Insulin-like growth factor I (IGF-I) has been successfully tested in the SOD1-G93A mouse model of familial amyotrophic lateral sclerosis (ALS) and proposed for clinical treatment. However, beneficial effects required gene therapy or intrathecal application. Circumventing the dosing issues we recently found that polyethylene glycol (PEG) modified IGF-I (PEG-IGF-I) modulated neuromuscular function after systemic application, and protected against disease progression in a motor neuron disease model. Here we investigated its effects in two SOD1-G93A mouse lines, the G1L with a milder and the G1H with a more severe phenotype. Results showed that in G1L mice, PEG-IGF-I treatment significantly improved muscle force, motor coordination and animal survival. In contrast, treatment of G1H mice with PEG-IGF-I or IGF-I even at high doses did not beneficially affect survival or functional outcomes despite increased signalling in brain and spinal cord by both agents. In conclusion, the data point towards further investigation of the therapeutic potential of PEG-IGF-I in ALS patients with less severe clinical phenotypes.
Opioid dependence can be difficult to manage using existing pharmacotherapies. A long-acting opioid with low abuse liability that substitutes for a shorter-acting opioid may improve treatment of opioid use disorders (OUDs). We recently characterized an endomorphin (EM) analog (ZH853) that produced a longer duration of antinociception compared with morphine, but did not produce self-administration or several other adverse effects preclinically. Here, we further characterized ZH853 in tests of antinociception, abuse liability, and drug discrimination. A conditioned place preference (CPP) procedure, that included a locomotor activity assessment, was used to test abuse liability in rats. Subsequently, dopamine (DA) cell-somas located in the ventral tegmental area (VTA) from these rats were assessed by size using immunohistochemistry and Stereo Investigator software. A hot-plate antinociception test in male and female mice confirmed central penetration. Morphine-substitution effects of several EM analogs (ZH850, ZH831, and ZH853) were tested in a drug discrimination (DD) procedure in rats. Morphine produced dose-dependent CPP and locomotor sensitization and reduced the size of DA cell somas in VTA, whereas ZH853 did not produce any of these effects relative to control. The antinociceptive effects of ZH853 were m-receptor selective since b-funaltrexamine antagonized these effects. Rats responded on a morphinetrained lever when injected with ZH831 and ZH853 during DD experiments. The favorable morphine-substitution effects of these EM analogs relative to their low abuse liability indicate promising novel compounds that may improve treatment of OUD. SIGNIFICANCE STATEMENT In this experiment, we investigated the preclinical effects of novel endomorphin analogs for use as substitution therapies for opioid use disorder, a problem that has contributed to an opioid overdose epidemic. Several endomorphin analogs substituted for morphine without producing adverse effects, including reward behaviors associated with abuse liability. These compounds have the potential to become important additional tools to treat opioid use disorders.
Cannabinoids can enhance the antinociceptive effects of opioids in a synergistic manner, potentially reducing the analgesic dosage of opioids and improving pain therapy. This strategy has also been used as a rationale to combine certain antidepressants and opioids. In this experiment, opioid-induced thermal antinociception was assessed in rhesus macaques using a warm-water tail-withdrawal procedure with 3 water temperatures (40, 50, and 55 °C). In general, the acute antinociceptive effects of intramuscular (i.m.) cumulative doses of heroin were studied alone or in combination with i.m. (-)-trans-delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), or the tricyclic antidepressant amitriptyline. A nonantinociceptive dose of THC (1 mg/kg) shifted the ED50 for the heroin dose-effect curve 3.6-fold leftward at 50 °C and 1.9-fold leftward at 55 °C compared with heroin alone. When the cannabinoid type-1 receptor (CB1R) antagonist, rimonabant, was administered prior to the most effective THC-heroin combination, rimonabant blocked the THC enhancement of heroin antinociception. When CBN (1–3.2 mg/kg) was administered prior to heroin, or 1 mg/kg of CBN was administered prior to a combination of 0.32 mg/kg of THC and heroin, no shifts were evident in the heroin dose-effect curves at either temperature. However, similar to THC, amitriptyline (0.32–1 mg/kg) administered prior to heroin significantly shifted the heroin dose-effect curve leftward. Heroin produced both dose- and temperature-dependent thermal antinociception in nonhuman primates and THC produced opioid-enhancing effects in a CB1R-dependent manner. These effects of THC were not shared by cannabinol, but were quantitatively similar to that of amitriptyline.
Cannabinoid administration prior to opioid administration can produce opioid‐sparing antinociceptive effects in several species by reducing the dosage of opioid needed to produce effective antinociception. These potentially valuable clinical effects could be undermined, however, if the cannabinoids also enhance the disruptive effects of opioids on neurobehavioral function. To address this question, the combined effects of THC and heroin were examined in nonhuman primates (rhesus macaques, n=4) responding in a learning and performance task and concurrently exposed to a tail‐withdrawal antinociception procedure. Testing in this case was facilitated by examining 4 discrete cycles of acquisition and performance that were separated by timeout periods to facilitate tail‐withdrawal tests and cumulative dosing. Each cycle included a 10‐min time out period for drug onset, a 15‐min acquisition component, and a 5‐min performance component. In the learning and performance task, subjects acquired a new 5‐response key‐sequence, or emitted a well‐rehearsed 5‐response key‐sequence, respectively. Responding in both components of the task was reinforced with a food pellet after every three completions of the sequence (i.e., a second‐order fixed‐ratio [FR3] schedule of food reinforcement). Warm‐water tail‐withdrawal antinociception was measured using three water temperatures (40°, 50°, and 55°C). Heroin alone dose‐dependently decreased response rates in the acquisition and performance components without markedly increasing percent errors. When the opioid antagonist naltrexone (1 mg/kg) preceded the cumulative heroin injections, the heroin dose‐effect curves for both the behavioral disruptions and antinociception were shifted rightward indicating both effects were mediated by mu‐opioid receptors. In contrast, THC alone disrupted both behaviors at doses that had no antinociceptive effect, but it shifted the heroin dose‐effect curves for learning, performance, and antinociception leftward. Overall, these data demonstrate that THC produces its opioid‐sparing antinociceptive effects at doses that are behaviorally disruptive alone and in combination with heroin.Support or Funding InformationThis work was supported by a National Institute of Drug Abuse Fellowship (F32DA47013‐01)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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