Receptors involved in dexketoprofen analgesia in murine visceral pain.

Various animal models, especially rodents, are used to study pain, due to the difficulty of studying it in humans. Many drugs that produce analgesia have been studied and there is evidence among which NSAIDs deserve to be highlighted. Dexketoprofen (DEX) provides a broad antinociceptive profile in different types of pain; therefore, this study was designed to evaluate the profile of antinociceptive potency in mice. Analgesic activity was evaluated using the acetic acid abdominal constriction test (writhing test), a chemical model of visceral pain. Dose-response curves for i.p. DEX administration (1, 3, 10, 30 and 100 mg/kg), using at least six mice in each of at least five doses, was obtained before and 30 min after pre-treatment with different pharmacological agents. Pretreatment of the mice with opioid receptor antagonists was not effective; however, the serotonin receptor antagonist and nitric oxide synthase inhibitor produce a significant increase in DEX-induced antinociception. The data from the present study shows that DEX produces antinociception in the chemical twisting test of mice, which is explained with difficulty by the simple inhibition of COX. This effect appears to be mediated by other mechanisms in which the contribution of the NO and 5-HT pathways has an important effect on DEXinduced antinociception.

G protein ßγ subunits play a critical role in the actions of amphetamine.

Abnormal levels of dopamine (DA) are thought to contribute to several neurological and psychiatric disorders including drug addiction. Extracellular DA levels are regulated primarily via reuptake by the DA transporter (DAT). Amphetamine, a potent psychostimulant, increases extracellular DA by inducing efflux through DAT. Recently, we discovered that G protein ßγ subunits (Gßγ) interact with DAT, and that in vitro activation of Gßγ promotes DAT-mediated efflux. Here, we investigated the role of Gßγ in the actions of amphetamine in DA neurons in culture, ex vivo nucleus accumbens (NAc), and freely moving rats. Activation of Gßγ with the peptide myr-Ser-Ile-Arg-Lys-Ala-Leu-Asn-Ile-Leu-Gly-Tyr-Pro-Asp-Tyr-Asp (mSIRK) in the NAc potentiated amphetamine-induced hyperlocomotion, but not cocaine-induced hyperlocomotion, and systemic or intra-accumbal administration of the Gßγ inhibitor gallein attenuated amphetamine-induced, but not cocaine-induced hyperlocomotion. Infusion into the NAc of a TAT-fused peptide that targets the Gßγ-binding site on DAT (TAT-DATct1) also attenuated amphetamine-induced but not cocaine-induced hyperlocomotion. In DA neurons in culture, inhibition of Gßγ with gallein or blockade of the Gßγ-DAT interaction with the TAT-DATct1 peptide decreased amphetamine-induced DA efflux. Furthermore, activation of Gßγ with mSIRK potentiated and inhibition of Gßγ with gallein reduced amphetamine-induced increases of extracellular DA in the NAc in vitro and in freely moving rats. Finally, systemic or intra-accumbal inhibition of Gßγ with gallein blocked the development of amphetamine-induced, but not cocaine-induced place preference. Collectively, these results suggest that interaction between Gßγ and DAT plays a critical role in the actions of amphetamine and presents a novel target for modulating the actions of amphetamine in vivo.

Neonatal exposure to oestradiol increases dopaminergic transmission in nucleus accumbens and morphine-induced conditioned place preference in adult female rats.

Steroid sex hormones produce physiological effects in reproductive tissues and also in nonreproductive tissues, such as the brain, particularly in cortical, limbic and midbrain areas. Dopamine (DA) neurones involved in processes such as prolactin secretion (tuberoinfundibular system), motor circuit regulation (nigrostriatal system) and driving of motivated behaviour (mesocorticolimbic system) are specially regulated by sex hormones. Indeed, sex hormones promote neurochemical and behavioural effects induced by drugs of abuse by tuning midbrain DA neurones in adult animals. However, the long-term effects induced by neonatal exposure to sex hormones on dopaminergic neurotransmission have not been fully studied. The present study aimed to determine whether a single neonatal exposure with oestradiol valerate (EV) results in a programming of dopaminergic neurotransmission in the nucleus accumbens (NAcc) of adult female rats. To answer this question, electrophysiological, neurochemical, cellular, molecular and behavioural techniques were used. The data show that frequency but not amplitude of the spontaneous excitatory postsynaptic current is significantly increased in NAcc medium spiny neurones of EV-treated rats. In addition, DA content and release are both increased in the NAcc of EV-treated rats, caused by an increased synthesis of this neurotransmitter. These results are functionally associated with a higher percentage of EV-treated rats conditioned to morphine, a drug of abuse, compared to controls. In conclusion, neonatal programming with oestradiol increases NAcc dopaminergic neurotransmission in adulthood, which may be associated with increased reinforcing effects of drugs of abuse.

Amphetamine treatment affects the extra-hypothalamic vasopressinergic system in a sex- and nucleus-dependent manner.

The lateral septum (LS), a brain structure implicated in addictive behaviours, regulates the activation of dopaminergic neurones in the ventral tegmental area. Vasopressinergic projections from the extended amygdala to the LS, which are sexually dimorphic, could be responsible for the vulnerability to addiction in a sex-dependent manner. The present study aimed to investigate the modulatory effects of amphetamine (AMPH) on the expression of vasopressin (AVP) in the vasopressinergic extra-hypothalamic system in sensitised male and female rats. Adult male and female Sprague-Dawley rats underwent an AMPH-locomotor sensitisation protocol. Acute AMPH increased AVP mRNA expression in the medial amygdala (MeA), whereas AMPH-induced sensitisation increased AVP mRNA expression in the bed nucleus of the stria terminalis (BNST) only in females. Interestingly, the increase in AVP expression in BNST was higher in oestrus females compared to dioestrus females and acute AMPH resulted in a decrease in AVP levels in the LS, only in males. Thus, there are complex and region-specific interactions between AMPH and the extra-hypothalamic vasopressinergic system in the brain, underlying possible alterations in different behaviours caused by acute and chronic AMPH exposure.

Neonatal exposure to estradiol valerate increases dopamine content in nigrostriatal pathway during adulthood in the rat.

Research in programming has focused in the study of stimuli that affect sensitive periods of development such as prenatal and neonatal stage. We previously showed that exposure to estradiol valerate to female rats during the first 12 h of life increased catecholamine content in ventromedial-arcuatus hypothalamus of the adult rat. However, changes in others dopaminergic circuits have not been studied. The purpose of this work was to determine the neurotransmitters changes induced by neonatal estradiol valerate (0.1 mg/50 µl s. c. per rat) administration on nigrostriatal pathway of adult female rats. Sesame oil (50 µl s. c. per rat) was administered in a control parallel group. EV-1 adult rats presented effective markers of long-term estrogenization as decreased serum levels of progesterone and a reduction in the size of estrogen-sensitive organs. In the brain, neonatal estradiol valerate administration led to a significant increase in dopamine content in striatum, substantia nigra and ventral tegmental area. With respect to the contents of dopamine metabolites, only 3-methoxytyramine content increased in substantia nigra and ventral tegmental area. In addition, the content of noradrenaline increased only in striatum. Interestingly, estrogenized rats lacked locomotor activity induced by acute dose of amphetamine (1 mg/kg i. p.). Altogether, these results show that neonatal exposure to estradiol valerate permanently modified the content of monoamine neurotransmitters in nigrostriatal pathway and amphetamine-induced locomotor activity of adult female rats. This might imply that estrogenized rats could have changes in the expression of key proteins in dopaminergic regulation, as tyrosine hydroxylase and dopamine transporter.