Analgesic Effects of the GIRK Activator, VU0466551, Alone and in Combination with Morphine in Acute and Persistent Pain Models

Kristopher K. Abney, Michael Bubser, Yu Du, Krystian A. Kozek, Thomas M. Bridges, Craig W. Linsdley, J. Scott Daniels, Ryan D. Morrison, Kevin D Wickman, Corey R. Hopkins, Carrie K. Jones, C. David Weaver

Research output: Contribution to journalArticle

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Abstract

G protein-gated inwardly rectifying potassium (GIRK) channels are potassium-selective ion channels. As their name suggests, GIRK channels are effectors of Gi/o G protein-couple receptors whereby activation of these GPCRs leads to increased GIRK channel activity resulting in decreased cellular excitability. In this way, GIRK channels play diverse roles in physiology as effectors of Gi/o-coupled GPCRs: peacemaking in the heart rate, modulation of hormone secretion in endocrine tissues, as well as numerous CNS functions including learning, memory, and addiction/reward. Notably, GIRK channels are widely expressed along the spinothalamic tract and are positioned to play roles in both ascending and descending pain pathways. More notably, GIRK channel knockout and knock-down studies have found that GIRK channels play a major role in the action of opioid analgesics which act predominantly through Gi/o-coupled, opioid-activated GPCRs (e.g., μ-opioid receptors). Recent advances in GIRK channel pharmacology have led to the development of small molecules that directly and selectively activate GIRK channels. Based on research implicating the involvement of GIRK channels in pain pathways and as effectors of opioid analgesics, we conducted a study to determine whether direct pharmacological activation of GIRK channels could produce analgesic efficacy and/or augment the analgesic efficacy morphine, an opioid receptor agonist capable of activating μ-opioid receptors as well as other opioid receptor subtypes. In the present study, we demonstrate that the small-molecule GIRK activator, VU0466551, has analgesic effects when dosed alone or in combination with submaximally effective doses of morphine.

Original languageEnglish (US)
Pages (from-to)1294-1299
Number of pages6
JournalACS Chemical Neuroscience
Volume10
Issue number3
DOIs
StatePublished - Mar 20 2019

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Acute Pain
Opioid Receptors
Morphine
Analgesics
G Protein-Coupled Inwardly-Rectifying Potassium Channels
Opioid Analgesics
Spinothalamic Tracts
Chemical activation
Gi-Go GTP-Binding Protein alpha Subunits
Pharmacology
Inwardly Rectifying Potassium Channel
Pain
Molecules
mu Opioid Receptor
Potassium Channels
Physiology
Reward
Ion Channels
GTP-Binding Proteins
Names

Keywords

  • GIRK
  • activator
  • analgesia
  • formalin assay
  • hot plate
  • morphine

PubMed: MeSH publication types

  • Journal Article

Cite this

Analgesic Effects of the GIRK Activator, VU0466551, Alone and in Combination with Morphine in Acute and Persistent Pain Models. / Abney, Kristopher K.; Bubser, Michael; Du, Yu; Kozek, Krystian A.; Bridges, Thomas M.; Linsdley, Craig W.; Daniels, J. Scott; Morrison, Ryan D.; Wickman, Kevin D; Hopkins, Corey R.; Jones, Carrie K.; Weaver, C. David.

In: ACS Chemical Neuroscience, Vol. 10, No. 3, 20.03.2019, p. 1294-1299.

Research output: Contribution to journalArticle

Abney, KK, Bubser, M, Du, Y, Kozek, KA, Bridges, TM, Linsdley, CW, Daniels, JS, Morrison, RD, Wickman, KD, Hopkins, CR, Jones, CK & Weaver, CD 2019, 'Analgesic Effects of the GIRK Activator, VU0466551, Alone and in Combination with Morphine in Acute and Persistent Pain Models', ACS Chemical Neuroscience, vol. 10, no. 3, pp. 1294-1299. https://doi.org/10.1021/acschemneuro.8b00370
Abney, Kristopher K. ; Bubser, Michael ; Du, Yu ; Kozek, Krystian A. ; Bridges, Thomas M. ; Linsdley, Craig W. ; Daniels, J. Scott ; Morrison, Ryan D. ; Wickman, Kevin D ; Hopkins, Corey R. ; Jones, Carrie K. ; Weaver, C. David. / Analgesic Effects of the GIRK Activator, VU0466551, Alone and in Combination with Morphine in Acute and Persistent Pain Models. In: ACS Chemical Neuroscience. 2019 ; Vol. 10, No. 3. pp. 1294-1299.
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