![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington
Received April 15, 2006; accepted August 16, 2006
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
-arrestin-mediated uncoupling from G-protein signaling and receptor internalization, have been suggested to be crucial (Borgland, 2001
; Liu and Anand, 2001; Bohn et al., 2002; Kieffer and Evans, 2002). Long-term morphine administration clearly induces behavioral tolerance in animals and humans but fails to strongly desensitize µ-receptors. Instead, long-term morphine use causes adenylyl cyclase (AC) supersensitization, which may underlie opioid tolerance and dependence at the cellular level (Avidor-Reiss et al., 1995, 1996; Harrison et al., 1998; Nestler, 2004a, b). Adaptations in adenylyl cyclase activities have been noted in several brain regions, including the ventral tegmental area (VTA) and nucleus accumbens (NAc) areas (which are critical for opioid drug reinforcement), and in the locus coeruleus and dorsal raphe nucleus (which are critical for opioid withdrawal) (Nestler and Aghajanian, 1997; Jolas et al., 2000; Williams et al., 2001; Chao and Nestler, 2004).
Although adenylyl cyclases have been suggested to mediate some of the actions of opioids, a lack of specific inhibitors has slowed progress in defining the roles of different AC isozymes. To date, genes for 10 ACs have been cloned, each with a distinct expression pattern in the central nervous system and the peripheral sensory nervous system (Xia and Storm, 1997). Among them, AC1 and AC8 are uniquely stimulated by Ca2+/calmodulin in the brain (Xia et al., 1993; Watson et al., 2000). AC1 and AC8 are widely distributed in the different brain regions including VTA, NAc, locus coeruleus, and dorsal raphe nucleus (Lane-Ladd et al., 1997). Many studies have shown the involvement of Ca2+/calmodulin in morphine action (Nemmani et al., 2005; Tang et al., 2006). Therefore, by using AC1 and AC8 single knockout (KO) mice as well as DKO mice, we assessed short-term tolerance, long-term tolerance, and long-term withdrawal after morphine in both wild-type and KO mice to define the roles of these cyclases in the cellular and behavioral adaptations to opiate. We also measured morphine-induced locomotion and place preference to assess the roles of AC1 and AC8 in morphine reinforcement. We then tested the contributions of AC1 and AC8 to morphine cAMP-response element binding protein (CREB) activation to further characterize the underlying mechanisms.
|
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
; Schaefer et al., 2000). Heterozygous breeding pairs, backcrossed >10 generations onto C57BL/6 backgrounds, were used to generate knockout mice (-/-) used for this study. The presence or absence of the AC8 gene was confirmed in genomic DNA isolated from tail tissue samples taken from each mouse using PCR analysis and a procedure described previously (Muglia et al., 1999). In brief, a fraction of isolated DNA was used in PCR assays using the following primers: AC8, exon 1, sense primer: 5'-CTGCCTCTCTATTCTCTGG-3' and antisense primer: 5'-CGCAGATCACCACCTCGAT-3'; neomycin, sense primer: 5'-GGTGGATGTGGAATGTGTGC-3' and antisense primer: 5'-GTTCAGACATCTGTGTCCAC-3'. PCR products were resolved on a 1.5% agarose gel with ethidium bromide and then photographed for analysis. Homologous AC8 KO animals produced PCR products with the neomycin (
300 bp) but not AC8 primer, whereas homologous wild-type and AC1 KO mice produced PCR products with the AC8 (400 bp) but not neomycin primer (Fig. 1A). The presence or absence of the AC1 gene was confirmed in genomic DNA isolated from tail tissue samples taken from each mouse using Southern blotting (Wu et al., 1995). In brief, tail DNA from each mouse was digested with restriction enzyme BglII and electrophoresed on a 0.8 to 1.0% agarose gel. The probe DNA was a 600-bp AvaI/XbaI fragment of AC1 gene locus [
-32P]dCTP by using random primers and a DNA labeling system. Homologous AC1 KO animals showed up as 6 kb bands, whereas homologous wild-type mice showed up as 5 kb bands (Fig. 1B). The DKO mice were confirmed by combining two analyses. Mice used were 10 to 14 weeks of age and weighed 20 to 25 g at the time of the start of the procedures. Both wild-type and mutant mice were well-groomed and did not show any obvious motor deficits. No indication of tremor, seizure, or ataxia was observed. Mice were housed two to four per cage within the animal care facility at the University of Washington with access to food and water ad libitum. Mice were transferred 1 week before training into a colony room adjacent to the testing room to acclimatize to environment. Housing rooms were maintained on a 12-h light/dark cycle (lights on from 7:00 AM to 7:00 PM) under standard conditions (22 ± 1°C room temperature, 33% humidity). Each animal was used only once.
Nociceptive Assays
A digital hotplate (IITC Life Sciences, Woodland Hills, CA) set at 53.5 ± 0.1°C and a water bath (Precision Scientific, Chicago, IL) set at 55.0 ± 0.5°C were chosen in this study. In each assay, latencies for the mouse to lick a hind paw or jump off the plate (hotplate) and to move the tail from the water (tail withdrawal) were taken as the endpoint. Cutoff values were 50 s (hotplate) and 15 s (tail withdrawal) to prevent tissue damage. Antinociception (maximal possible effect) was calculated by the following equation: % MPE = 100 x (test latency - control latency)/(cutoff - control latency).
Development of Tolerance
Short-Term Tolerance. Short-term antinociceptive tolerance was assessed by a second subcutaneous injection of morphine (10 mg/kg) 3 h after an initial injection (10 mg/kg s.c.). Previous studies have shown that a decrease in latency was not due to repeated injection, handling, or testing of the mice, because mice receiving saline in place of drug in the first injection displayed a normal antinociceptive response to a subsequent administration of morphine (data not shown).
Long-Term Tolerance. Wild-type and transgenic mice were treated daily (between 3:00 PM and 4:00 PM) with morphine (10 mg/kg s.c.), and antinociception was assessed 30 min later on each day for the first 5 days (Bohn et al., 2002).
Development of Withdrawal Behaviors
Morphine dependence was induced by repeated drug injection at escalating doses from 10 to 80 mg/kg s.c. over a period of 8 days. The numbers inside the parenthesis represent the doses of morphine (in milligrams per kilogram) injected at 8:00 AM and 6:00 PM, respectively: 1st and 2nd day (10, 10); 3rd and 4th day (20, 20); 5th and 6th day (40, 40); and 7th and 8th day (80, 80). On the 9th day, mice were injected with morphine (40 mg/kg) in the morning. Morphine withdrawal behavior was precipitated by intraperitoneal naloxone injection (10 mg/kg) 3 h after the last morphine administration. Mouse behavior was observed for 20 min immediately after naloxone administration, and the total number of wet-dog shakes, total number of jumps, and the number of minutes during which paw tremor and teeth chattering behaviors occurred was recorded (Terman et al., 2004). After the 20-min observation period, the mouse and filter paper on which the mouse was standing during the test were weighed again to quantify body weight change and amount of urination/defecation (both were converted to the percentage of body weight). No stereotypic opioid withdrawal behaviors were observed from either morphine-pretreated/saline-treated wild-type and DKO mice or saline-pretreated/naloxone-treated wild-type and DKO mice (data not shown).
Conditioned Place Preference
Mice were used in place-conditioning studies using a three-compartment box as described previously (McLaughlin et al., 2003). The compartmentalized box was divided into two equal-sized outer sections (25 x 25 x 25 cm) joined by a small central compartment (8.5 x 25 x 25 cm) accessed through a single doorway (3 x 3 cm). The compartments differ in wall striping (vertical versus horizontal alternating black and white lines, 1.5 cm in width) and floor texture [wood chips (The Andersons, Maumee, OH) versus Bed-o Cob (Northeastern Products Corporation, Warrensburg, NY)]. Mice were screened for initial preferences on the morning of day 1 by placing mice in the small central compartment and allowing them to move freely throughout the entire apparatus for 30 min while recording time spent in the two outer compartments. The biased design was used. On day 2, mice were injected (subcutaneously) with saline immediately placed in the compartment in which they had spent more time in the preconditioning test for 30 min. Four hours later, mice received morphine (2.5 or 5 mg/kg s.c.) and were immediately confined for 30 min to the opposite outer compartment. The morphine doses were chosen based on previous studies (Langroudi et al., 2005; Rezayof et al., 2006) in which the doses of 1 to 10 mg/kg morphine have been shown to induce place preference, and the maximal response was obtained with 5.0 mg/kg morphine. On days 3 and 4, mice again were conditioned first with saline followed by morphine 4 h later in the appropriate compartments. On day 5, mice were placed in the small central compartment and were allowed to roam freely between the two outer compartments for 30 min, and movement through the chambers was detected by infrared beam sensors (LabLinc; Coulbourn Instruments, Allentown, PA). Time spent in the two outer compartments was then calculated by GraphicState 2 software (Coulbourn Instruments). Data were plotted as the difference in the times spent on the drug-paired side before training subtracted from the times spent on the drug-paired side after training.
Locomotor Activity
Activity of each mouse was evaluated in the test chamber using video tracking and motion analysis, which was performed via a personal computer-based data acquisition system (Ethovision version 3.0; Noldus, Wageningen, The Netherlands) that received video input from a digital camera (ZR60; Canon, Tokyo, Japan). The camera was placed 3 m above the chamber, and the acquisition program collected five images per second for each recording episode. To evaluate the effects of morphine on locomotor behavior, mice were placed in test chamber for 60 min of environmental habituation. Then, immediately after the habituation period, mice were injected with morphine (10 mg/kg s.c.) or saline (s.c.) and then placed back into the test chamber. Locomotor activity was recorded during the subsequent 180 min.
Brain Dissections
Mice were killed by cervical dislocation, and the brains were rapidly removed and sliced into 1-mm thick sections using a brain matrix (Zivic Laboratories Inc., Pittsburgh, PA). VTA and NAc areas were identified according to a mouse brain stereotaxic atlas (Franklin and Paxinos, 1997). The areas were then dissected from the appropriate slices and frozen in liquid nitrogen.
Immunoblotting
Tissue samples were homogenized in ice-cold lysis buffer containing the following: 50 mM Tris-HCl, 300 mM NaCl, 1 mM EDTA, 1 mM Na3VO4, 1 mM NaF, 10% glycerol, 1% Nonidet P-40, 1:100 of Phosphatase Inhibitor Cocktail Set 1 (Calbiochem, La Jolla, CA), and 1:100 of Protease Inhibitor Cocktail Set 1 (Calbiochem). Lysates were sonicated for 20 s and then centrifuged for 15 min (14,000g, 4°C), the pellet was discarded, and sample supernatants were stored at -20°C. Protein concentration was determined by Pierce bicinchoninic assay with bovine serum albumin as the standard before loading 50 µg onto nondenaturing 10% bisacrylamide precast gels (Invitrogen, Carlsbad, CA) and running at 150 V for 1.5 h. For the determination of molecular weight, Benchmark prestained standards (Invitrogen) were loaded alongside protein samples. Blots were transferred to nitrocellulose for 1.5 h at 30 mV, blocked in 1x TBS/5% milk for 1 h, incubated overnight at 4°C with a 1:1000 dilution of goat-anti-rabbit phospho-CREB antibody which detects endogenous levels of CREB only when phosphorylated at serine 133 (pCREB; Cell Signaling Technologies, Danvers, MA). After overnight incubation, membranes were washed 4 x 15 min in Tris-buffered saline/1% Tween 20 and then incubated with the IRDye 800-conjugated affinity-purified anti-rabbit IgG (Rockland, Gilbertsville, PA) at a dilution of 1:10,000 in a 1:1 mixture of 5% milk/TBS and Li-Cor Blocking Buffer (Li-Cor Biosciences, Lincoln, NE) for 1 h at room temperature. Membranes were then washed 4 x 15 min in Trisbuffered saline/1% Tween 20 and 1 x 10 min in TBS to remove Tween 20, which can cause high background on the Odyssey Imaging System, and analyzed as described below. Membranes were reprobed with rabbit anti--actin (3 h at room temperature, 5% milk/TBS) and secondary antibody (as above) to confirm equal protein loading in each lane. Immunoblots were scanned using the Odyssey Infrared Imaging System (Li-Cor Biosciences); pCREB bands were detected at 43 kDa, and -actin bands were detected at 46 kDa. Band pixel intensity was measured using the Odyssey software, which subtracts background and calculates band density in pixels. Data were normalized to a percentage of control samples.
Data Analysis
The results were expressed as mean ± S.E.M. Differences in withdrawal behaviors and locomotor activities between groups were assessed by the Student's t test. Differences in tolerance, conditioned place preference (CPP) behavioral test, and pCREB immunoblotting staining between groups were analyzed by one-way or two-way analyses of variance (ANOVAs); post hoc pairwise comparisons were made with the Bonferroni test. ED50 value was calculated using the WinNonlin software (Pharsight, Mountain View, CA). In all analyses, the null hypothesis was rejected at the 0.05 level.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
|
|
Morphine-Induced Antinociceptive Tolerance. The basal responses to noxious thermal stimuli in tail-flick test were identical in wild-type, AC1, AC8, or DKO mice, which were consistent with the previous findings (Wei et al., 2002). In addition, mice lacking either AC1 or AC8 genes or both displayed morphine antinociceptive responses that were not different from wild-type mice (Fig. 3A). Two-way repeated-measure ANOVA (factor genotype + factor time) showed there were significant effects of time but no significant effects of genotype and interaction (Fgenotype/3,234 = 1.88, P > 0.05; Ftime/5, 234 = 42.55, P < 0.001; Fgenotype x time/15, 234 = 0.26, P > 0.05). Morphine tolerance that developed immediately within 3 h after an initial morphine administration (10 mg/kg s.c.) was reduced in the DKO mice and AC8 single knockout mice. Two-way repeated-measure ANOVA (factor genotype + factor time) showed there were significant effects of both genotype and time (Fgenotype/3,234 = 13.4, P < 0.001; Ftime/5, 234 = 23.57, P < 0.001). It is noteworthy that a decrease in latency in the wild-type mice was not due to repeated injection, handling, or testing of the mice, because mice receiving one injection of saline in the place of morphine did not display changes in tail-withdrawal latency when measured every 30 min (data not shown).
To assess the roles of AC1 and AC8 in the development of long-term morphine tolerance, we treated animals with morphine on a daily basis and monitored their responsiveness in the tail-withdrawal assay. Both wild-type and KO mice began to lose their sensitivity to morphine on the second day of treatment. However, the DKO mice displayed significantly less morphine tolerance than wild-type mice. Two-way repeated-measure ANOVA (factor genotype + factor day) showed there were significant effects of both genotype and days (Fgenotype/3,224 = 12.34, P < 0.001; Ftime/4, 224 = 86.81, P < 0.001; Fig. 3B). However, by the fourth day of treatment, the DKO mice were not different from the wild-type mice in their responsiveness to morphine, and both genotypes of mice seemed to be completely tolerant to morphine challenge (10 mg/kg s.c.) in the tail-withdrawal assay.
Morphine-Induced Withdrawal Behaviors. Consistent with a reduced morphine tolerance in the DKO mice, the severity of withdrawal behaviors precipitated by injection of the opioid antagonist naloxone (10 mg/kg i.p.) after 8-day repeated morphine treatment was also reduced in the DKO mice. There were significantly attenuated appearance of wet dog shakes and forepaw tremor in the DKO mice compared with the wild-type mice (Student's t test, P < 0.05; Fig. 4). In contrast, other withdrawal behaviors (e.g., jumping, teeth chatter, diarrhea, and weight loss) were not different in the wild-type and DKO mice (Fig. 4).
|
Morphine-Induced Hyperlocomotor Activity and CPP. To examine the effects of the deletion of both AC1 and AC8 genes on reinforcing and psychomotor properties of morphine, we assessed morphine induced hyperlocomotor activity and conditioned place preference in the KO mice and wild-type mice. Morphine (10 mg/kg s.c.) produced marked increases in locomotor activity in both genotypes during a 120-min period compared with saline-treated group. It is interesting that the wild-type mice seemed to be significantly more active than the DKO (two-way ANOVA, time: Ftime/23,528 = 8.25, P < 0.001; genotype: Fgenotype/1,528 = 31.84, P < 0.001; interaction: Fgenotype x time/23,528 = 1.78, P < 0.05, Fig. 5A). Compared with wild-type mice, DKO mice displayed significantly less total distance traveled as accumulated during 30- to 60-min and 60- to 90-min periods after morphine treatment (Student's t test, P < 0.05; Fig. 5B).
|
|
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
The findings are consistent with prior studies showing that AC1 and AC8, but not other types of ACs, were up-regulated by long-term exposure to morphine (Lane-Ladd et al., 1997; Nestler and Aghajanian, 1997; Jolas et al., 2000). The observations that the deletion of AC1 and AC8 genes strongly reduced the development of morphine short-term tolerance and partially reduced morphine long-term tolerance only at the first 2 days suggest that the AC system contributes the morphine antinociceptive tolerance at the initial stages and that an alternative mechanism may mediate response at the late course of long-term morphine antinociceptive tolerance.
The DKO mice also displayed significantly attenuated withdrawal behaviors (e.g., wet dog shakes and forepaw tremor). The cellular basis for these effects is not clear, but long-term opiate exposure in the NAc and VTA brain regions up-regulates the cAMP pathway within 
-aminobutyric acidcontaining GABAergic neurons that innervate the dopaminergic and serotonergic cells (Bonci and Williams, 1996, 1997; Tolliver et al., 1996). A reduced serotonergic tone in the neuraxis may contribute to both somatic and motivational aspects of withdrawal (Koob and LeMoal, 1997; Nestler and Aghajanian, 1997). We note that the removal of both AC1 and AC8 genes only attenuated some but not all of the withdrawal behaviors. This finding is consistent with other reports in which the CREB antisense oligonucleotide infusion significantly attenuated the appearance of withdrawal behaviors (teeth chatter, wet dog shakes, ptosis, vacuous chewing, and irritability) but not other withdrawal behaviors (lacrimation, salivation, piloerection, stereotypy, weight loss, and diarrhea) (Lane-Ladd et al., 1997), and CREB knockout mice displayed attenuated withdrawal behaviors including piloerection, teeth chattering, and paw tremor but had no effect on jumping, ptosis, and body tremor (Valverde et al., 2004). The detailed mechanisms and circuitry underlying different morphine withdrawal behaviors are incompletely understood.
Several studies have also examined the involvement of CREB activation in morphine response (Lane-Ladd et al., 1997). For example, a single morphine injection was reported to increase the number of pCREB-positive cells in VTA (Walters et al., 2003). Moreover, long-term morphine exposure increases cAMP response element-mediated transcription in the both VTA and the locus coeruleus (Widnell et al., 1994; Olson et al., 2005). The mechanisms linking opioid receptor activation to pCREB are not clear. CREB phosphorylation may involve cAMP-activated protein kinase A, calcium/calmodulin-dependent protein kinase, or mitogen-activated protein kinase pathways (Bito et al., 1996; Soderling, 2000; Licata and Pierce, 2003; Thomas and Huganir, 2004). In this study, we found that an increase of pCREB induction in VTA by long-term morphine treatment was significantly reduced in the DKO mice, suggesting that AC1 and AC8 mediate the CREB activation in these neurons. However, the presence of a significant residual pCREB in morphine-injected DKO mice indicates that Ca2+-stimulated AC1 and AC8 are not solely responsible. This conclusion is consistent with a recent report showing that a Ca2+-independent form of adenylyl cyclase, AC5, has also been implicated in morphine actions within the striatum (Kim et al., 2006).
The removal of AC1 and AC8 genes reduced both the hyperlocomotor response and conditioned place preference, indicating that AC1 and AC8 mediate morphine reinforcement. This observation is consistent with the results using CREB
mutant mice that did not show morphine CPP (Walters and Blendy, 2001). CPP is a complex learning paradigm (Bardo and Bevins, 2000), and cAMP-CREB signaling is critical for memory formation and synaptic plasticity (Wong et al., 1999; Wang et al., 2004). These results suggest that the impairment of memory and learning caused by the removal of both AC1 and AC8 signaling may contribute to the reduction in morphine CPP. However, this effect may be specific for morphine CPP because CREB-deficient mice displayed an augmented cocaine CPP paradigm (Walters and Blendy, 2001). The cellular mechanisms underlying morphine effects are not completely clear, but it is known that morphine disinhibits VTA dopaminergic cell firing by inhibiting neighboring GABAergic neurons. A reduction of cAMP/CREB signaling in these GABAergic neurons might prevent morphine's effects in the nucleus accumbens and reduce the reinforcing properties of morphine (Walters and Blendy, 2001).
In conclusion, the studies here support a fundamental reconsideration of the roles of calmodulin-stimulated adenylyl cyclases in the morphine response. We demonstrated that AC1 and AC8 contribute to the initial stages of morphine tolerance. We found that AC1 and AC8 contribute to the expression of the somatic signs of opiate withdrawal and severity of morphine physical dependence. Finally, we found that AC1, AC8, and CREB contribute to the reinforcing properties of morphine. Further work is needed to identify the downstream targets of these enzymes and cellular pathways contributing to the morphine response.
|
Footnotes |
|---|
ABBREVIATIONS: AC, adenylyl cyclase KO, disrupted gene or knockout mouse; DKO, double knockout mouse; CREB, cAMP-response element binding protein; pCREB, phosphorylated cAMP-response element binding protein; CPP, conditioned place preference; VTA, ventral tegmental area; NAc, nucleus accumbens; PCR, polymerase chain reaction; kb, kilobase(s); bp, base pair(s); TBS, Tris-buffered saline; ANOVA, analysis of variance.
Address correspondence to: Dr. Charles Chavkin, Department of Pharmacology, Box 357280, University of Washington School of Medicine, Seattle, WA 98195-7280. E-mail: cchavkin{at}u.washington.edu
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Avidor-Reiss T, Nevo I, Levy R, Pfeuffer T, and Vogel Z (1996) Chronic opioid treatment induces adenylyl cyclase V superactivation. Involvement of G. J Biol Chem 271: 21309-21315.
Bardo MT and Bevins RA (2000) Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl) 53: 31-43.
Bito H, Deisseroth K, and Tsien RW (1996) CREB phosphorylation and dephosphorylation: a Ca2+- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87: 1203-1214.[CrossRef][Medline]
Bohn LM, Lefkowitz RJ, and Caron MG (2002) Differential mechanisms of morphine antinociceptive tolerance revealed in arrestin-2 knock-out mice. J Neurosci 22: 10494-10500.
Bonci A and Williams JT (1996) A common mechanism mediates long-term changes in synaptic transmission after chronic cocaine and morphine. Neuron 16: 631-639.[CrossRef][Medline]
Bonci A and Williams JT (1997) Increased probability of GABA release during withdrawal from morphine. J Neurosci 17: 796-803.
Borgland SL (2001) Acute opioid receptor desensitization and tolerance: is there a link? Clin Exp Pharmacol Physiol 28: 147-154.[CrossRef][Medline]
Chao J and Nestler EJ (2004) Molecular neurobiology of drug addiction. Annu Rev Med 55: 113-132.[CrossRef][Medline]
Franklin BJK and Paxinos G (1997) The Mouse Brain in Stereotaxic Coordinates. Academic Press, San Diego.
Harrison LM, Kastin AJ, and Zadina JE (1998) Opiate tolerance and dependence: receptors, G-proteins, and antiopiates. Peptides 19: 1603-1630.[CrossRef][Medline]
Jolas T, Nestler EJ, and Aghajanian GK (2000) Chronic morphine increases GABA tone on serotonergic neurons of the dorsal raphe nucleus: association with an up-regulation of the cyclic AMP pathway. Neuroscience 95: 433-443.[Medline]
Kieffer BL and Evans CJ (2002) Opioid tolerance-in search of the holy grail. Cell 108: 587-590.[CrossRef][Medline]
Kim KS, Lee KW, Lee KW, Im JY, Yoo JY, Kim SW, Lee JK, Nestler EJ, and Han PL (2006) Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action. Proc Natl Acad Sci USA 103: 3908-3913.
Koob GF and LeMoal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science (Wash DC) 278: 52-58.
Lane-Ladd SB, Pineda J, Boundy VA, Pfeuffer T, Krupinski J, Aghajanian GK, and Nestler EJ (1997) CREB (cAMP response element-binding protein) in the locus coeruleus: biochemical, physiological, and behavioral evidence for a role in opiate dependence. J Neurosci 17: 7890-7901.
Langroudi RM, Khoshnoodi MA, Abadi NY, Fahadan PT, Ghahremani MH, and Dehpour AR (2005) Effect of cyclosporin A on morphine-induced place conditioning in mice: involvement of nitric oxide. Eur J Pharmacol 507: 107-115.[CrossRef][Medline]
Licata SC and Pierce RC (2003) The roles of calcium/calmodulin-dependent and Ras/mitogen-activated protein kinases in the development of psychostimulant-induced behavioral sensitization. J Neurochem 85: 14-22.[Medline]
Liu JG and Anand KJ (2001) Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence. Brain Res Brain Res Rev 38: 1-19.[CrossRef][Medline]
McLaughlin JP, Marton-Popovici M, and Chavkin C (2003) Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci 23: 5674-5683.
Muglia LM, Schaefer ML, Vogt SK, Gurtner G, Imamura A, and Muglia LJ (1999) The 5'-flanking region of the mouse adenylyl cyclase type VIII gene imparts tissue-specific expression in transgenic mice. J Neurosci 19: 2051-2058.
Nemmani KV, Lalonde J, and Mogil JS (2005) Region-specific changes of calcium/calmodulin-dependent protein kinase IV in the mouse brain following chronic morphine treatment. Neuroreport 16: 879-882.[CrossRef][Medline]
Nestler EJ (2004a) Historical review: molecular and cellular mechanisms of opiate and cocaine addiction. Trends Pharmacol Sci 25: 210-218.[CrossRef][Medline]
Nestler EJ (2004b) Molecular mechanisms of drug addiction. Neuropharmacology 47 (Suppl 1): 24-32.[CrossRef][Medline]
Nestler EJ and Aghajanian GK (1997) Molecular and cellular basis of addiction. Science (Wash DC) 278: 58-63.
Olson VG, Zabetian CP, Bolanos CA, Edwards S, Barrot M, Eisch AJ, Hughes T, Self DW, Neve RL, and Nestler EJ (2005) Regulation of drug reward by cAMP response element-binding protein: evidence for two functionally distinct subregions of the ventral tegmental area. J Neurosci 25: 5553-5562.
Rezayof A, Zatali H, Haeri-Rohani A, and Zarrindast MR (2006) Dorsal hippocampal muscarinic and nicotinic receptors are involved in mediating morphine reward. Behav Brain Res 166: 281-290.[CrossRef][Medline]
Schaefer ML, Wong ST, Wozniak DF, Muglia LM, Liauw JA, Zhuo M, Nardi A, Hartman RE, Vogt SK, Luedke CE, et al. (2000) Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient mice. J Neurosci 20: 4809-4820.
Soderling TR (2000) CaM-kinases: modulators of synaptic plasticity. Curr Opin Neurobiol 10: 375-380.[CrossRef][Medline]
Tang L, Shukla PK, Wang LX, and Wang ZJ (2006) Reversal of morphine antinociceptive tolerance and dependence by the acute supraspinal inhibition of Ca2+/calmodulin-dependent protein kinase II. J Pharmacol Exp Ther 317: 901-909.
Terman GW, Jin W, Cheong YP, Lowe J, Caron MG, Lefkowitz RJ, and Chavkin C (2004) G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal. Br J Pharmacol 141: 55-64.[CrossRef][Medline]
Thomas GM and Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5: 173-183.[CrossRef][Medline]
Tolliver BK, Ho LB, Reid MS, and Berger SP (1996) Evidence for involvement of ventral tegmental area cyclic AMP systems in behavioral sensitization to psychostimulants. J Pharmacol Exp Ther 278: 411-420.
Valverde O, Mantamadiotis T, Torrecilla M, Ugedo L, Pineda J, Bleckmann S, Gass P, Kretz O, Mitchell JM, Schutz G, et al. (2004) Modulation of anxiety-like behavior and morphine dependence in CREB-deficient mice. Neuropsychopharmacology 29: 1122-1133.[CrossRef][Medline]
Walters CL and Blendy JA (2001) Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse. J Neurosci 21: 9438-9444.
Walters CL, Kuo YC, and Blendy JA (2003) Differential distribution of CREB in the mesolimbic dopamine reward pathway. J Neurochem 87: 1237-1244.[CrossRef][Medline]
Wang H, Ferguson GD, Pineda VV, Cundiff PE, and Storm DR (2004) Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP. Nat Neurosci 7: 635-642.[CrossRef][Medline]
Watson EL, Jacobson KL, Singh JC, Idzerda R, Ott SM, DiJulio DH, Wong ST, and Storm DR (2000) The type 8 adenylyl cyclase is critical for Ca2+ stimulation of cAMP accumulation in mouse parotid acini. J Biol Chem 275: 14691-14699.
Wei F, Qiu CS, Kim SJ, Muglia L, Maas JW, Pineda VV, Xu HM, Chen ZF, Storm DR, Muglia LJ, et al. (2002) Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36: 713-726.[CrossRef][Medline]
Widnell KL, Russell DS, and Nestler EJ (1994) Regulation of expression of cAMP response element-binding protein in the locus coeruleus in vivo and in a locus coeruleus-like cell line in vitro. Proc Natl Acad Sci USA 91: 10947-10951.
Williams JT, Christie MJ, and Manzoni O (2001) Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 81: 299-343.
Wong ST, Athos J, Figueroa XA, Pineda VV, Schaefer ML, Chavkin CC, Muglia LJ, and Storm DR (1999) Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron 23: 787-798.[CrossRef][Medline]
Wu ZL, Thomas SA, Villacres EC, Xia Z, Simmons ML, Chavkin C, Palmiter RD, and Storm DR (1995) Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice. Proc Natl Acad Sci USA 92: 220-224.
Xia Z, Choi EJ, Wang F, Blazynski C, and Storm DR (1993) Type I calmodulinsensitive adenylyl cyclase is neural specific. J Neurochem 60: 305-311.[CrossRef][Medline]
Xia Z and Storm DR (1997) Calmodulin-regulated adenylyl cyclases and neuromodulation. Curr Opin Neurobiol 7: 391-396.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  S. Pierre, C. Maeurer, O. Coste, W. Becker, A. Schmidtko, S. Holland, C. Wittpoth, G. Geisslinger, and K. Scholich Toponomics Analysis of Functional Interactions of the Ubiquitin Ligase PAM (Protein Associated with Myc) during Spinal Nociceptive Processing Mol. Cell. Proteomics, December 1, 2008; 7(12): 2475 - 2485. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Coste, C. Brenneis, B. Linke, S. Pierre, C. Maeurer, W. Becker, H. Schmidt, W. Gao, G. Geisslinger, and K. Scholich Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing J. Biol. Chem., November 21, 2008; 283(47): 32442 - 32451. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
, P < 0.05 compared with wild-type mice by ANOVA followed by Bonferroni post hoc test. The following data show the real mean time scores ± S.E.M. (in seconds) of preconditioning (Pre) and postconditioning (Post) sessions on initially nonpreferred compartment in each genotype. Wild-type mice [Pre/Post, n], DKO mice [Pre/Post]: saline ([531.0 ± 26.7/588.0 ± 51.0, 6], [517.7 ± 69.9/529.0 ± 40.0, 7), morphine 2.5 mg/kg ([504.8 ± 26.2/788.1 ± 50.1, 11], [581.5 ± 25.2/651.3 ± 49.9, 10]), and morphine 5 mg/kg ([574.9 ± 28.4/931.2 ± 53.6, 12], [637.7 ± 22.5/901.5 ± 44.4, 9]).