Over a third of the world's population is infected with parasitic worms. One of the most burdensome infections underpins the neglected tropical disease schistosomiasis (Bilharzia) caused by parasitic flatworms of the genus Schistosoma, which afflicts ~200 million people worldwide. Consequently, there is a need to discover and develop next generation anthelmintics, active against a broad spectrum of parasitic helminths.Flatworm musculature is regulated by bioaminergic signalling: addition of exogenous 5‐HT to isolated flatworm muscle fibres causes contraction. This effect is likely mediated by engagement of serotonergic G protein coupled receptors (GPCRs). For example, in free living planarians, knockdown of a serotonergic GPCR (S7.1) impairs worm motility. Here, we demonstrate that the psychoactive agent, lysergic acid diethylamide (LSD) acts as a agonist at the planarian S7.1 receptor (EC50 = 1.3±0.5nM, Emax 99±5% of 5‐HT response). LSD evoked contraction inhibited the motility of free living planarian worms (distance moved 16±2% versus control worms) and potently blocked bipolar regeneration evoked by praziquantel (IC50 = 0.5±0.2nM). These data raises the possibility that other psychoactive drugs, including psychotropics with known activity at human 5‐HT2 receptors, could serve as efficacious lead compounds to disrupt flatworm mobility.Therefore, we screened a variety of psychoactive agents on the motility of free living planarian flatworms, as well as the functionality of heterologously expressed S7.1 using a real time cAMP biosensor. Agents were discovered that modulated flatworm movement and regeneration, and efficacy of the screened molecules provided information about structural features necessary for activity at this abundant flatworm serotonergic GPCR. These data also identify features of ligands conveying activity at flatworm 5‐HT GPCRs.Support or Funding InformationSupported by NSF (MCB1615538, to JSM).
Opioids have been increasingly prescribed to treat chronic pain since the 1980s, despite evidence that long‐term use of opioids may lead to tolerance and pain sensitization called opioid‐induced hyperalgesia (OIH). OIH has been demonstrated in both preclinical models and healthy human volunteers, but is understudied and there is need for novel analgesics capable of mitigating OIH. α2/α3‐selective GABAA receptor positive allosteric modulators (PAMs) act specifically at subunits of the GABAA receptor found to mediate analgesia, and have demonstrated antinociceptive effects in models of chronic inflammatory and neuropathic pain. However, the efficacy of these compounds at relieving opioid‐induced pain hypersensitivity have not yet been investigated. This study systematically examined the antinociceptive effects of α2/α3‐selective GABAA receptor PAMs alone and in combination with acetaminophen in an OIH rat model wherein repeated treatment with the opioid fentanyl induces mechanical hyperalgesia. The von Frey test was used to measure mechanical nociception. Duration of actions of α2/α3‐selective GABAA receptor PAMs (KRM‐II‐81, NS16085, HZ‐166) alone were studied, and combinations of KRM‐II‐81 and acetaminophen were also studied at fixed ratios (1:1, 1:3, 3:1). Dose‐addition analysis was used to assess the antinociceptive interactions between KRM‐II‐81 and acetaminophen. α2/α3‐selective GABAA receptor PAMs were able to fully reverse mechanical sensitivity caused by OIH. Furthermore, KRM‐II‐81/acetaminophen combinations produced additive to supra‐additive interactions depending on the drug mixture ratios. These findings support the idea that α2/α3‐selective GABAA receptor PAMs could serve as novel analgesics for treating OIH, and may interact favorably with other non‐opioid analgesics.
Approximately 20% of U.S. adults suffer from chronic pain. Current therapies for treatment of chronic pain are limited, ineffective for a large number of patients, and often produce undesirable side effects. Though not used clinically to treat pain, benzodiazepines alleviate pain when administered into the spinal canal. This analgesic effect is due to their action at α2 and α3 subunits of the GABAA receptor: since α2/α3 subtype‐selective GABAA positive allosteric modulators (PAMs) act specifically at these subunits, they produce analgesia without eliciting side effects typically seen with classical benzodiazepines, such as sedation or cognitive impairment. This study evaluates the analgesic efficacy of combinations of two α2/α3 subtype‐selective PAMs (KRM‐II‐81 and NS16085) with the NSAID acetaminophen and two opioids (fentanyl and buprenorphine) in a rat model of chronic inflammatory pain (complete Freund’s adjuvant). We used a fixed ratio approach to evaluate combinations of drugs, assessing both mechanical pain (von Frey) and thermal pain (Hargreaves), in order to visualize the onset and duration of action of each of these drugs alone and in combination. We found that combining KRM‐II‐81 (4.0 mg/kg) and buprenorphine (0.048 mg/kg) produced greater analgesia than either of these drugs alone at comparable doses. These data are among the first to systematically examine the performance of α2/α3 subtype‐selective GABAA PAMs in combination with other analgesics, and are an important step towards developing novel therapies for treating chronic pain. Support or Funding Information R01DA047967
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