Interaction between mu and kappa receptors located in the parabrachial area in the opioid control of preference threshold for saccharin: modulatory role of lateral hypothalamic neurones.

In the course of our previous analyses of gustatory reward processes, we showed that, in normal or sham-lesioned rats, the preference threshold for saccharin over water was observed with a 0.3mM solution of the sweetener. The same solution was neutral for rats whose lateral hypothalamic neurones had been destroyed by ibotenic acid. Furthermore, injection of small dose of morphine (50ng) in the second gustatory relay-station, the parabrachial area, suppressed preference for the 0.3mM saccharin solution in sham-lesioned rats, while the same injection induced preference in lesioned rats. The aim of the present study was to determine if this paradoxical effect of morphine, in particular the suppressive action observed in sham-lesioned rats, could be explained by a differential activation of µ and kappa receptors located in the parabrachial area. Using the choice test between 0.3mM solution of saccharin and water, we compared the effect of intra-parabrachial injection of 50ng of morphine to those obtained with the µ agonist DAGO, the putative endogenous kappa ligand, dynorphin A(1-13) (Dyn A(1-13)) and the kappa antagonist, nor-binaltorphimine (nor-BNI). Increasing doses of each agonist and the antagonist were tested in independent groups of rats including lesioned and sham-lesioned animals. The same doses of DAGO that increased preference in sham-lesioned animals, decreased saccharin and water intakes in lesioned rats. On the contrary, Dyn A(1-13) dose-dependently decreased preference in the control rats and increased preference in lesioned animals. The effects of increasing doses of nor-BNI were more variable. To clarify the respective roles of the µ and kappa receptors, we tested the effect of two mixtures: (1) the simultaneous injection of DAGO and Dyn A(1-13) at doses ineffective when tested separately reproduced the paradoxical effect of morphine in each group of rats; (2) morphine effects were reversed when kappa receptors were blocked by a prior injection of nor-BNI. Taken together, the results suggest that: (1) in the parabrachial area of the normal rat, two opioidergic components, behaving antagonistically to each other, are implicated in the control of gustatory preference, a µ component with rewarding properties and a kappa component with aversive properties; (2) the main effect of the lateral hypothalamic lesion is to invert the properties of these two components; and (3) at least in the parabrachial area, µ and kappa receptors are functionally coupled and must be co-activated to reproduce the full effect of morphine.