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.

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.

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.

Delta opioid discrimination learning in the rat: assessment with the selective delta agonist SNC80.

The majority of reports assessing opioid drug discrimination learning (DDL) have concentrated on characterizing the stimulus properties of compounds selective for mu and kappa opioid receptors. Assessments of delta opioid DDL have been limited and, to date, these assessments have been restricted to the monkey and pigeon. No assessment of delta stimulus control has been examined in rodents. To that end, the present experiment examined discriminative control by the selective delta agonist SNC80 in rats and its generalization to and antagonism by compounds relatively selective to the delta and mu receptor subtypes using the conditioned taste aversion baseline of DDL. Animals injected with 5.6 mg/kg of SNC80 prior to a saccharin-LiCl pairing and with the SNC80 vehicle prior to saccharin alone acquired the discrimination within seven conditioning cycles. The discriminative effects of SNC80 were maximal at 20 min, partial at 120 min, and lost at 240 min. The discrimination was dose dependent in that as the dose of SNC80 increased, the amount of saccharin consumed decreased. In subsequent generalization tests, the delta agonist SNC162 produced SNC80-appropriate responding at a dose of 18 mg/kg. Conversely, the mu agonist morphine produced vehicle-appropriate responding at all doses tested. These selective generalization patterns with SNC162 and morphine suggest that the discriminative effects of SNC80 are mediated at the delta, but not the mu, receptor, a conclusion supported by the fact that SNC80's discriminative control was completely blocked by the delta-selective antagonist NTI, but not by the mu-selective antagonist naltrexone. The present findings indicate that not only do rats readily discriminate both mu- and kappa-selective agonists from their respective vehicles, but they also discriminate compounds that are selective for the delta receptor subtype, thus extending the class of compounds that can serve such discriminative functions for the rat.