The behavioural effects of opioids such as heroin have long been considered to be mediated by central mechanisms. However in recreational use, opioids are administered systemically and can therefore influence peripheral μ-opioid receptor-dependent systems before they reach the brain. In humans, interoception, the bottom-up sensing and integration of physiological signals arising from outside the central nervous system which depends on the insular cortex, is involved in opioid use disorder either as a predictor or the outcome of opioid abuse. Yet the role of peripheral opioidergic mechanisms in the behavioural effects of heroin and its addictive properties remains unclear. Similarly, whether the interoceptive effects of heroin are peripherally- or centrally-generated and whether they functionally recruit the insular cortex remains to be established. I hypothesised that peripheral μ-opioid receptors (pMORs) mediate the interoceptive effects of heroin which are integrated by the insular cortex. Using behavioural pharmacology, functional manipulations and biochemical assays on post-mortem tissue samples, I aimed to characterise the role of pMORs in the locomotor, reinforcing and discriminative properties of heroin in male Sprague-Dawley rats. The General Introduction to the literature laying the foundations for this thesis and the General Methods are presented in Chapter 1 and 2, respectively.

In Chapter 3, I establish that pΜOR antagonism abolishes the acute locomotor effects of systemic heroin exposure and alters the associated insular-striatal functional connectivity.

In Chapter 4, I subsequently demonstrate that the sedative effects of heroin strongly correlate with the β-endorphin concentrations in the plasma. I then show that the β-endorphin release is mediated via central MORs and that selective antagonism of central or peripheral MORs abolishes the correlation between plasma β-endorphin concentration and locomotion.

In Chapter 5, I demonstrate that pΜOR antagonism increases heroin intake during the acquisition of self-administration and leads to persistent responding early on during an extinction challenge.

In Chapter 6, I demonstrate that pΜOR antagonism exacerbates the development of escalation of heroin self-administration under protracted access (an operationalisation of loss of control) and subsequently increases heroin intake at relapse following forced abstinence. However, post-escalation pMORs antagonism does not affect the maintenance of escalated intake.

Building on the results of Chapter 3 and 6, in Chapter 7, I aimed to investigate the effect of a causal manipulation of the anterior insular cortex (AIC) on the development and maintenance of loss of control over heroin intake. In rats with a history of escalated heroin intake, bilateral excitotoxic AIC lesions exert an inhibitory effect on the maintenance of loss of control but increase relapse propensity after forced abstinence. However, the same AIC lesions performed before heroin exposure in naïve animals do not affect the subsequent development of loss of control.

In Chapter 8, I demonstrate using a drug discrimination task that pΜOR antagonism enhances the discriminative properties of heroin as revealed by an increase in the response accuracy for the heroin-paired lever as compared to controls. This suggests that pMOR-dependent mechanisms and the central effects of heroin exert opposing influence on its discriminative properties.

Taken together these results shed new light on the role of pMOR-dependent mechanisms and their crosstalk with those mediated by central MORs in the behavioural effects of heroin and their underlying neural systems.