Κ-Opioid Receptors (k-ORs)

Κ-Opioid Receptors (k-ORs)

The k-Opioid receptor, encoded by the OPRK1 gene, was first identified based on studies with the k-type agonist ketocyclazocine but binds primarily to the endogenous opioid peptide dynorphin, although it does bind other alkaloid ligands. There is evidence to suggest this opioid receptor is involved in addiction and dynorphin is an endogenous agonist to the body’s natural addiction control mechanism and so there is a lot of interest in developing therapeutic applications that target this receptor. Of particular interest is the fact that it has been shown that stressed/abused children display abnormal kappa and Mu opioid receptor distributions, with studies proving k-ORs involvement in human stress responses and their ability to counteract the effects of Mu-opioid receptors. k-OR ligands also have a characteristic diuretic activity due to their negative regulation of antidiuretic hormone (ADH), as well as k-Opioid agonisms being seen to be neuroprotective against hypoxia/ischaemia. Additionally,  k-ORs observed involvment in the delevopment of dysphoria suggests that k-OR mediated therapies, with k-OR agonists and antagonists as viable drug candidates, could also provide a potential treatment for depression. 

Although there are three subtypes of k-OR receptors only one cDNA has been found, thereby suggesting these different receptor subtypes arise through interactions with different membrane proteins. All k-ORs are then coupled to a cytoplasmic G_i/G₀ protein, which upon receptor activation increases cAMP phosphodiesterase activity resulting in a decrease in physiological cAMP levels and the shutting down of cAMP-dependent sodium channels, thus inhibiting the propagation of any neuronal action potential signal. k-ORs are also coupled to potassium channels and calcium channels, to increase membrane hyperpolarisation and inhibit neurotransmitter release respectively. Like other GPCRs, the activation of the k-OR has also been associated with the activation of MAPKs, strongly suggesting involvement in, or at least crosstalk with, other essential pathways in cell functioning (See Figure 2).

JDTic is an opioid antagonist which specifically blocks the k-OR agonist U50,488-induced antinociception, while not antagonizing mu-OR agonist-induced analgesia. Its effects are long lasting and animal studies with rodents have shown it can have an antidepressive and anti-anxiolytic effects. It is a 4-phenylpiperine derivative which contains piperidine and isoquinoline groups (See Figure3) ,which are important determinants of its high affinity interaction with the kappa opioid receptor that is of particular interest for the development of highly specific theraputic k-OR ligand drugs.

Figure 2. k-OR mediated signalling. This receptor can trigger signalling cascades through cAMP modulation and activation of the PKC pathway and Src-mediated phosphorylation of JNK protein. kOR-mediated signalling can also result in gene regulation through pCREB and zif298 transcription factors. Note the negative feedback loop that operates on the potassium channels and the receptor agonists and antagonists^[2].

Figure 3. Structure of the kappa opioid receptor antagonist ligand, JDTic^[3]. Acidic  groups have been depicted in red and basic groups in blue.