Previous research has shown an increase in hypothalamo-pituitary-adrenal axis activity following naloxone administration to morphine-dependent rats. In the present study, we investigated the adaptive changes in the noradrenaline (NA) and dopamine (DA) systems in the hypothalamic paraventricular nucleus (PVN) during morphine dependence and withdrawal. Additionally, we examined the possible change in 3′,5′-cyclic adenosine monophosphate (cAMP) levels in that nucleus under the same conditions. Rats were made dependent on morphine by morphine or placebo (naïve) pellet implantation for 7 days. On day 8, rat groups received an acute injection of saline or naloxone (1 mg/kg subcutaneously) and were decapitated 30 min later. NA and DA content as well as their metabolite production in the PVN were estimated by HPLC/ED. Both plasma corticosterone levels and cAMP concentration in the PVN were measured by RIA. Naloxone administration to morphine-dependent rats (withdrawal) induced a pronounced increase in the production of both the NA metabolite MHPG and the DA metabolite DOPAC and an enhanced NA and DA turnover. Furthermore, an increase in corticosterone secretion was observed in parallel to the changes in catecholamine turnover. However, no alterations in cAMP levels were seen during morphine withdrawal. These results raise the possibility that catecholaminergic afferents to the PVN could play a significant role in the alterations of PVN functions and consequently in the pituitary-adrenal response during morphine abstinence syndrome. These data provide further support for the idea of adaptive changes in catecholaminergic neurons projecting to the PVN during chronic morphine exposure.

In order to visualize neuroanatomical alterations in specific brain regions, light microscopy autoradiography was carried out on offsprings (postnatal day 10) from female rats stressed in different periods of gestation and controls. Group 1 was subjected to restraint stress from day 2 to 6; group 2, from day 7 to 11; group 3, from day 12 to 16; group 4 from day 2 to 16. Group 2 showed decreases in δ-opioid receptor density in different hypothalamic regions. The decrease in δ-opioid receptor density was less marked in groups 1 and 3 whereas there was no modification in group 4. Present data suggest that the prenatal stress induces a downregulation of δ-receptors in different hypothalamic regions.

Morphine is thoroughly used for pain control; however, it has a high addictive potential. Opioid liposome formulations produce controlled drug release and have been thoroughly tested for pain treatment although their role in addiction is still unknown. This study investigated the effects of free morphine and morphine encapsulated in unilamellar and multilamellar liposomes on antinociception and on the expression and extinction of the positive and negative memories associated with environmental cues. The hot plate test was used to measure central pain. The rewarding effects of morphine were analyzed by the conditioned-place preference (CPP) test, and the aversive aspects of naloxone-precipitated morphine withdrawal were evaluated by the conditioned-place aversion (CPA) paradigm. Our results show that encapsulated morphine yields prolonged antinociceptive effects compared with the free form, and that CPP and CPA expression were similar in the free- or encapsulated-morphine groups. However, we demonstrate, for the first time, that morphine encapsulation reduces the duration of reward and aversive memories, suggesting that this technological process could transform morphine into a potentially less addictive drug. Morphine encapsulation in liposomes could represent a pharmacological approach for enhancing extinction, which might lead to effective clinical treatments in drug addiction with fewer side effects.

The aim of the present study was to examine whether changes in temperature alter the effects of morphine on isolated right atria. Morphine dose-response curves at different temperatures (30, 37 or 40 °C) from right atria of the rat were obtained. The maximal negative chronotropic effect induced by morphine was 11 ± 3% at 37 °C and 20 ± 1 % at 30 °C. However, when the temperature was increased to 40 °C, morphine induced a positive chronotropic effect. The increase in auricular automaticity induced by morphine at 40 °C was antagonized in the presence of naloxone (5 × 10^–6 mol/l). These data demonstrated that: (1) hyperthermia modifies the effects of morphine on isolated right atria and (2) at 40 °C morphine induces a positive chronotropic effect by activation of opioid receptors.