Kappa opioid receptor (KOR) belongs to the opioid system. This system plays an essential role in addiction. Opioid receptors and endogenous opioid peptides are very widely present in brain structures that control reward phenomena, particularly the mesolimbic system. These opioid receptors and peptides participate selectively in several aspects of the addictive processes induced by opiates, cannabinoids, psychostimulants, alcohol and nicotine.[1]
Though they are also found in the spinal cord and the peripheral tissues, those receptors are mainly located in most brain regions.
Structure
[2]
The Kor structure consists on a 7TM bundle of alpha helices and an helix VII, parallel to the membrane. It is crystallized in a parallel-dimer form composed of helices I, II and VIII in contact each others for study. Kor has a disulfide bound between its Cys131 and Cys210. The Thr273 stabilize the inactive structure whereas the NPxxY motif, in the helix VII, composed of Asn326, Pro327, Ile328, Leu239 and Tyr 330 is supposed to be responsible for the molecular switch needed for the activation. Kor’s Arg156 is use to made hydrogen bonds to the helix VI residue.
This crystalar structure forms ionic, polar and hydrophobic interactions with the receptor. This structure allowed numerous rotable bonds, which permit different conformations. It also facilate the ligand passage through the narrow binding pocket entrance. This repose on an interaction of two amino groups linked to Asp138, wich fixe the ligand in a V-shape. The N- and C- termini domain are totally disordered in this structure. This structure is selected thanks to the Glu297 specificty for JDTic and its derivatives.
BNI and GNTI are ligands which can forme a salt bridge with Kor’s Glu297 thanks to their amino groups, which give them ans important selectivity for Kor and its morphinan derivatives
The kappa opioid receptor, just as the oher opioid receptors is a powerful analgesic and hence could be used as a pain regulator. Nevertheless, unlike other opioid receptors such as morphin, the clinical use of the KOR is extreamely rare because of the impornt psychological effects triggered by this receptor such as dysphoria, dissociations or drug predispositions :
By using a forced swim stress test, it has been determined that the releasing of endogenous dynorphin opioids (which are KOR agonists) by the organism in a stress situation activates the kinase fonction of the KOR which leads to the phosphoryllation of ERK1/2 MAPK. Hence the activation of their pathways which leads to the attenuation of stress effects over the organism.
However, it appears that regular stress situations, so regular ERK1/2 MAPK activation, cause the well known psychological problems which prevent the use of the kappa opioids as pain regulators.
It has also been proved that the mice possessing inactiv KOR due to prior inhibition by KOR antagonists have proved to be inapt to activate the ERK1/2 MAPK pathways due to the non posphorylation of those two. Thus those mice didn’t show any sign of psychological disorder.
Therefore the KOR antagonist molecules are now looked for their potenial against all type of addiction.
