Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants

Abstract

Buprenorphine has long been classified as a mu analgesic, although its high affinity for other opioid receptor classes and the orphanin FQ/nociceptin ORL1 receptor may contribute to its other actions. The current studies confirmed a mu mechanism for buprenorphine analgesia, implicating several subsets of mu receptor splice variants. Buprenorphine analgesia depended upon the expression of both exon 1-associated traditional full length 7 transmembrane (7TM) and exon 11-associated truncated 6 transmembrane (6TM) MOR-1 variants. In genetic models, disruption of delta, kappa1 or ORL1 receptors had no impact on buprenorphine analgesia, while loss of the traditional 7TM MOR-1 variants in an exon 1 knockout (KO) mouse markedly lowered buprenorphine analgesia. Loss of the truncated 6TM variants in an exon 11 KO mouse totally eliminated buprenorphine analgesia. In distinction to analgesia, the inhibition of gastrointestinal transit and stimulation of locomotor activity were independent of truncated 6TM variants. Restoring expression of a 6TM variant with a lentivirus rescued buprenorphine analgesia in an exon 11 KO mouse that still expressed the 7TM variants. Despite a potent and robust stimulation of 35S-GTPγS binding in MOR-1 expressing CHO cells, buprenorphine failed to recruit β-arrestin-2 binding at doses as high as 10 μM. Buprenorphine was an antagonist in DOR-1 expressing cells and an inverse agonist in KOR-1 cells. Buprenorphine analgesia is complex and requires multiple mu receptor splice variant classes, but other actions may involve alternative receptors.

Strategy for making safer opioids bolstered

“…These findings support the idea 14 that opioid agonists with a strong bias towards G-protein-mediated signalling will retain their analgesic properties, but produce fewer side effects than unbiased opioids. Several laboratories have since identified G-protein-biased µOR agonists 4,[15][16][17][18][19] , many of which clearly separate analgesia from adverse side effects. One of these compounds, known as TRV130, is currently in phase III clinical trials 16 .…”

“…This key parameter enumerates the increase in Earth's average surface temperature that would occur if atmospheric carbon dioxide concentrations were doubled and the climate system was given enough time to reach an equilibrium state. More than 150 estimates of equilibrium climate sensitivity (ECS) have been published 3 , many of which suggest that worryingly high sensitivities are possible -including one that was published in Nature just a few weeks ago 4 . On page 319, Cox et al 5 use an ingenious approach to rule out high estimates.…”

Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism

“…Although the analgesic action of BPN is mediated via MOR agonism and modulated by KOR, delta opioid receptors and nociceptin/orphanin FQ (N/OFQ) receptors (Lutfy et al, 2003), pharmacological and genetic blockade of opioid receptors confirmed that MORs alone are necessary for the analgesic properties of BPN (Grinnell et al, 2016; Ide et al, 2004). In the present studies, we demonstrate that the antinociceptive effects of BPN are dependent on the Oprm1 A112G SNP.…”

Genetic dissociation of morphine analgesia from hyperalgesia in mice

“…Analgesia produced by other compounds is significantly attenuated or completely absent in E11 KO mice (Majumdar et al 2011; Marrone et al 2016; Pan et al 2009). For example, buprenorphine analgesia was dependent upon both 6TM and 7TM variants (Grinnell et al 2016), as were morphine-6β-glucuronide and fentanyl, while IBNtxA analgesia was mediated only by 6TM ones (Majumdar et al 2011). 6TM variants also contribute to non-mu opioid analgesia (Marrone et al 2016).…”

“…In contrast, morphine analgesia is unaffected by the selective elimination of 6TM variants in the E11 KO mouse (Pan et al 2009). However, the activity of other analgesics is dependent upon 6TM variants, such as buprenorphine (Grinnell et al 2016). Morphine also produces hyperalgesia that can become manifest after its analgesic actions wane.…”