[Show abstract][Hide abstract] ABSTRACT: La comorbidité entre pathologies anxiodépressives et douleurs est à l’origine de nombreuses difficultés que rencontrent les cliniciens qui restent souvent démunis pour proposer une thérapeutique efficace. Afin d’identifier les mécanismes unissant ces pathologies, la modélisation chez l’animal est incontournable. Les protocoles de défaite sociale qui induisent des symptômes de type « anxiodépressif » sont parfaitement adaptés pour identifier la complexité de cette relation chez l’animal.
Douleur et Analgésie 03/2012; 25(1). DOI:10.1007/s11724-012-0279-7 · 0.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Using the microdialysis technique, the present study investigated the effects of a noxious stimulation on the extracellular levels of met-enkephalin and (sulfated octapeptide) cholecystokinin-like materials in the nucleus accumbens of freely moving rats. Injection of 50 microl of 5% formalin into the forepaw produced pain-related behaviours associated with an immediate and sustained (for approximately 2 h) increase (+27%) in the outflow of met-enkephalin-like material within the nucleus accumbens. This treatment also progressively enhanced the local outflow of cholecystokinin-like material that reached 200%-250% of the basal level at the end of the experiment, i.e. 4.5 h after formalin administration. Because naloxone (1.5 mg/kg i.p., 10 min prior to formalin injection) prevented the latter effect, it can be inferred that noxious stimulation-induced activation of cholecystokininergic neurotransmission in the nucleus accumbens probably resulted from the preceding activation of opioidergic systems. These data suggest that the nucleus accumbens may be another structure where interactions between opioids and cholecystokinin play a key role in the control of pain-processing mechanisms.
Archiv für Experimentelle Pathologie und Pharmakologie 05/2001; 363(4):399-406. DOI:10.1007/s002100000377 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The involvement of cholecystokinin (CCK) in the mechanisms of stress and/or anxiety was assessed by in vivo microdialysis in rats subjected to a social stress paradigm. During the initial 30 min period of each conditioning session, a male Sprague Dawley rat (intruder) was placed in a protective cage inside the cage of a male Tryon Maze Dull rat (resident), allowing unrestricted visual, olfactory, and auditory contacts but precluding close physical contact between them. During the following 15 min period, both the protective cage and the resident were removed (nondefeated intruders) or only the protective cage was removed allowing the resident to attack the intruder (defeated rats). This procedure was repeated once daily for 4 d. On the fifth day, a guide cannula was implanted into the prefrontal cortex of intruders. During a single 30 min test session, performed 4 d later, intruders were subjected to only the 30 min protected confrontation to the resident. Anxiety-like behavior (immobility, ultrasonic vocalizations, and defensive postures), associated with an increase (approximately +100% above baseline) in cortical outflow of CCK-like material (CCKLM), were observed in defeated intruders. Pretreatment with diazepam (5 mg/kg, i.p.), but not buspirone (0.5-2 mg/kg, i.p.), prevented both the anxiety-related behavior and CCKLM overflow. The selective CCK-B receptor antagonist CI-988 (2 mg/kg, i.p.) reduced the anxiety-like behavior without affecting the increase in CCKLM outflow. These data indicate that anticipation of social defeat induces a marked activation of cortical CCKergic neurons associated with anxiety-related behaviors in rats.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2001; 21(1):262-9. · 6.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Numerous pharmacological data have been accumulated in support of the existence of physiological interactions between cholecystokinin (CCK) and opioids in the central nervous system. With the aim of further characterizing these interactions, an in vivo microdialysis approach was used to directly assess the possible influence of opioids on the extracellular levels of CCK-like material (CCKLM) in the frontal cortex of the awake, freely moving rat. Systemic administration of a high dose of morphine (10 mg/kg i.p.) produced a marked increase (up to +200%) of cortical CCKLM outflow, and this effect could be completely prevented by systemic (1.5 mg/kg i.p.) as well as intracortical (10 microM) administration of the opioid receptor antagonist naloxone. The opioid receptors activated by morphine appeared to be of the delta type because the intracortical infusion of naltrindole (10 microM) also prevented the effect of morphine, whereas CTOP (10 microM), a selective mu-opioid receptor antagonist, and nor-binaltorphimine (10 microM), a selective kappa-opioid receptor antagonist, were inactive. In addition, naltriben (10 microM), which acts selectively at the delta(2) subtype, also abolished the stimulatory effect of morphine on cortical CCKLM outflow, whereas 7-benzylidenenaltrexone (10 microM), a selective delta(1)-opioid receptor antagonist (10 microM), did not alter the morphine effect. Conversely, the direct stimulation of cortical delta(2)-opioid receptors by local infusion of [D-Ala(2)] deltorphin II mimicked the stimulatory effect of systemic morphine on CCKLM outflow. These data indicate that delta(2)-opioid receptors play a key role in opioid-CCK interactions in the rat frontal cortex.
[Show abstract][Hide abstract] ABSTRACT: In line with the idea that cholecystokinin (CCK) is involved in anxiety-related behaviours, previous investigations showed that stressful conditions and an 'anxiogenic' drug, yohimbine, increased the cortical release of CCK like-material (CCKLM) in awake rats, and that this effect could be prevented by diazepam. Here, we investigated whether other anxiolytic drugs such as 5-HT1A receptor agonists could also affect cortical CCKLM release. Indeed, neither buspirone (1 mg/kg i.p.), alnespirone (1 mg/kg i.p.) nor lesopitron (3 mg/kg i.p.) affected, on their own, CCKLM release. However, pretreatment with the latter drugs completely abolished the stimulatory effect of restraint stress on the peptide outflow. As expected of the involvement of 5-HT1A receptors, tertatolol (10 mg/kg i.p) markedly reduced the inhibitory effect of buspirone on restraint stress-evoked CCKLM overflow. On the other hand, pretreatment with buspirone, alnespirone or lesopitron also inhibited the stimulatory effect of yohimbine (5 mg/kg i.p.) on cortical CCKLM outflow. These data support the idea that the anxiolytic action of 5-HT1A receptor agonists could be mediated, at least partly, through their inhibitory influence on cortical CCK-ergic systems.
[Show abstract][Hide abstract] ABSTRACT: Because cholecystokinin (CCK) acts as a "functional" endogenous opioid antagonist, it has been proposed that changes in central CCKergic neurotransmission might account for the relative resistance of neuropathic pain to the analgesic action of morphine. This hypothesis was addressed by measuring CCK-related parameters 2 weeks after unilateral sciatic nerve section in rats. As expected, significant decreases (-25-38%) in the tissue concentrations and in vitro release of both substance P and calcitonin gene-related peptide were noted in the dorsal quadrant of the lumbar spinal cord on the lesioned side. In contrast, the tissue levels and in vitro release of CCK were unchanged in the same area in lesioned rats. Measurements in dorsal root ganglia at L4-L6 levels revealed no significant changes in proCCK mRNA after the lesion. However, sciatic nerve section was associated with a marked ipsilateral increase in both CCK-B receptor mRNA levels in these ganglia (+70%) and the autoradiographic labeling of CCK-B receptors by [3H]pBC 264 (+160%) in the superficial layers of the lumbar dorsal horn. Up-regulation of CCK-B receptors rather than CCK synthesis and release probably contributes to increased spinal CCKergic neurotransmission in neuropathic pain.
Journal of Neurochemistry 03/1999; 72(2):858-67. · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract : Because cholecystokinin (CCK) acts as a “functional” endogenous opioid antagonist, it has been proposed that changes in central CCKergic neurotransmission might account for the relative resistance of neuropathic pain to the analgesic action of morphine. This hypothesis was addressed by measuring CCK-related parameters 2 weeks after unilateral sciatic nerve section in rats. As expected, significant decreases (-25-38%) in the tissue concentrations and in vitro release of both substance P and calcitonin gene-related peptide were noted in the dorsal quadrant of the lumbar spinal cord on the lesioned side. In contrast, the tissue levels and in vitro release of CCK were unchanged in the same area in lesioned rats. Measurements in dorsal root ganglia at L4-L6 levels revealed no significant changes in proCCK mRNA after the lesion. However, sciatic nerve section was associated with a marked ipsilateral increase in both CCK-B receptor mRNA levels in these ganglia (+70%) and the autoradiographic labeling of CCK-B receptors by [3H]pBC 264 (+160%) in the superficial layers of the lumbar dorsal horn. Up-regulation of CCK-B receptors rather than CCK synthesis and release probably contributes to increased spinal CCKergic neurotransmission in neuropathic pain.
[Show abstract][Hide abstract] ABSTRACT: Numerous data suggest that cholecystokinin (CCK) acts as an opioid-modulating peptide. Because pharmacological and behavioural studies have shown that CCK reduces the analgesic effects of opioids, an opioid-mediated activation of CCK-containing neurones has been proposed to be responsible for the development of opioid tolerance. In an attempt to directly assess this hypothesis, we have examined, in naive or morphine-tolerant/dependent rats, the possible influence of opioid-receptor ligands on--1 the release of CCK from spinal cord slices and--2 the extracellular levels of CCK in the frontal cortex in awake, freely moving animals. Whereas the stimulation of mu or delta 1 receptors inhibited the release of the peptide, the stimulation of delta 2 receptors increased CCK release. Morphine also increased CCK release, via an action at delta 2 receptors. The blockade of delta 1 receptors resulted in an enhancement of the peptide release, suggesting that endogenous opioids probably exert inhibitory tonic influence on CCK release through the stimulation of delta 1 receptors. In rats rendered tolerant/dependent, the inhibitory effects of opioids on CCK release, due to the stimulation of mu or delta 1 receptors, and the enhancing effect of delta 1 receptor blockade, were no longer present. In contrast, the delta 2-mediated increase in CCK release persisted. Thus, in morphine-tolerant/dependent rats, opioids apparently retain only their excitatory effects on CCK-containing neurones. These data support the idea that morphine exerts an excitatory influence on central CCKergic neurones, which could tend to reduce the analgesic action of the alkaloid, and are in line with the hypothesis that morphine tolerance/dependence is associated with an activation of CCK-containing neurones.
Bulletin de l'Académie nationale de médecine 02/1998; 182(2):311-24. · 0.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Complex and contradictory data have been reported regarding the changes in spinal opioidergic systems associated with chronic inflammatory pain in the rat. In an attempt to solve these discrepancies, the in vivo release of met-enkephalin and dynorphin and the expression of the corresponding propeptide genes were investigated at the spinal level in arthritic rats and paired controls. A dramatic increase in the concentration of prodynorphin mRNA (+300-550%) and a less pronounced elevation of that of dynorphin-like material (+40-50%) were found in the dorsal part of cervical and lumbar segments of the spinal cord in rats rendered arthritic by an intradermal injection of Freund's adjuvant four weeks prior to these measurements. In addition, the spinal release of dynorphin-like material (assessed through an intrathecal perfusion procedure in halothane-anaesthetized animals) was approximately twice as high in arthritic rats as in controls. In spite of significant elevations in the levels of both met-enkephalin (+30-70%) and proenkephalin A mRNA (+40-50%) in the dorsal part of cervical and lumbar segments, the spinal release of met-enkephalin-like material was decreased (-50%) in arthritic rats as compared to paired controls. Proenkephalin A mRNA (but not prodynorphin mRNA) could be measured in dorsal root ganglia, and its levels were dramatically reduced in ganglia at the lumbar segments in arthritic rats. Such parallel reductions in the spinal release of met-enkephalin-like material and the levels of proenkephalin A mRNA in dorsal root ganglia of arthritic rats support the idea that the activity of primary afferent enkephalinergic fibres decreases markedly during chronic inflammatory pain.
Brain Research 03/1997; 749(1):18-28. DOI:10.1016/S0006-8993(96)01161-4 · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The in vivo release of cholecystokinin (CCK)-like material (CCKLM) was measured in the frontal cortex of freely moving rats using the microdialysis technique combined with a sensitive radioimmunoassay. Local perfusion of K+ (100 mM)-enriched artificial CSF resulted in a 10-fold increase in CCKLM outflow, as compared with that occurring under basal resting (K+ = 3.0 mM) conditions, and this effect could be completely prevented by removal of Ca2+ in the perfusing fluid. Chromatographic analyses demonstrated that CCK-8S contributed to 70% of CCKLM. Stressful stimuli such as a 2-min exposure to diethyl ether and a 30-min restraint produced a marked but transient increase in cortical CCKLM release. In addition, anxiety-like behavior induced by the systemic administration of yohimbine (5 mg/kg i.p.) was associated with a long-lasting enhancement in the peptide outflow. Pretreatment with the potent anxiolytic drug diazepam (5 mg/kg i.p., 5 min before each condition), which exerted no effect on its own, completely prevented CCKLM overflow due to diethyl ether, restraint, or yohimbine administration. In contrast, neither the systemic injection (0.1 mg/kg i.p.) nor the local application (100 microM through the microdialysis probe) of the serotonin 5-HT3 antagonist ondansetron affected the increased release of CCKLM in rats restrained for 30 min or treated with yohimbine. These results indicate that cortical CCKergic neurotransmission is increased during stress or anxiety-like behavior in rats. Prevention of this effect by diazepam suggests that an inhibitory influence of benzodiazepines on cortical CCKergic neurons might participate in the anxiolytic action of these drugs.
Journal of Neurochemistry 06/1996; 66(5):2041-9. DOI:10.1046/j.1471-4159.1996.66052041.x · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The K+-evoked release of cholecystokinin (CCK)-like material (CCKLM) from spinal cord slices of naive or placebo-treated rats was found to be under complex opioid control (inhibited by the activation of μ or one subtype of ∂ receptors, and enhanced by the activation of another ∂ receptor subtype), while the release from morphine-tolerant rats was only under the stimulatory influence of a ∂-dependent mechanism. Morphine itself exerted a biphasic effect (inhibitory at low concentrations through the activation of μ receptors, and stimulatory at a high concentration, 10 μM, through the activation of ∂ receptors) on spinal CCKLM release in control (naive or placebo-treated) rats, and only a stimulatory effect (at 10 μM) in morphine-tolerant rats. These data indicate that in morphine-tolerant rats opioids retain only their excitatory influence on spinal CCK-containing neurons, in line with the hypothesis that CCK release may be enhanced by chronic morphine treatment.
[Show abstract][Hide abstract] ABSTRACT: The expression of the preproenkephalin A gene was investigated in adult rat dorsal root ganglia (DRG). A radioimmunoassayable Met-enkephalin (ME)-like material was detected in 0.1 M HCl extracts of rat DRG, representing approximately 60 pg of ME equivalents/mg of protein. Chromatographic analyses indicated that the major component of the ME-like material coeluted with authentic ME. In northern blot experiments on total RNA extracted from DRG, a cDNA probe corresponding to the entire coding region of rat preproenkephalin A mRNA yielded a single band of the expected size for this mRNA, i.e., 1.5 kb. Polymerase chain reaction (PCR) experiments were carried out with DRG, striatum, and liver cDNAs using two primers flanking the 1,371-1,771 base region of the preproenkephalin A gene. Thirty PCR cycles performed on both striatum and DRG cDNAs generated a single band of 400 bp, as expected, whereas only trace amounts of this product were detectable using liver cDNAs. Nucleotide sequencing of the PCR product obtained with DRG cDNAs revealed a 100% homology with the 1,371-1,771 sequence of the preproenkephalin A gene. In situ hybridization with a cRNA probe showed that about 3.5% of DRG cells expressed the preproenkephalin A transcript. However, most of these cells probably did not process proenkephalin to enkephalins, as thorough immunohistochemical investigations with anti-ME antibodies allowed the detection of only one in approximately 6,000 cells (in 30 sections of DRG) that exhibited ME-like immunoreactivity. Cells expressing preproenkephalin A mRNA were intermediate-sized neurons, suggesting that primary afferent ME-containing fibers belong to the A category and may participate in a local (spinal) inhibitory control of nociception.
Journal of Neurochemistry 11/1994; 63(4):1226-34. DOI:10.1046/j.1471-4159.1994.63041226.x · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The possible modulations by morphine and various opioids of the spinal release of cholecystokinin-like material (CCKLM) evoked by 30 mM K+ was studied in vitro, using slices of the dorsal part of the rat lumbar enlargement superfused with an artificial cerebrospinal fluid. Addition of the mu agonist, DAGO (0.1-10 microM), to the perfusing fluid produced a concentration-dependent decrease in the peptide release, which could be prevented by the preferential mu antagonist, naloxone. Complex modulations were induced by the delta agonist, DTLET, as this drug inhibited CCKLM release when added at 10 nM-3 microM to the perfusing fluid, but enhanced it at 10 microM. Both effects were preventable by the delta antagonists naltrindole and ICI 154129, suggesting that delta receptors, possibly of different subtypes, mediated the inhibition and stimulation by DTLET. Morphine also exerted a biphasic effect, as the alkaloid decreased CCKLM release at 0.01-0.1 microM and enhanced it at 10 microM. Morphine-induced inhibition was preventable by naloxone, whereas its stimulatory effect could be blocked by naltrindole and ICI 154129. Although inactive on its own on CCKLM release, the selective kappa 1 agonist U 50488H (1 microM) prevented the inhibitory effects of both DAGO (10 microM) and morphine (0.1 microM), suggesting the existence of interactions between kappa 1 and mu receptors within the dorsal zone of the rat spinal cord. These data indicate that low concentrations of morphine exert an inhibitory influence on spinal CCKergic neurons that depends on the stimulation of mu opioid receptors. The excitatory influence of 10 microM morphine likely results from the simultaneous stimulation of mu, delta and kappa receptors, as the inhibitory effect of mu receptor stimulation can be masked by that of kappa 1 receptors, allowing only the expression of a delta-dependent excitatory effect similar to that induced by 10 microM DTLET.
Brain Research 09/1994; 653(1-2):81-91. DOI:10.1016/0006-8993(94)90375-1 · 2.83 Impact Factor