respiratory depression, and sedation (Sheldon et al., 1989;O'Neill et al., 1997;Su et al.,

Pain stimulates some behaviors (e.g., withdrawal responses) and depresses other behaviors (e.g., feeding, locomotion). We are developing methods for testing candidate analgesics using measurements of pain-depressed behaviors. Such assays may model important aspects of clinical pain and complement traditional procedures that measure pain-stimulated behaviors. The present study characterized the effects of a chronic pain manipulation (monosodium iodoacetate (MIA)-induced osteoarthritis) on wheel running in rats. Rats had 24hr voluntary access to running wheels. Duration of running wheel acquisition was manipulated such that rats had either 21 or 7 days of running wheel access prior to MIA administration. Wheel running was monitored for an additional 21 days following MIA administration. MIA produced concentration-and acquisition lengthdependent decreases in wheel running. Parallel experiments demonstrated that MIA produced concentration-dependent tactile allodynia and shifts in hind limb weight bearing. MIA was differentially potent across assays with a potency rank: weight-bearing ≥ von Frey > running wheel. MIA produced greater depression of wheel running in rats with relatively high baseline running rates compared to rats with relatively low baseline running rates. The differential potency of MIA across assays and apparent rate-dependent effects in running wheels may impact our traditional interpretations of preclinical nociceptive and antinociceptive testing.

Pain stimulates some behaviors (e.g. withdrawal responses) but depresses many other behaviors (e.g. feeding). Pain-stimulated behaviors are widely used in preclinical research on pain and analgesia, but human and veterinary medicine often rely on measures of functional impairment and paindepressed behavior to diagnose pain or assess analgesic efficacy. In view of the clinical utility of measures of pain-depressed behaviors, our laboratory has focused on methods development for preclinical assays of pain-depressed behavior in rodents. The present study compared the effects of a chemical noxious stimulus (IP lactic acid injections) and an opioid analgesic (morphine) administered alone or in combination on the stretching response (a pain-stimulated behavior) and intracranial self-stimulation (ICSS; a behavior that may be depressed by pain) in rats. For the ICSS procedure, rats implanted with electrodes in the lateral hypothalamus responded for electrical stimulation across a range of current frequencies to permit rapid determination of frequency-rate curves and evaluation of curve shifts following treatment. Lactic acid alone produced a concentrationdependent stimulation of stretching and depression of ICSS, expressed as rightward shifts in ICSS frequency-rate curves. Morphine had little effect alone, but it produced a dose-dependent blockade of both acid-stimulated stretching and acid-depressed ICSS. Both lactic acid and morphine were equipotent in the stretching and ICSS procedures. These results suggest that ICSS may be useful as a behavioral baseline for studies of pain-depressed behavior.

Aims-Pain depresses expression of many behaviors, and one goal of analgesic treatment is to restore pain-depressed behaviors. Assays that focus on pain-depressed behaviors may contribute to preclinical assessment of candidate analgesics.Main Methods-This study compared effects of the mu opioid receptor agonist morphine (an acknowledged analgesic), the dopamine receptor antagonist haloperidol (a non-analgesic sedative), the adenosine receptor antagonist caffeine (a non-analgesic stimulant) and the neurokinin-1 receptor antagonist CJ 11,974-01 (a candidate analgesic) on acetic acid-induced writhing (a traditional painstimulated behavior) and acetic acid-induced suppression of locomotor activity (a pain-depressed behavior) in male ICR mice. Drug effects on non-depressed (baseline) locomotor activity were also examined.Key findings-I.P. administration of acetic acid (0.18-1%) was equipotent in stimulating writhing and depressing locomotor activity. Morphine blocked both acid-induced stimulation of writhing and depression of locomotion, although it was 56-fold less potent in the assay of acid-depressed locomotion. Haloperidol and CJ 11,974-01 decreased acid-stimulated writhing, but failed to block acid-induced depression of locomotion. Caffeine had no effect on acid-stimulated writhing or aciddepressed locomotor activity, although it did increase non-depressed locomotion. Thus, morphine was the only drug to block both acid-stimulated writhing and acid-depressed locomotion. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. potency of morphine to block acid-induced depression of locomotion suggests that locomotor activity may be a relatively insensitive measure for studies of pain-depressed behavior. Significance-Complementary NIH Public Access

Pain-depressed behavior can be defined as any behavior that decreases in rate, frequency, duration or intensity in response to a putative pain state. Common examples include pain-related decreases in feeding, locomotion and expression of positively reinforced operant behavior. In humans, depression of behavior is often accompanied by a co-morbid depression of mood. Measurements of pain-depressed behaviors are used to diagnose pain in both human and veterinary medicine, and restoration of pain-depressed behavior is often a priority of treatment. This article describes two strategies for integrating measures of pain-depressed behaviors into preclinical assays of pain and analgesia. Assays of pain-depressed behaviors may contribute both to improved translational efficiency in analgesic drug development and to new insights regarding the mechanisms and determinants of pain and analgesia.