Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Increased sensitivity to cocaine-induced analgesia in Spontaneously Hypertensive Rats (SHR)

Increased sensitivity to cocaine-induced analgesia in Spontaneously Hypertensive Rats (SHR) This study examined the analgesic effect of cocaine in Spontaneously Hypertensive Rats (SHR), which are considered a suitable model for the study of attention deficit hyperactivity disorder (ADHD), and in Wistar (WIS) rats of both sexes using the hot-plate test. In addition, we tested whether habituation to the unheated hot-plate apparatus, that "normalizes" the basal hypoalgesic phenotype of SHR, alters the subsequent cocaine-induced analgesia (CIA) in this strain. SHR of both sexes were hypoalgesic compared to WIS rats in the hot-plate test and showed higher sensitivity to CIA. Habituation to the unheated hot-plate reduced the basal nociceptive latency of SHR, suggesting cognitive/emotional modulation of pain in this strain, but did not alter the magnitude of CIA. The present study shows increased sensitivity to CIA in SHR, which may be related to abnormalities in the mesocorticolimbic dopaminergic system. Further studies using SHR strain may reveal new information on the neurobiological mechanisms underlying ADHD and its co-morbidity with drug addiction. apparatus, suggesting that their hypoalgesic phenotype Findings Pain is a complex and subjective experience that involves may involve cognitive processes (e.g. distraction) [8]. This the transduction of noxious stimuli by nociceptive fibers, is consistent with the fact that SHR have been considered but also cognitive and emotional aspects [1]. For instance, an animal model for the study of attention deficit hyper- human studies indicate that pain is perceived as less activity disorder (ADHD), since they show inattention intense when individuals are distracted from the pain [2]. and impulsivity/hyperactivity [10,11]. It remains to be Gender and genetic differences also influence the pain clarified whether this characteristic of SHR interferes with perception and a number of animal models have been the analgesic properties of drugs. used to study the influence of these factors on nociception [3]. The Spontaneously Hypertensive Rats (SHR) show Alterations in the dopaminergic system in ADHD patients abnormal nociceptive reactivity in several nociceptive as well as in SHR have been identified [10,11]. Methyl- tests [4-8]. In the hot-plate test, SHR are hypoalgesic when phenidate, the first-choice treatment for ADHD, is known compared to rats of other strains [4,5,7,8], but they show to block dopamine (DA) uptake by brain DA transporters normal properties of nociceptive fibers [9]. We have in a similar way to potent psychostimulants like cocaine recently reported that hypoalgesia was no longer observed and amphetamine [12]. In addition, the mesocorticolim- in SHR rats after habituation to the unheated hot-plate bic dopaminergic system is one of the main neurochemi- Page 1 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:9 http://www.behavioralandbrainfunctions.com/content/3/1/9 habituation to the unheated hot-plate apparatus, that "normalizes" the basal nociception of SHR, alters the sub- sequent cocaine-induced analgesia (CIA) in this strain. Animals of both sexes were included in this study because there is a considerable amount of evidence for quantita- tive and qualitative sex differences in nociceptive-related behaviors [3]. Adult (12 weeks old) SHR and WIS rats from our own col- onies were used [8]. The weight of the animals was 230– 310 g for males and 150–210 g for females. They were housed collectively in plastic cages (5–6/cage), under con- trolled temperature (23 ± 2°C) with a 12-h light/dark cycle (lights on at 07:00) with free access to rat chow and tap water. All experiments were carried out during the light phase of the cycle. The animals were injected with cocaine (20 mg/kg, Merck ) dissolved in physiological solution or an equiva- lent amount of vehicle (2 ml/kg) via intraperitoneal (i.p.) route 15 min before the nociceptive tests. The dose of cocaine was selected based on a pilot study and a previous report [14]. All procedures performed complied with the "Principles of laboratory animal care" from NIH. The hot-plate (Ugo Basile, model-DS37) was maintained at 52.2 ± 0.5°C following a previously reported procedure [8]. Briefly, the animals were placed in a glass cylinder of 24-cm diameter on the heated metal surface, and the time Cocaine- H Figure 1 ypertensive Rats induced anal in th gee hot-p sia in Wi late test star and Spontaneously between placement and hind paw licking or jumping Cocaine-induced analgesia in Wistar and Spontaneously (whichever occurred first) was recorded as nociceptive Hypertensive Rats in the hot-plate test. Male and female rats latency. A 70-s cut-off was established to prevent tissue of Wistar (WIS) and Spontaneously Hypertensive Rats (SHR) damage. The procedure of the habituation to the hot-plate strains were evaluated in the hot-plate test 15 min after i.p. injection of cocaine (20 mg/kg) (upper panel). SHR rats were apparatus has been described elsewhere [8]. SHR were habituated to the unheated hot-plate apparatus and 1 h after submitted to five sessions of 90-s exposure (at 10-min evaluated for CIA in the hot-plate test (lower panel). Data inter-trial intervals) to the unheated hot-plate apparatus. are presented as nociceptive latencies (s) or the percentage Another group of rats remained undisturbed in their of maximum possible effects (%MPE). * p < 0.05 vs WIS rats home cages and served as non-habituated animals (test of the corresponding gender (upper panel) or vs SHR naive naive rats). One hour after the last habituation session, rats (lower panel) (Newman-Keuls post hoc test). habituated and non-habituated rats were injected with cocaine as previously described and tested on the hot- plate. Because cocaine-induced analgesia was of similar cal pathways involved in the interface between pain, intensity in both genders, this experiment was carried out cognition and emotionality [13]. Systemic administration only with female rats due to their greater availability in of DA re-uptake blockers induces analgesia in rodents, our laboratory. probably by acting on brain dopaminergic pathways [14,15]. The results were expressed as the latency (s) to nocicep- tion or the percentage of maximum possible effect (% The first aim of this study was to examine the effects of MPE) defined by the following equation: cocaine on nociceptive responses in the SHR and in the outbred Wistar (WIS) rat strain (representing a "normal" post-drug latency − basal latency %MPE = × 1 100 genetically heterogenic population) using the hot-plate cut-off − basal latency test. In order to evaluate the contribution of cognitive/ emotional processes in the analgesic effect of cocaine, Statistical analysis was performed using one-, two- or another objective of our study was to evaluate whether three-way ANOVA with condition (habituated and non- Page 2 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:9 http://www.behavioralandbrainfunctions.com/content/3/1/9 habituated) or strain and gender as factors. Repeated uations in SHR suggest that this hypoalgesic phenotype is measure was included as an analysis factor for compari- more likely to be a result of distraction of the SHR from sons of nociceptive latencies before and after drug treat- the nociceptive stimulus (heated plate) rather than reflect- ment. The Newman-Keuls test was used for post-hoc ing stress-induced analgesia. Confirming our previous comparisons. The accepted level of significance was p < study [8], habituation of SHR to the unheated hot-plate 0.05. resulted in a striking reduction of the basal nociceptive latency. These findings, taken together with the fact that The three-way ANOVA (strain, gender and repeated meas- the SHR strain is considered a suitable model of ADHD ure) for the nociceptive latencies in the hot-plate test [10,11], emphasizes that SHR hypoalgesia probably revealed effect for strain [F = 50.45; p < 0.0001], involves cognitive/emotional processes. Finally, several (1,24) repeated measure [F = 62.94; p < 0.0001] and for studies suggest that the nociception of SHR is not associ- (1,24) strain vs repeated measure interaction [F = 18.69; p < ated with their inherited hypertensive trait [4,7]. (1,24) 0.001]. SHR of both sexes (males: 23.7 ± 2.4 s, females: 26.7 ± 2.3 s) showed higher basal latencies to nociception SHR show increased sensitivity to CIA compared to WIS (i.e. hypoalgesia) than WIS rats (males: 15.8 ± 1.1 s, rats. Moreover, habituation to the hot-plate that "normal- females: 11.0 ± 1.1 s). The analgesic effect of cocaine in izes" the hypoalgesic phenotype of SHR did not influence the hot-plate test displayed by SHR and WIS rats of both CIA intensity. There are findings in support of an sexes is illustrated in Figure 1 (upper panel). The two-way increased sensitivity of SHR to other behavioral effects of ANOVA for the % MPE revealed an overall effect of strain psychostimulants. For instance, SHR show increased sus- [F = 29.59; p < 0.0001], indicating that male and ceptibility to convulsions induced by cocaine [18] and (1,24) female SHR showed higher CIA compared to their WIS increased psychomotor stimulation induced by ampheta- counterparts (p < 0.05). mine [19] or methylphenidate [20]. (Although see [21,22]). Alterations in DA neurotransmission have been Figure 1 (lower panel) illustrates the basal hot-plate laten- extensively described in the SHR strain, including reduced cies and % MPE of habituated and nonhabituated SHR. release of DA in the prefrontal cortex, nucleus accumbens One-way ANOVA (condition) for the basal latencies (NAcc) and striatum [23], decreased DA turnover in the revealed that habituated SHR showed lower nociceptive substantia nigra, ventral tegmental area and frontal cortex latencies compared to test naive rats [F = 18.18; p < [23], reduced DA vesicular storage [24] and increased den- (1,11) 0.005]. Habituated and nonhabituated rats displayed sity of the D1/D5 receptors in the anterior forebrain [25]. analgesic effects of cocaine [F = 27.46; p < 0.001]. Interestingly, stimulus-evoked release of DA was lower in (1,11) However, one-way ANOVA (condition) for the % MPE the striatum of SHR [26], although d-amphetamine indicated that CIA was similar in these groups [F = evoked greater release of DA in the prefrontal cortex, NAcc (1,11) 0.63; p = 0.44]. and striatum of SHR compared to Wistar-Kyoto rats [24]. This study provides evidence of increased sensitivity to In summary, SHR have increased sensitivity to behavioral cocaine in terms of analgesia in the SHR strain when com- and neurochemical effects of psychostimulants, which pared to the WIS strain in the hot-plate test. Moreover, may be related to abnormalities in the mesocorticolimbic habituation to the unheated hot-plate reduced the basal dopaminergic system. Because hyperlocomotion and nociceptive latency of SHR without altering the magni- analgesia share a common neural substrate with the tude of the analgesic effect of cocaine. rewarding effects of drugs of abuse [13], it is possible to suggest that the enhanced behavioral effects of cocaine in SHR are hypoalgesic compared to Wistar, Wistar-Kyoto, SHR could reflect the higher preference of SHR for drugs Sprague-Dawley and Lewis rats [4-8,16]. Thus, the results of abuse [27]. Thus, further studies using SHR strain may here presented for basal nociception are in agreement reveal new information on the neurobiological mecha- with the aforementioned findings. As pointed out by Tay- nisms underlying ADHD and its co-morbidity with drug lor et al., the exaggerated fight-or-flight stress responses addiction. and sympathetic activation in SHR may be related to their abnormal nociceptive phenotype [7]. Several studies have Competing interests shown that stress can cause intense analgesia [8,17]; how- The author(s) declare that they have no competing inter- ever, we have reported that when a more severe stressor ests. was employed (forced swimming in cold water), SHR were less vulnerable to stress-induced analgesia compared Authors' contributions to Lewis and WIS rats [8]. This apparent discrepancy FAP carried out the data collection, designed the study regarding an "analgesic" effect produced by exposure in a and wrote the manuscript. LFV and RNT participated in novel environment and the reduced impact of stressful sit- the data analyses, interpretation of data and elaboration Page 3 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:9 http://www.behavioralandbrainfunctions.com/content/3/1/9 20. Amini B, Yang PB, Swann AC, Dafny N: Differential locomotor of the manuscript. All authors read and approved the final responses in male rats from three strains to acute methyl- manuscript. phenidate. Int J Neurosci 2004, 114(9):1063-1084. 21. Sagvolden T: The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and Acknowledgements impulsiveness in an animal model of Attention-Deficit/ FAP had a scholarship from CNPq, Brazil; LFV had a scholarship from Hyperactivity Disorder (ADHD). Behav Brain Funct 2006, 2:41. CAPES, Brazil; and RNT had a fellowship also from CNPq, Brazil. The 22. Sagvolden T, Metzger MA, Schiorbeck HK, Rugland AL, Spinnangr I, present work was partially funded by a grant from FAPESC/CNPq/ Sagvolden G: The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): changed PRONEX. reactivity to reinforcers and to psychomotor stimulants. Behav Neural Biol 1992, 58(2):103-112. References 23. Russell VA: Hypodopaminergic and hypernoradrenergic activ- ity in prefrontal cortex slices of an animal model for atten- 1. Julius D, Basbaum AI: Molecular mechanisms of nociception. Nature 2001, 413(6852):203-210. tion-deficit hyperactivity disorder--the spontaneously hypertensive rat. Behav Brain Res 2002, 130(1-2):191-196. 2. Villemure C, Bushnell MC: Cognitive modulation of pain: how do attention and emotion influence pain processing? Pain 24. Russell V, de Villiers A, Sagvolden T, Lamm M, Taljaard J: Differences between electrically-, ritalin- and D-amphetamine-stimu- 2002, 95(3):195-199. 3. Mogil JS, Sternberg WF, Marek P, Sadowski B, Belknap JK, Liebeskind lated release of [3H]dopamine from brain slices suggest impaired vesicular storage of dopamine in an animal model JC: The genetics of pain and pain inhibition. Proc Natl Acad Sci U S A 1996, 93(7):3048-3055. of Attention-Deficit Hyperactivity Disorder. Behav Brain Res 1998, 94(1):163-171. 4. Maixner W, Touw KB, Brody MJ, Gebhart GF, Long JP: Factors influencing the altered pain perception in the spontaneously 25. Carey MP, Diewald LM, Esposito FJ, Pellicano MP, Gironi Carnevale UA, Sergeant JA, Papa M, Sadile AG: Differential distribution, hypertensive rat. Brain Res 1982, 237(1):137-145. 5. Plesan A, Hoffmann O, Xu XJ, Wiesenfeld-Hallin Z: Genetic differ- affinity and plasticity of dopamine D-1 and D-2 receptors in the target sites of the mesolimbic system in an animal model ences in the antinociceptive effect of morphine and its potentiation by dextromethorphan in rats. Neurosci Lett 1999, of ADHD. Behav Brain Res 1998, 94(1):173-185. 26. Russell VA: The nucleus accumbens motor-limbic interface of 263(1):53-56. 6. Ramos A, Kangerski AL, Basso PF, Da Silva Santos JE, Assreuy J, Ven- the spontaneously hypertensive rat as studied in vitro by the superfusion slice technique. Neurosci Biobehav Rev 2000, druscolo LF, Takahashi RN: Evaluation of Lewis and SHR rat strains as a genetic model for the study of anxiety and pain. 24(1):133-136. 27. Vendruscolo LF, Terenina-Rigaldie E, Raba F, Ramos A, Takahashi RN, Behav Brain Res 2002, 129(1-2):113-123. 7. Taylor BK, Roderick RE, St Lezin E, Basbaum AI: Hypoalgesia and Mormede P: Evidence for a female-specific effect of a chromo- some 4 locus on anxiety-related behaviors and ethanol drink- hyperalgesia with inherited hypertension in the rat. Am J Phys- iol Regul Integr Comp Physiol 2001, 280(2):R345-54. ing in rats. Genes Brain Behav 2006, 5(6):441-450. 8. Vendruscolo LF, Pamplona FA, Takahashi RN: Strain and sex dif- ferences in the expression of nociceptive behavior and stress-induced analgesia in rats. Brain Res 2004, 1030(2):277-283. 9. Bulka A, Wiesenfeld-Hallin Z: Comparison of response charac- teristics of cutaneous mechanoreceptors in normal and neu- ropathic Sprague-Dawley and spontaneously hypertensive rats. Neurosci Lett 2003, 340(1):61-64. 10. Russell VA, Sagvolden T, Johansen EB: Animal models of atten- tion-deficit hyperactivity disorder. Behav Brain Funct 2005, 1:9. 11. Sagvolden T, Johansen EB, Aase H, Russell VA: A dynamic develop- mental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and com- bined subtypes. Behav Brain Sci 2005, 28(3):397-419; discussion 419-68. 12. Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS: Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci 1996, 58(12):231-239. 13. Altier N, Stewart J: The role of dopamine in the nucleus accumbens in analgesia. Life Sci 1999, 65(22):2269-2287. 14. Lin Y, Morrow TJ, Kiritsy-Roy JA, Terry LC, Casey KL: Cocaine: evi- dence for supraspinal, dopamine-mediated, non-opiate anal- gesia. Brain Res 1989, 479(2):306-312. 15. Shyu BC, Kiritsy-Roy JA, Morrow TJ, Casey KL: Neurophysiologi- cal, pharmacological and behavioral evidence for medial tha- lamic mediation of cocaine-induced dopaminergic analgesia. Publish with Bio Med Central and every Brain Res 1992, 572(1-2):216-223. scientist can read your work free of charge 16. Vendruscolo LF, Vendruscolo JC, Terenina-Rigaldie E, Raba F, Ramos A, Takahashi RN, Mormede P: Genetic influences on behavioral "BioMed Central will be the most significant development for and neuroendocrine responses to predator-odor stress in disseminating the results of biomedical researc h in our lifetime." rats. Neurosci Lett 2006, 409(2):89-94. Sir Paul Nurse, Cancer Research UK 17. Vendruscolo LF, Takahashi RN: Synergistic interaction between mazindol, an anorectic drug, and swim-stress on analgesic Your research papers will be: responses in the formalin test in mice. Neurosci Lett 2004, available free of charge to the entire biomedical community 355(1-2):13-16. 18. Rockhold RW, Surrett RS, Acuff CG, Zhang T, Hoskins B, Ho IK: peer reviewed and published immediately upon acceptance Antagonism of the toxicity of cocaine by MK-801: differential cited in PubMed and archived on PubMed Central effects in spontaneously hypertensive and Wistar-Kyoto rats. Neuropharmacology 1992, 31(12):1269-1277. yours — you keep the copyright 19. Tsai CF, Lin MT: Locomotor hyperactivity in hypertensive rats. BioMedcentral Submit your manuscript here: Pharmacology 1988, 36(1):27-34. http://www.biomedcentral.com/info/publishing_adv.asp Page 4 of 4 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Increased sensitivity to cocaine-induced analgesia in Spontaneously Hypertensive Rats (SHR)

Download PDF
4 pages

Loading next page...
 
/lp/springer-journals/increased-sensitivity-to-cocaine-induced-analgesia-in-spontaneously-j9QFD1T0uG

References (29)

Publisher
Springer Journals
Copyright
Copyright © 2007 by Pamplona et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
eISSN
1744-9081
DOI
10.1186/1744-9081-3-9
pmid
17298672
Publisher site
See Article on Publisher Site

Abstract

This study examined the analgesic effect of cocaine in Spontaneously Hypertensive Rats (SHR), which are considered a suitable model for the study of attention deficit hyperactivity disorder (ADHD), and in Wistar (WIS) rats of both sexes using the hot-plate test. In addition, we tested whether habituation to the unheated hot-plate apparatus, that "normalizes" the basal hypoalgesic phenotype of SHR, alters the subsequent cocaine-induced analgesia (CIA) in this strain. SHR of both sexes were hypoalgesic compared to WIS rats in the hot-plate test and showed higher sensitivity to CIA. Habituation to the unheated hot-plate reduced the basal nociceptive latency of SHR, suggesting cognitive/emotional modulation of pain in this strain, but did not alter the magnitude of CIA. The present study shows increased sensitivity to CIA in SHR, which may be related to abnormalities in the mesocorticolimbic dopaminergic system. Further studies using SHR strain may reveal new information on the neurobiological mechanisms underlying ADHD and its co-morbidity with drug addiction. apparatus, suggesting that their hypoalgesic phenotype Findings Pain is a complex and subjective experience that involves may involve cognitive processes (e.g. distraction) [8]. This the transduction of noxious stimuli by nociceptive fibers, is consistent with the fact that SHR have been considered but also cognitive and emotional aspects [1]. For instance, an animal model for the study of attention deficit hyper- human studies indicate that pain is perceived as less activity disorder (ADHD), since they show inattention intense when individuals are distracted from the pain [2]. and impulsivity/hyperactivity [10,11]. It remains to be Gender and genetic differences also influence the pain clarified whether this characteristic of SHR interferes with perception and a number of animal models have been the analgesic properties of drugs. used to study the influence of these factors on nociception [3]. The Spontaneously Hypertensive Rats (SHR) show Alterations in the dopaminergic system in ADHD patients abnormal nociceptive reactivity in several nociceptive as well as in SHR have been identified [10,11]. Methyl- tests [4-8]. In the hot-plate test, SHR are hypoalgesic when phenidate, the first-choice treatment for ADHD, is known compared to rats of other strains [4,5,7,8], but they show to block dopamine (DA) uptake by brain DA transporters normal properties of nociceptive fibers [9]. We have in a similar way to potent psychostimulants like cocaine recently reported that hypoalgesia was no longer observed and amphetamine [12]. In addition, the mesocorticolim- in SHR rats after habituation to the unheated hot-plate bic dopaminergic system is one of the main neurochemi- Page 1 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:9 http://www.behavioralandbrainfunctions.com/content/3/1/9 habituation to the unheated hot-plate apparatus, that "normalizes" the basal nociception of SHR, alters the sub- sequent cocaine-induced analgesia (CIA) in this strain. Animals of both sexes were included in this study because there is a considerable amount of evidence for quantita- tive and qualitative sex differences in nociceptive-related behaviors [3]. Adult (12 weeks old) SHR and WIS rats from our own col- onies were used [8]. The weight of the animals was 230– 310 g for males and 150–210 g for females. They were housed collectively in plastic cages (5–6/cage), under con- trolled temperature (23 ± 2°C) with a 12-h light/dark cycle (lights on at 07:00) with free access to rat chow and tap water. All experiments were carried out during the light phase of the cycle. The animals were injected with cocaine (20 mg/kg, Merck ) dissolved in physiological solution or an equiva- lent amount of vehicle (2 ml/kg) via intraperitoneal (i.p.) route 15 min before the nociceptive tests. The dose of cocaine was selected based on a pilot study and a previous report [14]. All procedures performed complied with the "Principles of laboratory animal care" from NIH. The hot-plate (Ugo Basile, model-DS37) was maintained at 52.2 ± 0.5°C following a previously reported procedure [8]. Briefly, the animals were placed in a glass cylinder of 24-cm diameter on the heated metal surface, and the time Cocaine- H Figure 1 ypertensive Rats induced anal in th gee hot-p sia in Wi late test star and Spontaneously between placement and hind paw licking or jumping Cocaine-induced analgesia in Wistar and Spontaneously (whichever occurred first) was recorded as nociceptive Hypertensive Rats in the hot-plate test. Male and female rats latency. A 70-s cut-off was established to prevent tissue of Wistar (WIS) and Spontaneously Hypertensive Rats (SHR) damage. The procedure of the habituation to the hot-plate strains were evaluated in the hot-plate test 15 min after i.p. injection of cocaine (20 mg/kg) (upper panel). SHR rats were apparatus has been described elsewhere [8]. SHR were habituated to the unheated hot-plate apparatus and 1 h after submitted to five sessions of 90-s exposure (at 10-min evaluated for CIA in the hot-plate test (lower panel). Data inter-trial intervals) to the unheated hot-plate apparatus. are presented as nociceptive latencies (s) or the percentage Another group of rats remained undisturbed in their of maximum possible effects (%MPE). * p < 0.05 vs WIS rats home cages and served as non-habituated animals (test of the corresponding gender (upper panel) or vs SHR naive naive rats). One hour after the last habituation session, rats (lower panel) (Newman-Keuls post hoc test). habituated and non-habituated rats were injected with cocaine as previously described and tested on the hot- plate. Because cocaine-induced analgesia was of similar cal pathways involved in the interface between pain, intensity in both genders, this experiment was carried out cognition and emotionality [13]. Systemic administration only with female rats due to their greater availability in of DA re-uptake blockers induces analgesia in rodents, our laboratory. probably by acting on brain dopaminergic pathways [14,15]. The results were expressed as the latency (s) to nocicep- tion or the percentage of maximum possible effect (% The first aim of this study was to examine the effects of MPE) defined by the following equation: cocaine on nociceptive responses in the SHR and in the outbred Wistar (WIS) rat strain (representing a "normal" post-drug latency − basal latency %MPE = × 1 100 genetically heterogenic population) using the hot-plate cut-off − basal latency test. In order to evaluate the contribution of cognitive/ emotional processes in the analgesic effect of cocaine, Statistical analysis was performed using one-, two- or another objective of our study was to evaluate whether three-way ANOVA with condition (habituated and non- Page 2 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:9 http://www.behavioralandbrainfunctions.com/content/3/1/9 habituated) or strain and gender as factors. Repeated uations in SHR suggest that this hypoalgesic phenotype is measure was included as an analysis factor for compari- more likely to be a result of distraction of the SHR from sons of nociceptive latencies before and after drug treat- the nociceptive stimulus (heated plate) rather than reflect- ment. The Newman-Keuls test was used for post-hoc ing stress-induced analgesia. Confirming our previous comparisons. The accepted level of significance was p < study [8], habituation of SHR to the unheated hot-plate 0.05. resulted in a striking reduction of the basal nociceptive latency. These findings, taken together with the fact that The three-way ANOVA (strain, gender and repeated meas- the SHR strain is considered a suitable model of ADHD ure) for the nociceptive latencies in the hot-plate test [10,11], emphasizes that SHR hypoalgesia probably revealed effect for strain [F = 50.45; p < 0.0001], involves cognitive/emotional processes. Finally, several (1,24) repeated measure [F = 62.94; p < 0.0001] and for studies suggest that the nociception of SHR is not associ- (1,24) strain vs repeated measure interaction [F = 18.69; p < ated with their inherited hypertensive trait [4,7]. (1,24) 0.001]. SHR of both sexes (males: 23.7 ± 2.4 s, females: 26.7 ± 2.3 s) showed higher basal latencies to nociception SHR show increased sensitivity to CIA compared to WIS (i.e. hypoalgesia) than WIS rats (males: 15.8 ± 1.1 s, rats. Moreover, habituation to the hot-plate that "normal- females: 11.0 ± 1.1 s). The analgesic effect of cocaine in izes" the hypoalgesic phenotype of SHR did not influence the hot-plate test displayed by SHR and WIS rats of both CIA intensity. There are findings in support of an sexes is illustrated in Figure 1 (upper panel). The two-way increased sensitivity of SHR to other behavioral effects of ANOVA for the % MPE revealed an overall effect of strain psychostimulants. For instance, SHR show increased sus- [F = 29.59; p < 0.0001], indicating that male and ceptibility to convulsions induced by cocaine [18] and (1,24) female SHR showed higher CIA compared to their WIS increased psychomotor stimulation induced by ampheta- counterparts (p < 0.05). mine [19] or methylphenidate [20]. (Although see [21,22]). Alterations in DA neurotransmission have been Figure 1 (lower panel) illustrates the basal hot-plate laten- extensively described in the SHR strain, including reduced cies and % MPE of habituated and nonhabituated SHR. release of DA in the prefrontal cortex, nucleus accumbens One-way ANOVA (condition) for the basal latencies (NAcc) and striatum [23], decreased DA turnover in the revealed that habituated SHR showed lower nociceptive substantia nigra, ventral tegmental area and frontal cortex latencies compared to test naive rats [F = 18.18; p < [23], reduced DA vesicular storage [24] and increased den- (1,11) 0.005]. Habituated and nonhabituated rats displayed sity of the D1/D5 receptors in the anterior forebrain [25]. analgesic effects of cocaine [F = 27.46; p < 0.001]. Interestingly, stimulus-evoked release of DA was lower in (1,11) However, one-way ANOVA (condition) for the % MPE the striatum of SHR [26], although d-amphetamine indicated that CIA was similar in these groups [F = evoked greater release of DA in the prefrontal cortex, NAcc (1,11) 0.63; p = 0.44]. and striatum of SHR compared to Wistar-Kyoto rats [24]. This study provides evidence of increased sensitivity to In summary, SHR have increased sensitivity to behavioral cocaine in terms of analgesia in the SHR strain when com- and neurochemical effects of psychostimulants, which pared to the WIS strain in the hot-plate test. Moreover, may be related to abnormalities in the mesocorticolimbic habituation to the unheated hot-plate reduced the basal dopaminergic system. Because hyperlocomotion and nociceptive latency of SHR without altering the magni- analgesia share a common neural substrate with the tude of the analgesic effect of cocaine. rewarding effects of drugs of abuse [13], it is possible to suggest that the enhanced behavioral effects of cocaine in SHR are hypoalgesic compared to Wistar, Wistar-Kyoto, SHR could reflect the higher preference of SHR for drugs Sprague-Dawley and Lewis rats [4-8,16]. Thus, the results of abuse [27]. Thus, further studies using SHR strain may here presented for basal nociception are in agreement reveal new information on the neurobiological mecha- with the aforementioned findings. As pointed out by Tay- nisms underlying ADHD and its co-morbidity with drug lor et al., the exaggerated fight-or-flight stress responses addiction. and sympathetic activation in SHR may be related to their abnormal nociceptive phenotype [7]. Several studies have Competing interests shown that stress can cause intense analgesia [8,17]; how- The author(s) declare that they have no competing inter- ever, we have reported that when a more severe stressor ests. was employed (forced swimming in cold water), SHR were less vulnerable to stress-induced analgesia compared Authors' contributions to Lewis and WIS rats [8]. This apparent discrepancy FAP carried out the data collection, designed the study regarding an "analgesic" effect produced by exposure in a and wrote the manuscript. LFV and RNT participated in novel environment and the reduced impact of stressful sit- the data analyses, interpretation of data and elaboration Page 3 of 4 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:9 http://www.behavioralandbrainfunctions.com/content/3/1/9 20. Amini B, Yang PB, Swann AC, Dafny N: Differential locomotor of the manuscript. All authors read and approved the final responses in male rats from three strains to acute methyl- manuscript. phenidate. Int J Neurosci 2004, 114(9):1063-1084. 21. Sagvolden T: The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and Acknowledgements impulsiveness in an animal model of Attention-Deficit/ FAP had a scholarship from CNPq, Brazil; LFV had a scholarship from Hyperactivity Disorder (ADHD). Behav Brain Funct 2006, 2:41. CAPES, Brazil; and RNT had a fellowship also from CNPq, Brazil. The 22. Sagvolden T, Metzger MA, Schiorbeck HK, Rugland AL, Spinnangr I, present work was partially funded by a grant from FAPESC/CNPq/ Sagvolden G: The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): changed PRONEX. reactivity to reinforcers and to psychomotor stimulants. Behav Neural Biol 1992, 58(2):103-112. References 23. Russell VA: Hypodopaminergic and hypernoradrenergic activ- ity in prefrontal cortex slices of an animal model for atten- 1. Julius D, Basbaum AI: Molecular mechanisms of nociception. Nature 2001, 413(6852):203-210. tion-deficit hyperactivity disorder--the spontaneously hypertensive rat. Behav Brain Res 2002, 130(1-2):191-196. 2. Villemure C, Bushnell MC: Cognitive modulation of pain: how do attention and emotion influence pain processing? Pain 24. Russell V, de Villiers A, Sagvolden T, Lamm M, Taljaard J: Differences between electrically-, ritalin- and D-amphetamine-stimu- 2002, 95(3):195-199. 3. Mogil JS, Sternberg WF, Marek P, Sadowski B, Belknap JK, Liebeskind lated release of [3H]dopamine from brain slices suggest impaired vesicular storage of dopamine in an animal model JC: The genetics of pain and pain inhibition. Proc Natl Acad Sci U S A 1996, 93(7):3048-3055. of Attention-Deficit Hyperactivity Disorder. Behav Brain Res 1998, 94(1):163-171. 4. Maixner W, Touw KB, Brody MJ, Gebhart GF, Long JP: Factors influencing the altered pain perception in the spontaneously 25. Carey MP, Diewald LM, Esposito FJ, Pellicano MP, Gironi Carnevale UA, Sergeant JA, Papa M, Sadile AG: Differential distribution, hypertensive rat. Brain Res 1982, 237(1):137-145. 5. Plesan A, Hoffmann O, Xu XJ, Wiesenfeld-Hallin Z: Genetic differ- affinity and plasticity of dopamine D-1 and D-2 receptors in the target sites of the mesolimbic system in an animal model ences in the antinociceptive effect of morphine and its potentiation by dextromethorphan in rats. Neurosci Lett 1999, of ADHD. Behav Brain Res 1998, 94(1):173-185. 26. Russell VA: The nucleus accumbens motor-limbic interface of 263(1):53-56. 6. Ramos A, Kangerski AL, Basso PF, Da Silva Santos JE, Assreuy J, Ven- the spontaneously hypertensive rat as studied in vitro by the superfusion slice technique. Neurosci Biobehav Rev 2000, druscolo LF, Takahashi RN: Evaluation of Lewis and SHR rat strains as a genetic model for the study of anxiety and pain. 24(1):133-136. 27. Vendruscolo LF, Terenina-Rigaldie E, Raba F, Ramos A, Takahashi RN, Behav Brain Res 2002, 129(1-2):113-123. 7. Taylor BK, Roderick RE, St Lezin E, Basbaum AI: Hypoalgesia and Mormede P: Evidence for a female-specific effect of a chromo- some 4 locus on anxiety-related behaviors and ethanol drink- hyperalgesia with inherited hypertension in the rat. Am J Phys- iol Regul Integr Comp Physiol 2001, 280(2):R345-54. ing in rats. Genes Brain Behav 2006, 5(6):441-450. 8. Vendruscolo LF, Pamplona FA, Takahashi RN: Strain and sex dif- ferences in the expression of nociceptive behavior and stress-induced analgesia in rats. Brain Res 2004, 1030(2):277-283. 9. Bulka A, Wiesenfeld-Hallin Z: Comparison of response charac- teristics of cutaneous mechanoreceptors in normal and neu- ropathic Sprague-Dawley and spontaneously hypertensive rats. Neurosci Lett 2003, 340(1):61-64. 10. Russell VA, Sagvolden T, Johansen EB: Animal models of atten- tion-deficit hyperactivity disorder. Behav Brain Funct 2005, 1:9. 11. Sagvolden T, Johansen EB, Aase H, Russell VA: A dynamic develop- mental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and com- bined subtypes. Behav Brain Sci 2005, 28(3):397-419; discussion 419-68. 12. Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS: Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci 1996, 58(12):231-239. 13. Altier N, Stewart J: The role of dopamine in the nucleus accumbens in analgesia. Life Sci 1999, 65(22):2269-2287. 14. Lin Y, Morrow TJ, Kiritsy-Roy JA, Terry LC, Casey KL: Cocaine: evi- dence for supraspinal, dopamine-mediated, non-opiate anal- gesia. Brain Res 1989, 479(2):306-312. 15. Shyu BC, Kiritsy-Roy JA, Morrow TJ, Casey KL: Neurophysiologi- cal, pharmacological and behavioral evidence for medial tha- lamic mediation of cocaine-induced dopaminergic analgesia. Publish with Bio Med Central and every Brain Res 1992, 572(1-2):216-223. scientist can read your work free of charge 16. Vendruscolo LF, Vendruscolo JC, Terenina-Rigaldie E, Raba F, Ramos A, Takahashi RN, Mormede P: Genetic influences on behavioral "BioMed Central will be the most significant development for and neuroendocrine responses to predator-odor stress in disseminating the results of biomedical researc h in our lifetime." rats. Neurosci Lett 2006, 409(2):89-94. Sir Paul Nurse, Cancer Research UK 17. Vendruscolo LF, Takahashi RN: Synergistic interaction between mazindol, an anorectic drug, and swim-stress on analgesic Your research papers will be: responses in the formalin test in mice. Neurosci Lett 2004, available free of charge to the entire biomedical community 355(1-2):13-16. 18. Rockhold RW, Surrett RS, Acuff CG, Zhang T, Hoskins B, Ho IK: peer reviewed and published immediately upon acceptance Antagonism of the toxicity of cocaine by MK-801: differential cited in PubMed and archived on PubMed Central effects in spontaneously hypertensive and Wistar-Kyoto rats. Neuropharmacology 1992, 31(12):1269-1277. yours — you keep the copyright 19. Tsai CF, Lin MT: Locomotor hyperactivity in hypertensive rats. BioMedcentral Submit your manuscript here: Pharmacology 1988, 36(1):27-34. http://www.biomedcentral.com/info/publishing_adv.asp Page 4 of 4 (page number not for citation purposes)

Journal

Behavioral and Brain Functions – Springer Journals

Published: Feb 13, 2007

There are no references for this article.