Regional Differences in Cerebral Noradrenaline Turnover in Mice Withdrawn from Repeated Morphine Treatment and Tolerance to the Effects of Acute Morphine

Abstract

The effects of morphine withdrawal and challenge doses (10 or 30 mg/kg) on the alpha-methyl-p-tyrosine (alpha MT)-induced noradrenaline (NA) depletion as well as on the free 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG) concentration were studied in various brain areas of NMRI mice. Morphine was given subcutaneously 3 times daily for 5 days followed by 1 or 3 days' withdrawal. In morphine withdrawn mice the alpha MT-induced NA depletion and the free MOPEG concentrations were differentially altered. At 1-day withdrawal the alpha MT-induced NA depletion was retarded and the NA concentration was elevated in the forebrain area indicating reduced release of NA. Simultaneously, however, the free MOPEG concentration was significantly elevated in the forebrain area and in the lower brain stem suggesting enhanced NA turnover. No withdrawal-induced changes were found in the hypothalamic NA turnover. Acute morphine elevated the free MOPEG concentration and accelerated the alpha MT-induced NA depletion in all brain areas of control mice but not in mice withdrawn for 1 day from repeated morphine treatment. At 3 days' withdrawal, however, the 30 mg/kg morphine dose slightly accelerated the NA depletion in the forebrain area. These results show that morphine withdrawal differentially alters the alpha MT-induced NA depletion and the free MOPEG concentration in various mouse brain areas. These effects are relatively modest suggesting that in mice the noradrenergic mechanisms play a minor role in morphine withdrawal syndrome. However, in all brain areas of the morphine-withdrawn mice tolerance was found towards the NA turnover and release accelerating effect of acute morphine.

The involvement of noradrenergic transmission in the morphine‐induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment

“…Acute morphine elevated the free MOPEG concentration in all brain areas of the control mice but in the morphine‐withdrawn mice there was clear tolerance towards this effect. This agrees with reports ( Etemadzadeh, 1993 ; Airio et al ., 1995 ; Airio & Ahtee, 1997 ) indicating that in mice withdrawn from repeated morphine treatment there is tolerance to the cerebral NA turnover and release increasing effect of acute morphine at 1 or 3 days after the withdrawal and suggests that although withdrawal from repeated morphine treatment may not affect the basal NA turnover and release in mice, it alters the response of the cerebral noradrenergic systems to a morphine challenge dose.…”

“…Locomotor activity was measured immediately after morphine or saline administration at 5 min intervals for 2 h between 1030 and 1530 h. Each mouse was used only once. The magnitude and duration of the exploration phase, when compared with the onset and magnitude of the eect of acute morphine, was found to be small in our previous experiments (Airio et al, 1995). Therefore, mice were not habituated before measurement.…”

“…Indeed, we showed previously that tolerance to the effects of acute morphine on NA metabolism persisted in the hypothalamus longer after withdrawal from repeated morphine administration than in the other two brain areas studied ( Airio & Ahtee, 1997 ). Also, as discussed above, in contrast to other brain areas in the hypothalamus of mice withdrawn for 1 day from morphine the NA turnover was not enhanced ( Airio et al ., 1995 ). However, in combination with morphine idazoxan clearly enhanced the morphine‐induced increase of the free MOPEG in all brain areas of the morphine‐withdrawn mice elevating the MOPEG concentration to about same degree as in controls.…”

“…In mice 1 day withdrawal from repeated morphine treatment induces modest regional changes of the NA turnover in the forebrain area and the lower brain stem but not in the hypothalamus ( Airio et al ., 1995 ) while after longer withdrawal periods the α‐methyl‐ p ‐tyrosine‐induced depletion of cerebral NA or the cortical MOPEG concentration are not altered ( Etemadzadeh, 1993 ; Funada et al ., 1993 ; Airio & Ahtee, 1997 ). Furthermore, the striatal DA metabolism and turnover are weakened in mice after 1 day but no longer after 3 day withdrawal from repeated morphine treatment ( Ahtee et al ., 1987 ; Airio et al ., 1994 ; Airio & Ahtee, 1997 ).…”

“…In mice 1 day withdrawal from repeated morphine treatment induces modest regional changes of the NA turnover in the forebrain area and the lower brain stem but not in the hypothalamus (Airio et al, 1995) while after longer withdrawal periods the a-methyl-p-tyrosine-induced depletion of cerebral NA or the cortical MOPEG concentration are not altered Figure 5 Eect of acute morphine challenge dose (10 mg kg 71 s.c., 1 h before decapitation) on striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) concentrations in mice withdrawn for 3 days from 5 day repeated morphine treatment and pretreated with idazoxan (1 mg kg 71 i.p., 30 min before morphine challenge). The columns give the mean+s.e.mean of DA, DOPAC, HVA and 3-MT concentrations (mg g 71 ) and represent the following treatments: (A) repeated saline+acute saline+acute saline (n=25 ± 26); (B) repeated saline+acute saline+acute morphine (n=28 ± 29); (C) repeated saline+acute idazoxan+acute saline (n=6); (D) repeated saline+ acute idazoxan+acute morphine (n=12); (E) repeated morphine+ acute saline+acute saline (n=25 ± 27); (F) repeated morphine+acute saline+acute morphine (n=27 ± 28); (G) repeated morphine+acute idazoxan+acute saline (n=6); (H) repeated morphine+acute idazoxan+acute morphine (n=12).…”