Vol. 302, Issue 2, 759-765, August 2002

Characterization of Epibatidine Binding to Medial Habenula: Potential Role in Analgesia

Per Plenge, Erling T. Mellerup and Gitta Wörtwein

University Hospital, Laboratory of Neuropsychiatry, Copenhagen, Denmark

The objective of the present study was to characterize a recently described binding site in the habenula, which has high affinity for [³H]epibatidine and low affinity for nicotine and acetylcholine. We report that the extension of this binding area in coronal and horizontal sections corresponds to the anatomical extension of the medial habenula. The affinity (K_D) of the medial habenula receptors for [³H]epibatidine was estimated to be 0.5 nM using an autoradiographic saturation assay, whereas the affinity of the binding site for nicotine and acetylcholine was estimated to be 5 and 8 µM, respectively. The receptor density (B_max) in the medial habenula was estimated to be about 1100 fmol/mg wet weight using [³H]epibatidine. The subunit composition of the "epibatidine receptor" was investigated by the ability of different compounds with affinity to various subtypes of nicotinic receptors to displace [³H]epibatidine bound to the receptor. The results suggest that the receptor contains 3 subunits but that it is unlikely to be an 34 nicotinic receptor. Systemic administration of epibatidine has analgesic effects in rats. Here we report that 2 × 1 µl of 10 nM epibatidine, resulting in a 2 × 10-fmol dose, administered directly to the medial habenula by bilateral stereotactic injection had an analgesic effect measured in the hot-plate test. This dose of epibatidine increased hot-plate latency significantly, whereas 2 × 2 fmol of epibatidine or 2 × 10 fmol of nicotine were without effect. This leads us to suggest that the medial habenular epibatidine binding site might be a valuable target for the development of non-opiate analgesics.