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 βarrestin2 (βarr2) recruitment and chronic MMP-2200 induced cAMP tolerance and super-activation at the human delta and mu receptors in vitro. MMP-2200 efficaciously recruited βarr2 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 βarr2 recruitment or reduced cAMP tolerance and superactivation at the monomeric receptors in vitro.

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 21 days of prior voluntary access to wheels followed by OA induction, followed by 21 days 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 (3.2 mg/25 μl) 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, 21 days 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– 10 mg/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. controls. 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.

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.

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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 post-operative 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 hrs, 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.