THE OCCURRENCE AND RECEPTOR SPECIFICITY OF ENDOGENOUS OPIOID-PEPTIDES WITHIN THE PANCREAS AND LIVER OF THE RAT - COMPARISON WITH BRAIN

Our observations that opioid peptides have direct effects on islet insulin secretion and liver glucose production prompted a search for endogenous opiates and their receptors in these peripheral tissues. μ-, δ- and κ-receptor-active opiates were demonstrated in brain, pancreas and liver extracts by displacement studies using selective ligands for the three opiate receptor subtypes ([3H][D-Ala2,MePhe4,Gly5-ol]enkephalin, [3H][D-Ala2,D-Leu5]enkephalin and [3H]dynorphin respectively). Receptor-active opiates in brain extracts exhibited a stronger preference for δ-opiate-receptor sites than for μ and κ sites. Pancreatic extract opiates demonstrated a similar activity at μ and δ sites, but substantially less at κ sites. Liver extracts displayed similar selectivity for all three sites. The affinities of the receptor-active opiates for μ-, δ- and κ-receptor subtypes displayed a rank order of potency: brain >> pancreas > liver. Total immunoreactive β-endorphin and [Met5]enkephalin levels in liver and hepatocytes were greater than those in brain. Immunoreactive [Met5]enkephalin levels in pancreas were similar to, but β-endorphin levels were substantially higher than, those in brain. δ and κ opiate-binding sites of high affinity were identified in crude membrane preparations of islets of Langerhans, but no specific opiate-binding sites could be demonstrated in liver membrane preparations. Immunoreactive dynorphin and β-endorphin were demonstrated by immunogold labelling in rat pancreatic islet cells. No positive staining of liver sections for opioids was observed. These results suggest that the tissue content of opiate-receptor-active compounds in the pancreas and the liver is very significant and could contribute to the regulation of normal blood glucose levels.