Abstract
There is much pharmacological evidence that suggests the existence of multiple δ-opioid receptors. However to date only one gene encoding for the receptor and no functional splice variants of the δ-opioid receptor have been reported. It has been suggested that δ-opioid receptors that exist in different environments or are differently coupled to signalling pathways could be an explanation for the pharmacological data that suggest δ-opioid receptor subtypes. To address the influence of G-protein coupling of the receptor on ligand binding, the current study uses quantitative autoradiography and homogenate binding to characterise the selectivity of four δ-opioid receptor ligands for the G-protein coupled and uncoupled states of the δ-opioid receptor. Quantitative autoradiography was also carried out in the brains of mice lacking the μ-opioid receptor to determine the effect the absence of the u-opioid receptor has on the G-protein coupling of the δ-opioid receptor. In addition microphysiometry and isolated tissue pharmacology have been utilised to further characterise the functional responses of naltrindole and RATGLU at the δ-opioid receptor. SNC-121, a selective δ-opioid receptor agonist has previously been reported to have both an atypical binding profile at δ-opioid receptors and a non-opioid binding site. To address this issue the binding of [3H]SNC-121 in the brains of mice lacking the δ-opioid receptor was determined using autoradiography. The studies described in this thesis demonstrate that some δ-opioid receptors in some discrete, predominantly non-cortical brain regions become uncoupled from G-proteins in the absence of μ-opioid receptors. In addition this study demonstrates that [3H]SNC-121 binds to a receptor which is not an opioid receptor but which is localised to brain regions predominantly expressing high levels of δ-opioid receptors. This study also provides further evidence for the existence of a physically interacting complex between d and u-opioid receptors and further characterises the non-opioid binding of [3H]SNC-121.