Endomorphin-2 axon terminals contact mu-opioid receptor-containing dendrites in trigeminal dorsal horn

The endomorphins represent a novel group of endogenous opioid peptides that have high affinity for the mu-opioid receptor (MOR1). Endomorphin-2 is present in high density in the spinal and trigeminal dorsal horns and is localized to primary afferents. If endomorphin-2 were an endogenous ligand for the MOR1, we would expect to find the receptor at cellular sites in close association with the peptide. We used dual-labeling immunocytochemical methods combined with electron microscopy to determine if a cellular substrate exists for functional interactions between endomorphin-2 and MOR1. We confirmed the localization of endomorphin-2 to unmyelinated axons and axon terminals in the trigeminal dorsal horn. A small proportion of these endomorphin-2 axons contained MOR1, but many of the dendritic targets of endomorphin-2 terminals contained MOR1. Consistent with previous studies, endomorphin-2 was contained primarily in dense core vesicles and MOR1 was located primarily at non-synaptic sites. These morphological characteristics are consistent with the hypothesis that peptides are released extra-synaptically and their receptors may be located at sites distal to the synaptic junction. These anatomical data support the hypothesis that endomorphin-2 is a ligand for MORs in the trigeminal dorsal horn, particularly at postsynaptic sites.