Differences in antinociceptive signalling mechanisms following morphine and fentanyl microinjections into the rat periaqueductal gray

Abstract

Background Morphine and fentanyl are two of the most commonly used opioids to treat pain. Although both opioids produce antinociception by binding to mu‐opioid receptors (MOR), they appear to act via distinct signalling pathways. Objective This study will reveal whether differences in morphine and fentanyl antinociception are the result of selective activation of G‐protein signalling and/or selective activation of pre‐ or postsynaptic MORs. Methods The contribution of each mechanism to morphine and fentanyl antinociception was assessed by microinjecting drugs to alter G‐protein signalling or block potassium channels linked to pre‐ and postsynaptic MORs in the ventrolateral periaqueductal gray (PAG) of male Sprague‐Dawley rats. Results Both morphine and fentanyl produced a dose‐dependent antinociception when microinjected into the PAG. Enhancement of intracellular G‐protein signalling by microinjection of the Regulator of G‐protein Signalling 4 antagonist CCG‐63802 into the PAG enhanced the antinociceptive potency of morphine, but not fentanyl. Microinjection of α‐dendrotoxin into the PAG to block MOR activation of presynaptic Kv+ channels caused a significant rightward shift in the dose–response curve of both morphine and fentanyl. Microinjection of tertiapin‐Q to block MOR activation of postsynaptic GIRK channels caused a larger shift in the dose–response curve for fentanyl than morphine antinociception. Conclusions These findings reveal different PAG signalling mechanisms for morphine and fentanyl antinociception. In contrast with fentanyl, the antinociceptive effects of morphine are mediated by G‐protein signalling primarily activated by presynaptic MORs. Significance Microinjection of the opioids morphine and fentanyl into the periaqueductal gray (PAG) produce antinociception via mu‐opioid receptor signalling. This study reveals differences in the signalling mechanisms underlying morphine and fentanyl antinociception in the PAG. In contrast with fentanyl, morphine antinociception is primarily mediated by presynaptic opioid receptors and is enhanced by blocking RGS proteins.

Analgesic Interaction Between Morphine with Fentanyl In Experimental Murine Pain

“…The study shows that fentanyl is a more effective antinociceptive opioid than morphine. This nding is consistent with a previous study that revealed different mechanisms for the antinociception of morphine and fentanyl (Morgan et al 2020). Furthermore, it could be explained by the suggestion that some opioids could be acting through other mechanisms.…”

Mice Expressing Regulators of G protein Signaling–insensitive Gαo Define Roles of μ Opioid Receptor Gαo and Gαi Subunit Coupling in Inhibition of Presynaptic GABA Release

“…Since sub-maximal concentrations were used for each of the agonists, the lack of increase with fentanyl in the recordings from RGS-insensitive Het mice was not attributed to a ceiling effect. These data are consistent with recent data showing that inhibition of RGS4 in the PAG enhanced morphine, but not fentanyl, antinociception (Morgan, Tran, Wescom, & Bobeck, 2020). There is evidence that RGS protein GTPase accelerating activity is more evident with low compared to high efficacy MOR agonists (Clark, et al, 2008); however, the maximal inhibition by all agonists was comparable.…”

“…Although it is tempting to argue that postsynaptic MORs in the vlPAG do not play a role in opioid-induced antinociception, an equally valid interpretation is that MOR coupling to GIRK channels opposes supraspinal antinociceptive circuits and removal of this MOR signaling supports opioid analgesia in the RGS-insensitive Het mice (Lamberts, et al, 2013). Indeed, blocking both GIRK channels and presynaptic MOR signaling decreases morphine antinociception (Morgan, et al, 2020). Inhibition of RGS4 in the vlPAG enhances opioid-induced antinociception suggesting that RGS4 may play an important role in regulating presynaptic MOR signaling through Go.…”

Regulators of G Protein Signaling in Analgesia and Addiction

“…It is also important to mention that pharmacological inhibition of RGS4 activity in certain brain regions may also modulate the antinociceptive actions of opioids. Recent studies have reported that microinjection of compound CCG-63802 in the ventrolateral periaqueductal gray (vlPAG) enhances the antinociceptive potency of morphine but has no effect on fentanyl's actions in the same paradigm (Morgan et al 2020). While CCG-63802 is not a highly selective compound (Senese et al 2020), these data suggest an agonist-dependent role of RGS4 in the modulation of opioid actions in the PAG.…”