Voluntary exercise blocks ongoing pain and diminishes bone remodeling while sparing protective mechanical pain in a rat model of advanced osteoarthritis pain.

ABSTRACT: Exercise is the most common treatment recommended by healthcare providers for the treatment of musculoskeletal pain. We examined whether voluntary running wheel exercise improves pain and bone remodeling in rats with monosodium iodoacetate-induced unilateral knee joint pain. During acquisition of wheel running before osteoarthritis (OA) treatment, rats separated into 2 groups characterized by either high or low levels of voluntary wheel running as indicated by distance and peak speed. After the induction of knee joint OA, all rats showed diminished voluntary wheel running throughout the study. Voluntary wheel running failed to alter evoked nociceptive responses evaluated as weight asymmetry or hind paw tactile thresholds at any timepoint of the study. By contrast, relief of ongoing pain was demonstrated by conditioned place preference produced by lidocaine injection into the monosodium iodoacetate-treated knee in high but not low-running rats. Both high and low voluntary runners showed diminished trabecular bone loss compared with sedentary controls. These observations indicate that both high-intensity and low-intensity exercise is beneficial in protecting against bone remodeling in advanced OA. The data suggest that similar to clinical observation, bone remodeling does not correlate with pain. In addition, these results suggest that higher intensity exercise may relieve persistent ongoing OA pain while maintaining movement-evoked nociception. The relief of ongoing pain can potentially offer significant improvement in quality of life, whereas preservation of responses to movement-evoked pain may be especially important in protecting the joint from damage because of overuse.

Effects of Vancomycin on Persistent Pain-Stimulated and Pain-Depressed Behaviors in Female Fischer Rats With or Without Voluntary Access to Running Wheels.

The present experiments determined the effects of the narrow-spectrum antibiotic vancomycin on inflammatory pain-stimulated and pain-depressed behaviors in rats. Persistent inflammatory pain was modeled using dilute formalin (0.5%). Two weeks of oral vancomycin administered in drinking water attenuated Phase II formalin pain-stimulated behavior, and prevented formalin pain-depressed wheel running. Fecal microbiota transplantation produced a non-significant trend toward reversal of the vancomycin effect on pain-stimulated behavior. Vancomycin depleted Firmicutes and Bacteroidetes populations in the gut while having a partial sparing effect on Lactobacillus species and Clostridiales. The vancomycin treatment effect was associated with an altered profile in amino acid concentrations in the gut with increases in arginine, glycine, alanine, proline, valine, leucine, and decreases in tyrosine and methionine. These results indicate that vancomycin may have therapeutic effects against persistent inflammatory pain conditions that are distal to the gut. PERSPECTIVE: The narrow-spectrum antibiotic vancomycin reduces pain-related behaviors in the formalin model of inflammatory pain. These data suggest that manipulation of the gut microbiome may be one method to attenuate inflammatory pain amplitude.

Behavioral pharmacology of the mixed-action delta-selective opioid receptor agonist BBI-11008: studies on acute, inflammatory and neuropathic pain, respiration, and drug self-administration.

RATIONALE AND OBJECTIVES: The present study characterized the behavioral pharmacology of a novel, mixed-action delta-selective (78:1) opioid receptor agonist, BBI-11008. This glycopeptide drug candidate was tested in assays assessing antinociception (acute, inflammatory, and neuropathic pain-like conditions) and side-effect endpoints (respiratory depression and drug self-administration). RESULTS: BBI-11008 had a 78-fold greater affinity for the delta opioid receptor than the mu receptor, and there was no binding to the kappa opioid receptor. BBI-11008 (3.2-100; 10-32 mg kg-1, i.v.) and morphine (1-10; 1-3.2 mg kg-1, i.v.) produced antinociceptive and anti-allodynic effects in assays of acute thermal nociception and complete Freund's adjuvant (CFA)-induced inflammatory pain, with BBI-11008 being less potent than morphine in both assays. BBI-11008 (1-18 mg kg-1, i.v.) had similar efficacy to gabapentin (10-56 mg kg-1, i.v.) in a spinal nerve ligation (SNL) model of neuropathic pain. In the respiration assay, with increasing %CO2 exposure, BBI-11008 produced an initial increase (32 mg kg-1, s.c.) and then decrease (56 mg kg-1, s.c.) in minute volume (MV) whereas morphine (3.2-32 mg kg-1, s.c.) produced dose-dependent decreases in MV. In the drug self-administration procedure, BBI-11008 did not maintain self-administration at any dose tested. CONCLUSIONS: These results suggest that the glycopeptide drug candidate possesses broad-spectrum antinociceptive and anti-allodynic activity across a range of pain-like conditions. Relative to morphine or fentanyl, the profile for BBI-11008 in the respiration and drug self-administration assays suggests that BBI-11008 may have less pronounced deleterious side effects. Continued assessment of this compound is warranted.

Delta/mu opioid receptor interactions in operant conditioning assays of pain-depressed responding and drug-induced rate suppression: assessment of therapeutic index in male Sprague Dawley rats.

RATIONALE AND OBJECTIVES: Although delta/mu receptor interactions vary as a function of behavioral endpoint, there have been no assessments of these interactions using assays of pain-depressed responding. This is the first report of delta/mu interactions using an assay of pain-depressed behavior. METHODS: A mult-cycle FR10 operant schedule was utilized in the presence of (nociception) and in the absence of (rate suppression) a lactic acid inflammatory pain-like manipulation. SNC80 and methadone were used as selective/high efficacy delta and mu agonists, respectively. Both SNC80 and methadone alone produced a dose-dependent restoration of pain-depressed responding and dose-dependent response rate suppression. Three fixed ratio mixtures, based on the relative potencies of the drugs in the nociception assay, also produced dose-dependent antinociception and sedation. Isobolographic analysis indicated that all three mixtures produced supra-additive antinociceptive effects and simply additive sedation effects. CONCLUSIONS: The therapeutic index (TI) inversely varied as a function of amount of SNC80 in the mixture, such that lower amounts of SNC80 produced a higher TI, and larger amounts produced a lower TI. Compared to literature using standard pain-elicited assays, the orderly relationship between SNC80 and TI reported here may be a unique function of assessing pain-depressed behavior.

Exercise reverses pain-related weight asymmetry and differentially modulates trabecular bone microarchitecture in a rat model of osteoarthritis.

There is great interest in developing and utilizing non-pharmacological/non-invasive forms of therapy for osteoarthritis (OA) pain including exercise and other physical fitness regimens. AIMS: The present experiments determined the effects of prior wheel running on OA-induced weight asymmetry and trabecular bone microarchitecture. MAIN METHODS: Wheel running included 7 or 21days of prior voluntary access to wheels followed by OA induction, followed by 21days post-OA access to wheels. OA was induced with monosodium iodoacetate (MIA), and weight asymmetry was measured using a hind limb weight bearing apparatus. Bone microarchitecture was characterized using ex vivo µCT. KEY FINDINGS: Relative to saline controls, MIA (3.2mg/25µl) produced significant weight asymmetry measured on post-days (PDs) 3, 7, 14, 21 in sedentary rats. Seven days of prior running failed to alter MIA-induced weight asymmetry. In contrast, 21days of prior running resulted in complete reversal of MIA-induced weight asymmetry on all days tested. As a comparator, the opioid agonist morphine (3.2-10mg/kg) dose-dependently reversed weight asymmetry on PDs 3, 7, 14, but was ineffective in later-stage (PD 21) OA. In runners, Cohen's d (effect sizes) for OA vs. controls indicated large increases in bone volume fraction, trabecular number, trabecular thickness, and connective density in lateral compartment, and large decreases in the same parameters in medial compartment. In contrast, effect sizes were small to moderate for sedentary OA vs. SIGNIFICANCE: Results indicate that voluntary exercise may protect against OA pain, the effect varies as a function of prior exercise duration, and is associated with distinct trabecular bone modifications.

Evaluation of a Postoperative Pain-Like State on Motivated Behavior in Rats: Effects of Plantar Incision on Progressive-Ratio Food-Maintained Responding.

There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional postoperative pain manipulation on food-maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hr, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior.

The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence.

Previous work in our laboratories provides preclinical evidence that mixed-action delta/mu receptor glycopeptides have equivalent efficacy for treating pain with reduced side effect profiles compared to widely used mu agonist analgesics such as morphine. This study evaluated the rewarding and reinforcing effects of a lead candidate, mixed-action delta/mu agonist MMP-2200, using a conditioned place preference assay as well as a drug self-administration procedure in rats. In place conditioning studies, rats underwent a 2-week conditioning protocol and were then tested for chamber preference. Rats receiving MMP-2200, at previously determined analgesic doses, could not distinguish between the drug and saline-paired chamber, whereas rats receiving the opioid agonist morphine showed a strong preference for the morphine-paired chamber. In self-administration studies, rats were trained to respond for the high efficacy mu opioid receptor agonist fentanyl on an FR5 schedule of reinforcement. Following complete dose-response determinations for fentanyl, a range of doses of MMP-2200 as well as morphine were tested. Relative to the mu agonist morphine, MMP-2200 maintained a significantly lower number of drug infusions. To begin investigating potential molecular mechanisms for the reduced side effect profile of MMP-2200, we also examined ßarrestin2 (ßarr2) recruitment and chronic MMP-2200 induced cAMP tolerance and super-activation at the human delta and mu receptors in vitro. MMP-2200 efficaciously recruited ßarr2 to both receptors, and induced cAMP tolerance and super-activation equivalent to or greater than morphine at both receptors. The in vivo findings suggest that MMP-2200 may be less reinforcing than morphine but may have some abuse potential. The reduced side effect profile cannot be explained by reduced ßarr2 recruitment or reduced cAMP tolerance and superactivation at the monomeric receptors in vitro.

Monosodium iodoacetate-induced osteoarthritis produces pain-depressed wheel running in rats: implications for preclinical behavioral assessment of chronic pain.

Pain stimulates some behaviors (e.g., withdrawal responses) and depresses other behaviors (e.g., feeding and 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 24 h 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 length-dependent 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.

Rationale and methods for assessment of pain-depressed behavior in preclinical assays of pain and analgesia.

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 comorbid 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.

Targeting pain-depressed behaviors in preclinical assays of pain and analgesia: drug effects on acetic acid-depressed locomotor activity in ICR mice.

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 pain-stimulated 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 acid-depressed 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. SIGNIFICANCE: Complementary assays of pain-stimulated and pain-depressed behaviors may improve the predictive validity of preclinical studies that assess candidate analgesic drugs. The low 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.

Effects of pain- and analgesia-related manipulations on intracranial self-stimulation in rats: further studies on pain-depressed behavior.

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 pain-depressed 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 the development of methods 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. In the ICSS procedure, rats implanted with electrodes in the lateral hypothalamus responded to 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 concentration-dependent 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.

Discriminative stimulus properties of naloxone in Long-Evans rats: assessment with the conditioned taste aversion baseline of drug discrimination learning.

RATIONALE: The characterization of the discriminative stimulus properties of naloxone has focused primarily on its actions at the mu opioid receptor, although naloxone also displays an affinity for delta and kappa receptor subtypes. OBJECTIVES: The present study extends this characterization of the naloxone cue by investigating if relatively specific antagonists for the mu (naltrexone: 0.10-0.56 mg/kg), delta (naltrindole: 1-18 mg/kg), and kappa (MR2266: 1.8-10 mg/kg) opioid receptor subtypes will substitute for naloxone in animals trained to discriminate naloxone from its vehicle. The temporal nature of the naloxone cue was examined by varying pretreatment time points (15, 30, 45, 60 min). Finally, various doses of naltrexone methobromide (1-18 mg/kg) were assessed to determine peripheral mediation of the cue. MATERIALS AND METHODS: Female Long-Evans rats (N = 30) received an injection of naloxone (1 mg/kg; i.p.) 15 min prior to a pairing of saccharin (20-min access) and the emetic LiCl (1.8 mEq; i.p.; n = 16, group NL) or vehicle (n = 14, group NW); on other days, they were injected with saline prior to saccharin alone. Substitution tests with compounds with various receptor affinities and selective CNS and PNS actions were then assessed. RESULTS: Only naloxone and naltrexone produced dose-dependent decreases in saccharin consumption. Naloxone administered at 15 and 30 min before saccharin produced decreases in consumption similar to that displayed on training days. Naltrexone methobromide substituted only at the highest dose tested (18 mg/kg). CONCLUSIONS: Naloxone's stimulus effects appear to be mediated centrally via activity at the mu opioid receptor.

Micro/kappa opioid interactions in rhesus monkeys: implications for analgesia and abuse liability.

Micro 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 micro agonist-like abuse-related effects, suggesting that they may enhance the antinociceptive effects and/or attenuate the abuse-related effects of micro agonists. To evaluate this hypothesis, the present study examined interactions between the micro 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 degrees C. Fentanyl and U69,593 each produced dose-dependent antinociception, and effects were additive for all mixtures. In an assay of drug self-administration, rhesus monkeys responded for intravenous 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 rates of fentanyl self-administration. Moreover, addition of U69,593 increased the sensitivity of fentanyl self-administration to increases in the FR value. 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 micro agonists administered alone.

Electroencephalographic and convulsant effects of the delta opioid agonist SNC80 in rhesus monkeys.

Non-peptidic delta opioid receptor agonists are being evaluated for a wide range of clinical applications; however, the clinical utility of piperazinyl benzamide delta agonists such as SNC80 may be limited by convulsant activity. The purpose of the present study was to evaluate the electroencephalographic and convulsant activity produced by a high dose of 10 mg/kg SNC80 IM in rhesus monkeys. EEG and behavioral activity were examined in four adult male rhesus monkeys after IM administration of SNC80. Monkeys were seated in a standard primate restraint chair, and EEG activity was recorded using an array of 16 needle electrodes implanted subcutaneously in the scalp in a bipolar (scalp-to-scalp) montage in a longitudinal direction, with bilateral frontal, central, temporal, and occipital leads. Behavior was recorded using video monitoring equipment. Initially, all monkeys were tested with 10 mg/kg SNC80, which is a relatively high dose 3-10-fold greater than doses necessary to produce a variety of other behavioral effects. Behavioral convulsions and EEG seizures were observed in one of the four monkeys. In this monkey, neither behavioral convulsions nor EEG seizures were observed when a lower dose of 3.2 mg/kg was administered nine weeks later or when the same dose of 10 mg/kg SNC80 was administered one year later. These results suggest that IM administration of SNC80 is less potent in producing convulsant effects than in producing other, potentially useful behavioral effects (e.g. antinociception) in rhesus monkeys.

Naloxone, not proglumide or MK-801, alters effects of morphine preexposure on morphine-induced taste aversions.

Both cholecystokinin (CCK) antagonists and N-methyl-D-aspartate (NMDA) antagonists block or reduce the development of morphine tolerance in several analgesic assays. The present experiments were performed to assess the ability of the CCK antagonist proglumide and the NMDA antagonist MK-801 to affect tolerance to the aversive properties of morphine as indexed by conditioned taste aversion (CTA) learning. Specifically, male Sprague-Dawley rats were exposed to either vehicle or morphine (5 mg/kg) in combination with either proglumide (5 mg/kg; Experiment 1), MK-801 (0.1 mg/kg; Experiment 2) or naloxone (1, 3.2 mg/kg; Experiment 3). Saccharin was then presented and was followed by an injection of either vehicle or morphine (10 mg/kg). Animals preexposed to and conditioned with morphine acquired an attenuated morphine-induced aversion to saccharin. While neither proglumide nor MK-801 had an effect on this attenuation, naloxone blocked the effects of morphine preexposure, suggesting that neither CCK nor NMDA may be involved in the aversive effects of morphine (or their modulation by drug exposure). That the attenuating effects of morphine preexposure on a morphine-induced CTA can be blocked suggests that the weakening of the aversive effects of morphine with chronic use can be prevented, an effect that may have implications for overall drug acceptability.

Targeting pain-suppressed behaviors in preclinical assays of pain and analgesia: effects of morphine on acetic acid-suppressed feeding in C57BL/6J mice.

UNLABELLED: Pain increases the rate, frequency, or intensity of some behaviors (eg, withdrawal responses) and suppresses other behaviors (eg, feeding). Our laboratories are developing assays to test analgesic drug candidates using measurements of pain-suppressed rather than pain-elicited behaviors. Such assays may model important aspects of clinical pain and provide a means for distinguishing true analgesics from drugs that produce motor impairment. The present study compared effects of the mu opioid analgesic morphine and the nonanalgesic neuroleptic haloperidol on intraperitoneal acetic acid-induced writhing (a pain-elicited behavior) and suppression of feeding behavior (a pain-suppressed behavior). In feeding studies, C57BL/6J mice were given access to a dish containing 8 mL Ensure(trade mark) liquid food (0-100% in water) during daily sessions (7.5-120 min). Levels of consumption were dependent on both Ensure concentration and session duration. Intraperitoneal injection of acetic acid (0.10-0.56%) produced a time- and concentration-dependent decrease in Ensure consumption. Morphine (1 mg/kg) prevented both acid-induced writhing and acid-induced suppression of feeding, whereas the dopamine antagonist haloperidol inhibited writhing without preventing acid-induced suppression of feeding. The effects of morphine were time-dependent, selective for acid-suppressed feeding, and naltrexone-reversible. These results suggest that assays of pain-suppressed behaviors may complement assays of pain-elicited behaviors in preclinical studies of candidate analgesics. PERSPECTIVE: This paper presents a new preclinical strategy for assessing pain and analgesia in mice that is congruent with current methods of pain assessment in the clinic. This strategy may therefore be a useful complement to more traditional procedures for assessing pain and analgesia.

Interactions between delta and mu opioid agonists in assays of schedule-controlled responding, thermal nociception, drug self-administration, and drug versus food choice in rhesus monkeys: studies with SNC80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and heroin.

Interactions between delta and mu opioid agonists in rhesus monkeys vary as a function of the behavioral endpoint. The present study compared interactions between the delta agonist SNC80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist heroin in assays of schedule-controlled responding, thermal nociception, and drug self-administration. Both SNC80 (ED50 = 0.43 mg/kg) and heroin (ED50 = 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 degrees C) = 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 (ED50 = 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 delta/mu interactions depend on the experimental endpoint and further suggest that delta agonists may selectively enhance the antinociceptive effects of mu agonists while either not affecting or decreasing the sedative and reinforcing effects of mu agonists.

Effects of the mixed-action kappa/mu opioid agonist 8-carboxamidocyclazocine on cocaine- and food-maintained responding in rhesus monkeys.

The present study evaluated the effects of 8-carboxamidocyclazocine (8-CAC), a novel mixed-action kappa/mu agonist with a long duration of action, on food- and cocaine-maintained responding in rhesus monkeys to assess the potential utility of 8-CAC as a medication for the treatment of cocaine dependence. The effects of acute and chronic (10 days) 8-CAC were examined in rhesus monkeys responding under a multiple schedule for both cocaine and food reinforcement. Acute 8-CAC (0.032-0.56 mg/kg, i.m.) dose-dependently eliminated cocaine-maintained responding in all three monkeys. However, doses of 8-CAC that decreased cocaine self-administration typically also decreased food-maintained responding, and 8-CAC-induced decreases in cocaine self-administration diminished during chronic 8-CAC treatment. These results confirm that 8-CAC acutely decreases cocaine self-administration. However, non-selective effects of 8-CAC on food-maintained responding and tolerance to 8-CAC effects on cocaine self-administration may limit its potential for the treatment of cocaine dependence.

Opioid interactions in rhesus monkeys: effects of delta + mu and delta + kappa agonists on schedule-controlled responding and thermal nociception.

Agonists at delta, mu, and kappa 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 delta + mu and delta + kappa agonists in rhesus monkeys (n = 4-5) using two behavioral procedures, an assay of schedule-controlled 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 delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide (SNC80); the mu agonists methadone, fentanyl, morphine, and nalbuphine; and the kappa agonists (5alpha,7alpha,8beta)-(-)-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 + mu agonists produced additive or subadditive effects, whereas SNC80 + kappa agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas mu and kappa agonists produced dose-dependent antinociception. SNC80 + mu agonist mixtures produced superadditive effects manifested as leftward shifts in mu agonist dose-effect curves. This synergism was antagonized by the delta-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of mu agonist antinociception was delta receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective kappa agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective kappa agonist bremazocine. These results suggest that delta agonists may selectively enhance the antinociceptive effects of mu 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.