Yuko Fukunaga, Norihiro Inoue, Masahiko Miyamoto, Shiroh Kishioka and
Department of Pharmacology, Wakayama Medical College, 811-I Kimiidera, Wakayama 641-0012, Japan
Abstract: We examined the involvement of enkephalins in the caudal periaqueductal gray (cPAG) in morphine withdrawal in rats. Rats were treated with increasing doses of morphine (20 - 30 mg/kg/day, s.c., for 5 days) to develop morphine dependence. Morphine withdrawal was induced by naloxone (5 mg/kg, s.c.) 24 hr after the final morphine injection. The level of preproenkephalin (PPE) mRNA in the cPAG was estimated by quantitative in situ hybridization. PPE mRNA in the cPAG was increased 4 -24 hr after naloxone in morphine-treated rats. A mixture of peptidase inhibitors (0.5 microl of a solution of amastatin, captopril and phosphoramidon, 3 x 10-3 M each) microinjected into the cPAG suppressed morphine withdrawal (a decrease in the number of jumping, chin rubbing, paw rubbing and teeth chattering). Antiserum to methionine-enkephalin (1:10 dilution) microinjected into the cPAG did not significantly aggravate morphine withdrawal with or without the mixture of peptidase inhibitors. However, [D-Ala2, Met5]-enkephalinamide (20 nmol), an enkephalin analog, injected into the cPAG decreased the number of jumping without any influence on the other withdrawal signs. These results suggest that the increase in enkephalins in the cPAG may participate in the alleviation of morphine withdrawal (jumping behavior).
Keywords: Morphine withdrawal, Caudal periaqueductal gray, Peptidase inhibitor, [D-Ala2, Met5]-enkephalinamide, Preproenkephalin mRNA