On the Kappa Opioid Receptor in Analgesia, Aversion, and Reward in Mice

: (Alternative Format Thesis)

Abstract

Kappa opioid receptor (KOPr) signalling has a crucial role in aversion, counterbalanced by rewarding signalling through mu opioid receptors (MOPrs). This thesis explored the landscape of kappa opioid receptor signalling in mice across anatomical locations and therapeutic indications and addressed how KOPrs, through their effects on single neurons in key brain areas processing stress, aversion, and reward, critically shape motivational and drug-related behaviours.

The aversive and antinociceptive profile of nalfurafine, a putatively G-protein-biased KOPr agonist, was addressed in comparing its antinociceptive and aversive effects with that of the typical, non-biased KOPr agonist, U50,488 in tail withdrawal and conditioned place aversion (CPA) tests in mice. Neither nalfurafine nor U50,488 showed separation between their analgesic and aversive effects contradicting the hypothesis that nalfurafine is non-aversive. These findings caution against using nalfurafine as a non-aversive, KOPr agonist in rodent experiments.

Examination of mouse brain regions recruited in response to systemic doses of KOPr agonism, identified as a key region the paraventricular thalamus (PVT), which integrates stress and reward. Subsequent whole-cell voltage-clamp recording experiments investigated the function of KOPrs and MOPrs in single PVT neurons in brain slices from mice. The majority of PVT neurons co-expressed KOPrs and MOPr, with activation of either receptor type producing outward K+ currents. Additionally, MOPrs were found to be constitutively active, predominantly in the anterior PVT. Furthermore, it was inferred that MOPrs were located proximal to the cell body, whilst KOPrs were expressed more distally. KOPrs and MOPrs were both present presynaptically on glutamatergic nerve terminals, decreasing neurotransmitter release, whereas only KOPrs decreased presynaptic GABAergic neurotransmission. Together the data suggest that the balance of activation of KOPrs and MOPrs in the PVT may play a critical role in integrating stress- and reward-related signals.

Finally, the behavioural effects of aversive KOPr signalling on reward-related drug-associated memories were studied. The effect of KOPr agonists on drug-primed reinstatement was investigated in a conditioned place preference (CPP) model of cocaine and heroin-seeking in mice. A single injection of the KOPr agonist U50,488 (5mg/kg) or saline before the first extinction session decreased drug-primed reinstatement when animals were confined to the drug-conditioned chamber (inducing counter-conditioning), but not when they could explore both conditioned and unconditioned chambers (selectively inducing extinction). These results demonstrated that pharmacologically induced aversion via KOPrs can decrease contextual drug-seeking, but only when contingent to the drug-paired context.

In conclusion, this research demonstrates how KOPr signalling shapes motivational and drug-related behaviours. Furthermore, it shows how KOPr signalling affects single neurons in key brain areas that process stress, aversion, and reward. These findings give insight into the neural mechanisms underlying KOPr signalling in motivated behaviour.

Date of Award	26 Jun 2024
Original language	English
Awarding Institution	University of Bath
Supervisor	Chris Bailey (Supervisor), Sarah Bailey (Supervisor), Sue Wonnacott (Supervisor) & David Heal (Supervisor)