Trends in Pharmacological Sciences
ReviewNovel approaches to targeting neuropeptide systems
Section snippets
Membrane-bound zinc metallopeptidases and the interruption of neuropeptide effects
Peptide messengers are secreted, in active or inactive forms, by specialized cells via a Ca2+-dependent mechanism (Fig. 1). Most frequently, the peptide is released in its active form, which, in general, stimulates receptors located nearby in the CNS [e.g. two opioid peptides Met- and Leu-enkephalin both interact with G-protein-coupled mu and delta opioid receptors close to the site of peptide release3 (Fig. 1a) and the sulfated fragment of cholecystokinin, CCK-8, binds to CCK1 and CCK2
Peptidase-dependent diversification of physiological responses
Among the neuropeptides, CCK-8 was shown to be efficiently cleaved in vivo by APA (Ref. 22), leading to formation of CCK-7, and by the ubiquitously distributed tripeptidyl peptidase II (TPPII, EC 3.4.14.10), which is mainly enriched in the cytosol but is also present as an internal and/or external component of the cell membrane23 (Fig. 1). In contrast to various neuropeptides, including enkephalins, the degradation of CCK-8 by rat brain membranes is much slower, which suggests that peptidases
Dual inhibitors of NEP and aminopeptidase N
Compounds that elicit analgesic responses that are intermediate between NSAIDs and opioid analgesics are needed for efficient treatment of post-operative pain, severe osteoarticular pain, neuropathic pain, chronic inflammatory pain, and pain in children and the elderly.
Owing to the complementary roles of NEP and aminopeptidase N (APN, EC 3.4.11.2) in enkephalin inactivation, selective inhibition of only one of these peptidases provides a non-significant or weak antinociceptive effect (Fig. 3a),
Delta opioid receptors as possible targets for antidepressants
It has been known for a long time that opium and morphine possess euphorogenic and disinhibitory properties that are sometimes still used in psychiatry. Accordingly, enkephalins protected from their metabolizing enzymes have been shown to be active in all tests used to screen antidepressant drugs (e.g. forced swim, conditioned suppression of motility and learned helplessness). The effects of dual inhibitors such as RB101 or selective delta opioid receptor agonists were reversed by naltrindole
Mechanisms of opioid-induced physical and psychic dependence
Numerous studies have suggested that drug abuse could be a result of pre-existent or induced modifications of the endogenous opioid system. Accordingly, in animals and humans, opioid receptor antagonists were shown to reduce the craving of various drugs such as cocaine, ethanol and THC (Refs 12., 49., 50.). The use of dual NEP–APN inhibitors to either potentiate the various effects of enkephalins and their eventual association with agonists or antagonists of counteracting systems [e.g. CCK-8 (
Indirect modulation of rewarding effects of opiates by endogenous cannabinoids and substance P
The existence of dopamine-independent drug-craving mechanisms have also been postulated and recently reviewed55. Thus, deletion of genes encoding either the cannabinoid CB1 receptor56., 57. or the NK1 receptor58., 59. were recently shown to produce a large decrease or a complete lack of morphine-induced psychic dependence, measured by using self-administration and place-preference paradigms, respectively. Interestingly, mice with deletion of NK1 receptors showed a reduced agressivity towards an
Physiological antagonism between two neuropeptide systems (enkephalins and CCK)
Opponent processes have been proposed to play a crucial role in behavioural homeostasis60. Enkephalins and CCK-8 were shown to coexist within numerous brain regions and CCK and opioid receptors are colocalized in neurones of some structures61. The combined use of a dual NEP–APN inhibitor with a CCK2 receptor antagonist (Fig. 4) allowed the mechanism of this opponent process to be investigated.
Thus, the analgesic effects of RB101 in rodents is potentiated (two–eightfold) by co-administration of
Defects in endogenous opioids–CCK balance: anxiety and depressive syndrome
Another benefit of the opioid–CCK system might be gained in the field of depression. Some studies have reported that patients with severe depression have an increase in the concentration of CCK in the cerebrospinal fluid67. Chronic and unpredictable mild stress (CMS) leads to a reduction in the motility of mice and provides an animal model of anhedonia, which is often used to evaluate antidepressants. This test has been used to measure, by microdialysis in the nucleus accumbens, the
Concluding remarks
The need for potent and selective inhibitors of enzymes that metabolize neuropeptides is necessary to establish the exact physiological role of a given peptide in a given tissue. This approach is complementary to that which deletes the various targets for a peptide messenger. Pharmacological experiments achieved by using these two approaches is expected to direct the choice of a therapeutic route (stimulation or blockade of specific receptors). Indeed, modulation of the concentrations of
Acknowledgements
I gratefully acknowledge C. Dupuis for expert manuscript drafting. This work was supported by institutional grant from the European Community (BMH4 CT98 2267).
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