Millions of individuals suffer from chronic pain. Opioids are effective for treating chronic pain but their use is limited due to undesirable side‐effects. Previous studies have shown that different subunits of the GABAA receptor are associated with different actions of the benzodiazepine site. While α2/α3 subunit‐containing GABAA receptors mediate antinociceptive effects, α1 subunit‐containing GABAA receptors mediate sedative and abuse‐related effects. This study sought to examine the behavioral effects of two α2/α3‐subtype selective PAMs: KRM‐II‐81 and NS16085. In a rat model of inflammatory pain (complete Freund's adjuvant) and a rat model of neuropathic pain (chronic constriction injury), both PAMs and the classical benzodiazepine midazolam attenuated mechanical hyperalgesia (as measured by von Frey test). In the procedure of food‐maintained operant responding, KRM‐II‐81 and NS16085 did not significantly decrease the response rate at doses that produced maximal antinociception. Contrastingly, midazolam significantly reduced the response rate at doses that attenuated mechanical hyperalgesia. In a horizontal wire test aimed to measure muscle relaxation, within the dose range that produced antinociception, only midazolam dose‐dependently increased the percentage of rats unable to grasp the wire, indicating muscle‐relaxant activity. These behavioral effects can be attenuated by benzodiazepine receptor antagonist flumazenil, confirming that the behavioral effects of these subtype‐selective GABAA PAMs are mediated through the benzodiazepine site of GABAA receptors. Taken together, while midazolam produced antinociceptive, rate‐suppressing, and muscle‐relaxant activity at similar doses, both subtype‐selective GABAA receptor PAMs selectively produced antinocicpetive effects. Collectively, these data support the notion of α2/α3‐subtype selective GABAA PAMs as novel analgesics.Support or Funding InformationR01DA034806This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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.
Trace amine‐associated receptor 1 (TAAR1) is the best‐characterized sub‐family of receptors of trace amines. As a modulator of dopaminergic system, TAAR1 has been shown to play a critical role in regulating the rewarding properties of drugs of abuse such as cocaine. In our previous studies, we demonstrated that TAAR1 agonists were able to reduce cocaine intake and cue‐ and drug‐induced reinstatements of cocaine‐seeking under short‐access conditions. However, compared to the extended access of cocaine self‐administration model, the short‐access model could not mimic some core properties of addiction, such as escalation, compulsive motivation, and incubation of cocaine‐seeking. Furthermore, it remains unclear whether activation of TAAR1 would affect stress‐induced reinstatement of cocaine‐seeking. Here, we investigated the effects of TAAR1 partial agonist RO5263397 on the extended access of cocaine self‐administration. We also assessed the effects of the selective TAAR1 full agonist RO5166017 on the yohimbine‐induced reinstatement of cocaine‐seeking. We found that the TAAR1 partial agonist RO5263397 attenuated the escalation, break point, and cue‐seeking behavior in the extended access of cocaine self‐administration model. We also found that RO5166017 reduced yohimbine‐induced reinstatement of cocaine‐seeking and yohimbine‐potentiated cue‐induced reinstatement of cocaine seeking, indicating that activation of TAAR1 decreased the stress‐induced reinstatement of cocaine‐seeking. Taken together, our results suggest that TAAR1 is a promising therapeutic target for the treatment of cocaine addiction.Support or Funding InformationThis work was supported by the National Institute of Health Grants R21‐DA033426.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Drug addiction remains an unmanageable and costly disease. Apart from neuronal adaptation, growing recognition arises that glial proinflammatory activation importantly contributes to the rewarding effects of multiple drugs of abuse. Recent studies suggest the central importance of Toll‐like receptor 4 (TLR4), a candidate neuroimmune therapeutic target for drug addiction. While Interleukin‐1 receptor associated kinase 4 (IRAK4) plays a crucial role in TLR4 mediated innate immunity, there is no further studies support its functioning in drug addiction. We hypothesized that drug‐taking activates IRAK4 and induces reinforcing effects, and disruption of IRAK4 signaling attenuates the addictive behaviors. In the present study, IRAK4 and IRAK1 phosphorylation after morphine and cocaine self‐administration was evaluated using western blotting. The role of IRAK4 in morphine self‐administration and cue‐induced reinstatement was examined with its inhibitor, PF06650833. Moreover, local pharmacological manipulation was conducted to determine the role of IRAK4 in the nucleus accumbens (NAc) core in the cue‐induced reinstatement of morphine seeking. We found that morphine self‐administration significantly increased the phosphorylation of IRAK4, but not IRAK1, both in NAc and VTA. However, neither cocaine short access nor long access self‐administration had any effect on the phosphorylation of IRAK4. Systemic administration of PF06650833 significantly attenuated cue‐induced reinstatement of morphine seeking without affecting the spontaneous locomotion in rats, and microinjection of PF06650833 into NAc core sufficiently decreased cue‐induced morphine reinstatement. These results demonstrated that modulation of IRAK4 activity regulates the cue‐induced morphine reinstatement, and suggested it as a novel candidate target in treating drug addiction. Support or Funding Information This work was supported by NIDA [Grant R21DA040777]. 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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