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Aims: We have shown that chemokines injected into the periaqueductal gray region of the brain blocks opioid-induced analgesia in the rat cold-water tail flick test (CWTF). The present experiments tested whether chemokine receptor antagonists (CRAs), in combination with sub-analgesic doses of morphine, would provide maximal analgesia in the CWTF test and the mouse formalin pain assay. The effect of CRAs on respiratory depression was also evaluated., Main Methods: One, two or four CRAs (AMD3100/CXCR4, maraviroc/CCR5, RS504393/CCR2 orAZD8797/CX3CR1) were used in combination with sub-analgesic doses of morphine, all given systemically. Pain was assessed using the rat CWTF test or formalin injection into the paw of mice scored by licking. Respiration and oxygen saturation were measured in rats using a MouseOX® Plus - pulse oximeter., Key Findings: In the CWTF test, a sub-maximal dose of morphine in combination with maraviroc alone, maraviroc plus AMD3100, or with the four chemokine receptor antagonists, produced synergistic increases in antinociception. In the formalin test, the combination of four CRAs plus a sub-maximal dose of morphine resulted in increased antinociception in both male and female mice. AMD3100 had an additive effect with morphine in both sexes. Coadministration of CRAs with morphine did not potentiate the opioid respiratory depressive effect., Significance: These results support the conclusion that combinations of CRAs can increase the potency of sub-analgesic doses of morphine analgesia without increasing respiratory depression. The results support an "opioid sparing" strategy for alleviation of pain using reduced doses of opioids in combination with CRAs to achieve maximal analgesia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

C-C chemokine receptor type 5, also known as CCR5 or CD195, is best known as a viral co-receptor that facilitates entry of HIV into cells. Evidence that CCR5 knockout mice display fewer dopamine neurons, lower striatal dopamine levels, and reduced locomotor activation compared to wild types also suggest a link between CCR5 receptors and cocaine dependence. Here, we tested the hypothesis using male Sprague-Dawley rats that cocaine-induced locomotor activation and conditioned place preference (CPP) are inhibited by a FDA-approved CCR5 antagonist (maraviroc), and that CCR5 gene expression in mesolimbic substrates is enhanced by repeated cocaine exposure. Pretreatment with maraviroc (1, 2.5, 5 mg/kg, IP) reduced hyperlocomotion induced by acute cocaine (10 mg/kg) without affecting spontaneous locomotor activity. For CPP experiments, rats conditioned with cocaine (10 mg/kg × 4 days, IP) were injected with maraviroc (1, 2.5, 5 mg/kg, IP) before each injection of cocaine. Maraviroc dose-dependently inhibited development of cocaine CPP, with a dose of 5 mg/kg producing a significant reduction. In rats treated repeatedly with cocaine (10 mg/kg × 4 days, IP), CCR5 gene expression was upregulated in the nucleus accumbens and ventral tegmental area but mRNA levels of CCR5 ligands (i.e., CCL3, CCL4 and CCL5) were not affected. Our results suggest that mesolimbic CCR5 receptors are dysregulated by cocaine exposure and, similar to CXCR4 and CCR2 receptors, influence behavioral effects related to the abuse liability of cocaine., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Planarians, like rodents, instinctively spend more time in dark versus light environments when given a choice. This behavioral phenomenon is called negative phototaxis, which may reflect defensive responding related to an anxiety-like phenotype., New Method: We propose a planarian light/dark test, designated PLDT, to predict anxiogenic- or anxiolytic-like effects. Experimentally, we placed a planarian at the midline of a Petri dish, containing test compound or water, that was split evenly into light and dark compartments and determined time spent in the light over 10min., Results: A clinically-approved benzodiazepine agonist (clorazepate; 10μM) increased time spent in the light whereas an inverse benzodiazepine agonist (FG-7142; 1, 10μM) produced the opposite response. Fluoxetine (1μM) or ethanol (1%), as well as the 'bath salt' cathinone S-mephedrone (300μM), enhanced time spent in the light. Planarians exposed to predator (frog) odor spent more time in the dark., Comparison With Existing Methods: The light/dark box (LDB) test in rodents is used to screen putative medications for possible anxiolytic and anxiogenic effects. Our results showing that time spent in the light by planarians is enhanced by common anxiety-relieving drugs (e.g. benzodiazepine agonist, ethanol, fluoxetine) and decreased by anxiogenic substances (e.g. predator odor, benzodiazepine inverse agonist) reveal directionally similar effects in the established (LDB) and new (PLDT) assays., Conclusion: Our data identify the PLDT as a cost-effective, invertebrate assay for quantifying the effects of practically any water-soluble substance on defensive responding and for studying and teaching anxiety-like responses in a living organism., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glutamate carboxypeptidase II (GCPII) inhibitors are promising anti-glutamatergic and anti-addictive agents. We hypothesized that a GCPII inhibitor 2 (phosphonomethyl) pentanedioic acid (2-PMPA) would display anti-stereotypical activity in planarians. Experiments revealed that 2-PMPA displayed no overt behavioral activity by itself but attenuated stereotypical counts (C-shape hyperkinesias) elicited by four compounds (2-PMPA rank order potency: glutamate>NMDA>pilocarpine>cocaine). These data suggest GCPII inhibitors display broad-spectrum efficacy against behavioral activity produced by glutamatergic and non-glutamatergic compounds in an invertebrate assay.

Planarians are traditional animal models in developmental and regeneration biology. Recently, these organisms are arising as vertebrate-relevant animal models in neuropharmacology. Using an adaptation of published behavioral protocols, we have described the alleviation of cocaine-induced planarian seizure-like movements (pSLM) by a naturally-occurring sesquiterpene lactone, parthenolide. Interestingly, parthenolide does not prevent the expression of pSLM induced by amphetamines; in vertebrates, amphetamines interact with the same protein target as cocaine. Parthenolide is also unable to prevent pSLM elicited by the cholinergic com-pounds nicotine and cytisine or by the glutamatergic agents L- or D- glutamic acid or NMDA. Thus, we conclude that parthenolide is a specific anti-cocaine agent in this experimental organism.