ABSTRACT
BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence.
Subject(s)
Adamantane/analogs & derivatives , Analgesics, Opioid/pharmacology , Dipeptides/pharmacology , Drug Tolerance/physiology , Opioid-Related Disorders/physiopathology , Receptors, Neuropeptide/antagonists & inhibitors , Adamantane/pharmacology , Animals , Behavior, Animal/drug effects , Conditioning, Classical , Fentanyl/pharmacology , Hot Temperature , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Hyperalgesia/physiopathology , Male , Mice , Mice, Inbred C57BL , Morphine/pharmacology , Motor Activity/drug effects , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Opioid-Related Disorders/drug therapy , Pain/drug therapy , Pain/physiopathology , Receptors, Neuropeptide/physiology , Substance Withdrawal Syndrome/drug therapy , Substance Withdrawal Syndrome/physiopathologyABSTRACT
In Morocco, Thymus broussonetii is widely used in folk medicine for the treatment of a variety of diseases including gastroenteric and bronchopulmonary disorders and to relieve dolorous process. The antinociceptive effect of the aqueous, butanolic and ethyl acetate extracts of this species was examined in rats and mice using chemical and thermal models. The results obtained showed that aqueous and butanolic extracts exerted an antinociceptive activity in the two phases of formalin (50-300 mg/kg), tail immersion and writhing tests. Whereas, the ethyl acetate extract reduced the nociceptive response only in the second phase of formalin (100-300 mg/kg) and writhing tests. The aqueous extract, which is the most effective, contains active analgesic principles acting both centrally and peripherally. Furthermore, this antinociceptive effect has been avoided by naloxone at a dose of 1mg/kg in the first phase of formalin and hot plate tests indicating that this extract acts partly through an opioid-mediated mechanism. The present results demonstrated that Thymus broussonetii contains active constituents which possess antinociceptive activity justifying its popular use to relieve some pains.
Subject(s)
Analgesics/pharmacology , Pain Threshold/drug effects , Pain/prevention & control , Thymus Plant , Acetic Acid , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Dose-Response Relationship, Drug , Formaldehyde , Male , Mice , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Pain/chemically induced , Pain Measurement , Plant Bark , Plant Extracts/pharmacology , Plant Leaves , Rats , Rats, Sprague-DawleyABSTRACT
In the present work, we had tried to evaluate the immunotropic and behavioural effects of Thymus broussonetii Boiss. So, we tested the neurostimulant effects of four extracts. This preliminary study allowed to identify both the immunostimulant and the neurotropic antistress effects of the studied extracts. Among the four extracts, only the aqueous and ethyl acetate ones showed an apparent effect on the tested biological activities, whereas the butanolic extract and the essential oil did not show any interesting effect (data not shown). These results showed that the aqueous and ethyl extracts of this endemic species are of interest for two reasons: stimulation of the immunizing system and protection against the stress by a neurotropic activity. Thyme extracts increased in vivo the number of leucocyte categories studied including polynuclears, total lymphocytes, TCD4+, TCD8+ and NK cells. These data suggest that the intraperitoneal administration of Thymus broussonetii extract has a potent direct effect on leucocytes in vivo. The elevation of leucocyte and thrombocyte counts produced by thyme in the peripheral blood was already reported in the literature. These results could be of practical importance in the field of phytotherapy in the treatment of some cases of human immunodeficiency such as cancer, leukaemia and AIDS.
