Tolerance to the reinforcing effects of morphine in delta9-tetrahydrocannabinol treated mice.

Several studies have investigated interactions between opioid and cannabinoid systems. However, the results regarding the rewarding effects of opiates in animals pre-exposed to CB1 agonists, appear inconsistent. Using the conditioned place preference, it was shown that dependence to delta9-tetrahydrocannabinol (THC) was hardly reached, while the synthetic ligand WIN55,212-2 facilitate the rewarding effects of morphine. The aim of the present study was to establish whether a chronic THC treatment (10 mg/kg, i.p., 21 days) may facilitate, in mice, the rewarding effects of morphine used at low doses (0.5 and 2 mg/kg, i.p.) or high dose (10 mg/kg, i.p.) after a long drug-free period, as it was speculated that chronic cannabinoid exposure may induce long-lasting neural changes in brain regions involved in opiate addiction. Moreover, THC was used in conditions as close as possible to those leading to cannabis drawbacks. After 15 days of abstinence, the locomotor activating properties of morphine as well as its motivational properties were not facilitated by pretreatment with THC in mice and even reduced for the higher dose of morphine used in the conditioned place preference (CPP). This lack of CPP in animals pretreated with THC was not due to discrimination impairment between different environments, as demonstrated in a two-trial recognition task. In conclusion, it appears that chronic THC treatment leads to a reduction of reinforcing effects of morphine in the CPP. This result supports the occurrence of modulatory interaction between opioid and cannabinoid systems in the reward process.

CB1 receptor knockout mice show similar behavioral modifications to wild-type mice when enkephalin catabolism is inhibited.

Behavioral and biochemical studies have suggested a functional link between the endogenous cannabinoid and opioid systems. Different hypotheses have been proposed to explain the interactions between opioid and cannabinoid systems such as a common pathway stimulating the dopaminergic system, a facilitation of signal-transduction- and/or a cannabinoid-induced enhancement of opioid peptide release. However, at this time, all the studies have been performed with exogenous agonists (delta-9-tetrahydrocannabinol or morphine), leading to a generally excessive stimulation of receptors normally stimulated by endogenous effectors (anandamide or opioid peptides) in various brain structures. To overcome this problem, we have measured various behavioral responses induced by the stimulation of the endogenous opioid system using the dual inhibitor of enkephalin-degrading enzymes, RB101, in CB1 receptor knockout mice. Thus, analgesia, locomotor activity, anxiety and antidepressant-like effects were measured after RB101 administration (80 and 120 mg/kg i.p. or 10 mg/kg, i.v.) in CB1 receptor knockout mice and their wild-type littermates. In all the experiments, inhibition of enkephalin catabolism produced similar modifications in behavior observed in CB1 knockout and wild-type mice. These results suggest limited physiological interaction between cannabinoid and opioid systems.

Ontogenic and adult whole body distribution of aminopeptidase N in rat investigated by in vitro autoradiography.

Aminopeptidase N (APN), which is widely distributed in mammalian tissues, is able to cleave numerous regulatory peptides. The selective inhibitor of APN, [(125)I] RB129, has been used to study the distribution of this exopeptidase during rat prenatal development and adult life by in vitro whole-body autoradiography. In the central nervous system, APN shows a weak labeling compared to the major part of the non-nervous tissues in the embryo and in the adult. APN is progressively expressed in kidney, intestine, heart, lung, sensory organs, eye, and thymus. In organs such as the liver, the cartilages and the bones, altered levels of APN expression are observed during the development, or in the embryo compared to the adult, suggesting a role of APN during the liver haematopoiesis and bone growth. At this time, all the physiological functions of APN are still incompletely known, however its developmental pattern of expression strongly suggests a function of modulation of this enzyme during the development, next in physiological and/or pathological situations in adult. In this way, APN could represent a new therapeutic target in pathological processes, such as tumoral proliferation and/or angiogenesis associated with cancer development, where an increase in the level of this enzyme has been observed.