Withdrawal from chronic morphine induces marked upregulation of V1a vasopressin receptor binding in the mouse brain

Alexis Bailey, Majed Alshehri, Tatyana Sahabandu, Ian Kitchen. University of Surrey, Guildford, United Kingdom.

New evidence shows that the vasopressin system plays an important role in opiate and cocaine addiction (Koob 2008). To determine whether chronic morphine or acute or chronic withdrawal from morphine alters vasopressin receptor density, we carried out quantitative autoradiographic mapping of the vasopressin receptors labelled with [3H]AVP (2.5 nM) in brains of mice treated with chronic morphine and of mice acutely and chronically withdrawn from morphine. In order to discriminate between the two subtypes of vasopressin receptors (V1a, V1b), we displaced [3H]AVP (2.5 nM) binding with the selective V1b vasopressin receptor antagonist SSR149,514 (30nM). Male C57BL/6J mice (20-25gr) were injected with saline or morphine i.p. twice a day at 8h interval (2 x 20mg/kg/day on days 1 and 2, 2 x 40 mg/kg/day on days 3 and 4, 2 x 80 mg/kg/day on days 5 and 6 and 2 x 100 mg/kg/day for days 7 and 8) or cocaine three times a day at 1h intervals (3 x 15 mg/kg for 15 days) or withdrawn from morphine or cocaine for 1 day (acute withdrawal) or 7 or 14 days for morphine and cocaine respectively (chronic withdrawal). A small, across all regions increase in [3H]AVP and SSR149,514 resistant [3H]AVP binding was observed in chronic morphine treated brains, which persisted into 1 day withdrawal (P<0.01, two way ANOVA, n = 5-6). An overall increase in [3H]AVP and SSR149,514 resistant [3H]AVP binding was observed in brains of 7 day withdrawn (7dw) morphine treated mice compared to saline 7dw controls (P<0.001, two way ANOVA, n = 5-6). Significant 2-3 fold increase in SSR149,514 resistant [3H]AVP binding was observed in the prelimbic cortex, the cingulated cortex, the piriform nucleus, the olfactory tubercle and the nucleus accumbens core and shell of morphine 7dw mice compared to controls (P<0.05, LSD post hoc test, n = 5-6). SSR149,514 sensitive [3H]AVP binding sites were near to zero levels suggesting a lack of V1b receptors in the brain. Chronic morphine administration (P<0.01) but not acute or chronic withdrawal from morphine increased blood corticosterone levels in these mice, indicating an activation of the stress axis during chronic opioid administration, which is blunted after acute and long term withdrawal from morphine. These data suggest that chronic opioid treatment, but especially chronic withdrawal from opioids, triggers alterations in the V1a system which might play an important role in the mechanism of opioid craving after opioid abstinence followed by relapse.

Koob, G.F. (2008) A role for brain stress systems in addiction. Neuron, 59, 11-34.