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Early methylphenidate exposure enhances morphine antinociception and tolerance in adult rats
Neuropharmacology 57 (2009) 673–677
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Early methylphenidate exposure enhances morphine antinociception and tolerance in adult rats Michelle C. Cyr*, Michael M. Morgan Department of Psychology, Washington State University Vancouver, 14204 NE Salmon Creek Ave., Vancouver, WA 98686, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 April 2009 Received in revised form 26 June 2009 Accepted 22 July 2009
Methylphenidate (MPH) is often used to reduce the symptoms of Attention-Deficit/Hyperactivity Disorder. Early MPH treatment in rats has been shown to enhance adult morphine-induced antinociception. Although this enhanced antinociception could improve pain treatment, it could also lead to enhanced tolerance to morphine. This hypothesis was tested by examining the effects of MPH administration during the pre-weanling period on morphine-induced antinociception and tolerance in adulthood. Male and female Sprague–Dawley rats received daily IP injections of saline or MPH (2 or 5 mg/kg) for 10 consecutive days beginning on post-natal day (PD) 11. At 60 days of age, morphine (0, 1.8, 3.2, 5.6, 10.0, and 18 mg/kg) antinociception was assessed. Beginning one day later, rats received two daily injections of either saline or morphine (5 mg/kg) for two consecutive days to induce tolerance. On PD 63 cumulative doses of morphine were administered as before to assess the development of tolerance. Rats pretreated with MPH showed enhanced acute morphine antinociception compared to saline pretreated controls. In addition, tolerance to morphine was greater in rats pretreated with MPH early in life. The magnitude of this decrease in morphine potency was dependent on the dose of MPH, such that animals that received 5 mg/kg of MPH from PD 11 to 20 showed the greatest tolerance. These findings demonstrate that MPH exposure during the pre-weanling period has long-lasting effects that include enhanced morphine antinociception and tolerance. Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Methylphenidate Dopamine Opioid Analgesia Morphine tolerance
1. Introduction Attention-Deficit/Hyperactivity Disorder (ADHD) is the most diagnosed childhood psychiatric disorder, with estimated prevalence rates within the United States ranging from 3 to 7% of all school-age children (APA, 1994). Over 90% of these children are prescribed psychostimulants such as methylphenidate (MPH), which increase extracellular dopamine in the synapse (Kimko et al., 1999). Although MPH reduces ADHD symptomatology, little is known about the long-term consequences of early exposure to this compound. Recent research in rodents suggests that early MPH treatment leads to alterations in drug seeking behavior (AchatMendes et al., 2003; Brandon et al., 2001; Crawford et al., 2007). These findings raise concerns about the long term safety of MPH treatment (Kollins et al., 2001). This concern has been amplified in the past decade due to the increasing occurrence of MPH use in preschool-aged children (Vitiello, 2001; Zito et al., 2000) and children who do not meet the criteria for ADHD diagnosis
* Corresponding author. Tel.: þ1 360 546 9726; fax: þ1 360 546 9038. E-mail address: [email protected] (M.C. Cyr). 0028-3908/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2009.07.030
(Marshall, 2000). Thus, a better understanding of the long-term consequences of early MPH treatment is needed. Several studies have found that early MPH exposure alters the reinforcing potential of cocaine, but the direction of these effects is dependent upon the age of the rat during MPH pretreatment. For example, exposing rats to MPH during the periadolescent period (post-natal day (PD) 35–PD 45) (Andersen, 2003) increases drug responsiveness (Brandon et al., 2001), while MPH exposure during the earlier preadolescent period (PD 20–PD 35) (Andersen, 2003) reduces responsiveness to later psychostimulant administration (Andersen et al., 2002; Carlezon et al., 2003). MPH exposure during the pre-weanling stage of development (PD 11–PD 20), analogous to preschool age in children (Andersen, 2003) also increases morphine conditioned place preference and propensity to work for sucrose in adulthood (Crawford et al., 2007). More recently, MPH exposure during this time in ontogeny has been shown to potentiate the antinociceptive effects of morphine (Halladay et al., 2008). Changes in pain modulation are particularly interesting because morphine antinociception in not directly related to the dopamine reward system activated by MPH. The objective of this study is to determine whether the enhanced morphine antinociception produced by prior MPH treatment (Halladay et al., 2008) alters the
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development of morphine tolerance. It is hypothesized that rats exposed to MPH during the pre-weanling period will show enhanced responsiveness to morphine-induced antinociception initially and will show greater morphine tolerance. Moreover, given that morphine antinociception tends to be greater in male compared to female rats (Craft, 2008), MPH enhancement of morphine antinociception is expected to be greater in male rats.
group (MPH 0, 2, or 5 mg/kg) for HP and TW tests using non-linear regression (GraphPad Prism 5 software). The lower limit for calculating D50 values was set at the baseline response. The upper limit was the mean response produced by the highest dose of morphine (18 mg/kg). Differences in D50 values between groups were compared using ANOVA. Statistical significance was defined as probability of less than 0.05.
2. Materials and methods
3.1. Experiment 1: acute morphine antinociception
2.1. Animals Subjects were 102 male and female Sprague–Dawley rats, born and raised at Washington State University Vancouver. Rats were housed with their littermates and dam until weaned (PD 25) and were then moved to separate cages and housed with same sex littermates. The colony room was kept under a reverse 12L:12D cycle and was maintained at 22–24 C. Rats were given continuous access to food and water throughout the experiment except during testing. Experiments were conducted in accordance with the guidelines of the Committee for Research and Ethical Issues of the International Association for the Study of Pain. This experiment was approved by the Animal Care and Use Committee at Washington State University. 2.2. Drugs Methylphenidate hydrochloride (MPH) (Sigma Aldrich, St. Louis, USA) was dissolved in saline and injected intraperitoneally (i.p.) at a volume of 5 ml/kg. Morphine sulfate (a gift from NIDA) was dissolved in saline and injected subcutaneously (s.c.) at a volume of 1 ml/kg. 2.3. MPH pretreatment Starting at PD 11 rats were randomly assigned to one of three pretreatment groups and received daily i.p. injections of saline or MPH (2 or 5 mg/kg). Efforts were taken to ensure that within a given litter each of the three dose conditions were represented within both sexes to control for possible litter effects. These daily injections continued for 10 consecutive days at which time rats were left undisturbed except for twice weekly handling until PD 60. 2.4. Experiment 1: acute morphine antinociception At 60 days of age (analogous to adulthood in humans) (Andersen, 2003), morphine-induced antinociception was assessed using a within-subjects cumulative dosing procedure (for a more in depth description of this procedure see Wenger, 1980). This within-subjects procedure reduces the amount of animals needed for experimentation and yields comparable results to between subjects designs (Morgan et al., 2006). Rats were tested on the tail withdrawal (TW) and hot plate (HP) tests with increasing cumulative doses of morphine (0, 1.8, 1.4, 2.4, 4.4, and 8 mg/kg s.c. injections) resulting in quarter log doses of 0, 1.8, 3.2, 5.6, 10.0, and 18 mg/kg. Injections of morphine occurred every 20 min and rats were tested 15 min after each injection of morphine. Rats were tested on the HP and TW tests in rapid succession.
3. Results
Pretreatment with MPH had no effect on baseline HP latency when rats were tested as adults. Baseline responding was consistent across pretreatment groups on the HP test, (F (2, 96) ¼ 1.15, ns) (Fig. 1). Females (12.3 0.5) had a significantly higher mean baseline latency compared to males (10.7 0.5) (F (1, 96) ¼ 5.11, p < 0.05). This difference was consistent across conditions as indicated by the lack of a sex pretreatment interaction (F (2, 96) ¼ 1.01, ns). Morphine caused a dose dependent increase in HP latency in both male and female rats. There was no overall effect of sex on morphine HP antinociception, (F (1, 602) ¼ 0.1849, ns) (Fig. 2). Pretreatment with MPH during the pre-weanling stage of development altered acute morphine-induced antinociception on the HP test in adulthood, (F (2,606) ¼ 13.25, p < 0.0001). Specifically, rats pretreated with both 2 and 5 mg/kg showed a leftward shift in the dose response curve compared to saline pretreated controls (Fig. 3). D50 values for the MPH2 and MPH5 groups were 6.7 mg/kg and 6.9 mg/kg respectively, whereas saline pretreated animals had a D50 value of 8.4 mg/kg. Rats pretreated with 5 mg/kg MPH had a higher mean baseline TW latency (3.8 0.2) than rats pretreated with 2 mg/kg MPH (3.2 0.2) and saline (3.0 0.2) (F (2,96) ¼ 3.25, p < .05). Males had a higher mean baseline TW latency (3.9 0.2) than females (2.9 0.2) (F (1, 96) ¼ 16.02 p < 0.0001), but there was no significant sex by pretreatment interaction (F (2, 96) ¼ 2.58, ns). Administration of morphine caused an increase in TW latency for all groups, but there was no effect of pretreatment on acute morphine-induced antinociception on the TW test (F (2, 606) ¼ 0.90, ns). D50 values for saline, MPH2, and MPH5 groups were 3.5 mg/kg, 3.2 mg/kg, and 3.3 mg/kg respectively. Male rats (D50 ¼ 2.8 mg/kg) showed greater antinociception on the TW test compared to females (D50 ¼ 3.9 mg/kg) (F (1, 602) ¼ 14.05, p < 0.0001).
2.5. Experiment 2: morphine tolerance At 61 days of age rats were matched based on MPH pretreatment, sex and latency to lick their hind paw following morphine administration on the previous test day. They were then assigned to one of two groups to assess tolerance to morphine antinociception. Rats received two daily injections of either saline or morphine (5 mg/kg) at 09:00 and 15:00 for two consecutive days. At 63 days of age the cumulative-morphine-dose procedure described in Experiment 1 was repeated. 2.6. Measurement of antinociception The HP test consisted of placing the rat on an enclosed hot plate (52.5 C) and measuring the latency to lick a hind paw or attempt to jump out of the apparatus. If no response occurred within 50 s the rat was removed from the hot plate. The TW test consisted of placing the posterior 8–10 cm of the tail in hot water (52.5 C) while the rat rested on the arm of the researcher. The latency to flick the tail was measured. If no response occurred within 12 s the rat’s tail was removed from the water. 2.7. Data analysis Group means SEM were calculated for raw HP and TW latencies. Differences in baseline responding between sexes and pretreatment groups were determined using a 2 3 ANOVA. Morphine dose response curves and the half maximal antinociceptive effect (D50) (Tallarida, 2000) were calculated for each pretreatment
Fig. 1. Mean (SEM) baseline hot plate latency of rats pretreated with saline (SAL), MPH 2 mg/kg (MPH2), and MPH 5 mg/kg (MPH5) from PD 11 to 20 and tested on the HP on PD 60. Saline pretreated animals performed similarly to animals pretreated with 2 and 5 mg/kg of MPH on baseline HP measures (n ¼ 33–35 per group). Female rats had slightly higher baseline latencies than male rats (n ¼ 50–52 per group) across conditions.
M.C. Cyr, M.M. Morgan / Neuropharmacology 57 (2009) 673–677
Fig. 2. Comparison of morphine dose–response curves for male and female rats. Pretreatment groups were collapsed to determine whether there was a sex difference in morphine antinociception. Morphine dose response curves were calculated for male and female rats pretreated with saline (SAL), MPH 2 mg/kg (MPH2), and MPH 5 mg/kg (MPH5) from PD 11 to 20 and tested on the HP on PD 60 (n ¼ 16–19 per group). There was no effect of sex on acute morphine antinociception.
3.2. Experiment 2: morphine tolerance Rats treated with morphine for 2 days showed a reduction in morphine potency on the HP test compared to rats treated with saline for 2 days. This difference in morphine potency was significantly different for each pretreatment group (see Table 1). The magnitude of the rightward shift in tolerant animals varied according to pre-weanling pretreatment. Saline animals showed a 120% shift in D50, MPH2 animals showed a 140% shift in D50, and MPH5 exposed animals showed a 190% shift in D50 (see Fig. 4). 4. Discussion In the present study, pretreatment with the dopamine agonist MPH (2 and 5 mg/kg) from PD11 to 20 enhanced acute morphineinduced antinociception and tolerance on the HP test in adult rats. More specifically rats pretreated with MPH showed a leftward shift in the acute morphine dose response curve compared to saline pretreated controls, indicating enhanced sensitivity to morphine antinociception as adults following chronic MPH exposure during development. Repeated morphine administration to these rats caused an MPH dose dependent enhancement of morphine tolerance. There is a growing literature linking chronic MPH treatment during development to changes in responsiveness to common drugs of abuse (Andersen et al., 2002; Brandon et al., 2001; Crawford et al., 2007). For example, it has been shown that MPH pretreatment can both increase (Brandon et al., 2001) and decrease (Andersen et al., 2002) the rewarding properties of cocaine depending on the age at which rats are exposed to MPH. Adult rats given MPH during the pre-weanling period of ontogeny spend
Table 1 Change in morphine potency (D50) following morphine tolerance.
Saline MPH2 MPH5
Saline
Morphine
F
p
9.41 8.27 7.51
11.5 11.55 14.53
31.67 24.97 121.00
<0.01 <0.01 <0.01
Note: Sample sizes were 16–18 per condition.
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Fig. 3. Early MPH administration enhances morphine antinociception. Morphine dose response curves were calculated for rats pretreated with saline (SAL), MPH 2 mg/kg (MPH2), and MPH 5 mg/kg (MPH5) from PD 11 to 20 and tested on the HP on PD 60 (n ¼ 33–35 per group). Pretreatment with 2 and 5 mg/kg MPH produced a leftward shift in the morphine dose response curve compared to saline pretreated controls.
more time in a morphine-paired compartment compared to saline pretreated animals, indicating an enhanced response to the rewarding properties of morphine (Crawford et al., 2007). This change in morphine responsiveness does not appear to be specific to the reward system because MPH exposure from PD11 to20 also potentiates morphine-induced locomotor activity, hyperthermia, and antinociception in adulthood (Halladay et al., 2008). In particular, Halladay et al. (2008) found that female rats pretreated with MPH displayed a persistent increase in morphine-induced locomotor activity as adults. In this same study, following adult morphine administration, male and female rats exposed to MPH during development were shown to have higher rectal temperatures and HP latencies compared to saline controls. The results of the present study are in agreement with this previously reported enhancement of morphine-induced antinociception as measured by the HP test. Moreover, the demonstration of a leftward shift in the morphine dose response curve extends the work of Halladay et al. (2008). Importantly, the current study adds to the MPH literature by showing that early exposure to this compound also enhances the development of morphine tolerance. Past research reveals sex differences in the antinociceptive properties of acute morphine administration on the HP and TW tests (Candido et al., 1992; Craft, 2008; Kavaliers and Innes, 1987; Lipa and Kavaliers, 1990). A similar sex difference in morphine antinociception has been reported in rats pretreated with MPH early in life (Halladay et al., 2008). Specifically Halladay et al. (2008) found that regardless of MPH pretreatment male rats showed an enhancement of morphine antinociception on both the TW and HP tests compared to female rats. Sex differences were observed on the TW test in the present study, but it is unlikely that these sex differences were a result of MPH pretreatment given the absence of a sex by pretreatment interaction. Moreover, previous research indicates that biological differences between the sexes, such as estrodial levels, may account for the sex dependent differences in morphine antinociception in adult rats (Craft, 2008). Morphine dose dependently produced antinociception on the TW test, but there were no differences in overall tail flick responding between pretreatment groups. This finding is consistent with Halladay et al. (2008) who found effects of MPH on morphine antinociception measured by the HP, but not the TW test. Since the tail flick response is a spinal reflex it is possible that MPH
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involved since it has been shown to be integral in both the rewarding (Flores et al., 2006; Olmstead and Franklin, 1997) and acute antinociceptive properties of opiates (Flores et al., 2004). Specifically, 6-hydroxydopamine (6-OHDA)-induced lesions of the PAG (Olmstead and Franklin, 1997) and infusions of dopaminergic D2 antagonists into the PAG, (Flores et al., 2006) respectively abolished morphine and heroine CPP. Similarly 6-OHDA-induced lesions of large PAG neurons and infusions of dopaminergic D1 antagonists into the PAG, attenuated acute opiate-induced antinociception on the HP test (Flores et al., 2006). When microinjected into the PAG, the dopamine agonist apomorphine produced robust antinociception (Meyer et al., 2009) further demonstrating a relationship between the PAG and dopamine in antinociception. Additionally, acute spinal nociceptive pain reactions, as measured by the TW test, seem not to be affected after PAG manipulation (Flores et al., 2004). Increased acute responsiveness to morphine should lead to greater desensitization of morphine neurons during the induction of tolerance, so it is not surprising that exposure to MPH during the pre-weanling stage of development enhanced morphine tolerance in adulthood. In concordance with the acute effect, this enhanced expression of tolerance also implies the involvement of PAG neurons, since the PAG has been shown to be an important site in the development of tolerance to morphine (Jacquet and Lajtha, 1976; Morgan et al., 2005; Siuciak and Advokat, 1987; Tortorici et al., 1999). Moreover, selective blockade of opioid receptors in the PAG have been shown to prevent tolerance to the antinociceptive effect of systemically administered morphine (Lane et al., 2005). Interestingly, administration of D2 receptor agonists and antagonists have been shown to attenuate the development and expression of morphine tolerance (Zarrindast et al., 2002). Further studies will determine whether MPH pretreatment enhances morphine antinociception and tolerance following morphine microinjection into the PAG. While the underlying mechanisms by which pre-weanling MPH exposure exerts its effects on behavioral output in mature animals is still unclear, it is obvious that treatment with this compound early in life causes global changes in neural mechanisms that persist into adulthood. The ability of MPH to change drug responsiveness, in drugs with different mechanisms of action (psychostimulants and opioids) and across very different behavioral phenomenon (reward and antinociception), is unsettling considering the number of children, including many under age 5, currently taking MPH (Vitiello, 2001). More research in this area is necessary to determine the long-term impact of MPH treatment on ADHD and non-ADHD children. Specifically, further investigation looking at possible molecular changes in PAG dopamine receptors is needed. Fig. 4. Early MPH administration enhanced the development of morphine tolerance. Morphine dose response curves were calculated for rats that were pretreated with saline (SAL), MPH 2 mg/kg (MPH2), and MPH 5 mg/kg (MPH5) from PD 11 to 20 and later received saline (SAL) or morphine (MOR) twice daily from PD 61–62. Data shown is from rats tested on the HP on PD 63 (n ¼ 16–18 per group). Rats who received morphine from PD 61 to -62 showed an MPH dose dependant enhancement of morphine tolerance. (a) Tolerant rats pretreated with saline (SAL/MOR) showed a 120% rightward shift in the dose response curve compared to saline controls (SAL/SAL). (b) Tolerant rats pretreated with 2 mg/kg MPH (MPH2/MOR) showed a 140% rightward shift in the dose response curve compared to saline controls (MPH2/SAL). (c) Tolerant rats pretreated with 5 mg/kg MPH (MPH5/MOR) showed a 190% rightward shift in the dose response curve compared to saline controls (MPH5/SAL).
exposure during this pretreatment regimen is exerting its effects in an exclusively supraspinal manner. The central mechanisms underlying the behavioral changes associated with early exposure to MPH have not been elucidated. It is possible that the periaquiductal gray (PAG) dopamine network is
Acknowledgements Supported by NIDA grant DA015498.
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Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Early methylphenidate exposure enhances morphine antinociception and tolerance in adult rats Michelle C. Cyr*, Michael M. Morgan Department of Psychology, Washington State University Vancouver, 14204 NE Salmon Creek Ave., Vancouver, WA 98686, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 April 2009 Received in revised form 26 June 2009 Accepted 22 July 2009
Methylphenidate (MPH) is often used to reduce the symptoms of Attention-Deficit/Hyperactivity Disorder. Early MPH treatment in rats has been shown to enhance adult morphine-induced antinociception. Although this enhanced antinociception could improve pain treatment, it could also lead to enhanced tolerance to morphine. This hypothesis was tested by examining the effects of MPH administration during the pre-weanling period on morphine-induced antinociception and tolerance in adulthood. Male and female Sprague–Dawley rats received daily IP injections of saline or MPH (2 or 5 mg/kg) for 10 consecutive days beginning on post-natal day (PD) 11. At 60 days of age, morphine (0, 1.8, 3.2, 5.6, 10.0, and 18 mg/kg) antinociception was assessed. Beginning one day later, rats received two daily injections of either saline or morphine (5 mg/kg) for two consecutive days to induce tolerance. On PD 63 cumulative doses of morphine were administered as before to assess the development of tolerance. Rats pretreated with MPH showed enhanced acute morphine antinociception compared to saline pretreated controls. In addition, tolerance to morphine was greater in rats pretreated with MPH early in life. The magnitude of this decrease in morphine potency was dependent on the dose of MPH, such that animals that received 5 mg/kg of MPH from PD 11 to 20 showed the greatest tolerance. These findings demonstrate that MPH exposure during the pre-weanling period has long-lasting effects that include enhanced morphine antinociception and tolerance. Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Methylphenidate Dopamine Opioid Analgesia Morphine tolerance
1. Introduction Attention-Deficit/Hyperactivity Disorder (ADHD) is the most diagnosed childhood psychiatric disorder, with estimated prevalence rates within the United States ranging from 3 to 7% of all school-age children (APA, 1994). Over 90% of these children are prescribed psychostimulants such as methylphenidate (MPH), which increase extracellular dopamine in the synapse (Kimko et al., 1999). Although MPH reduces ADHD symptomatology, little is known about the long-term consequences of early exposure to this compound. Recent research in rodents suggests that early MPH treatment leads to alterations in drug seeking behavior (AchatMendes et al., 2003; Brandon et al., 2001; Crawford et al., 2007). These findings raise concerns about the long term safety of MPH treatment (Kollins et al., 2001). This concern has been amplified in the past decade due to the increasing occurrence of MPH use in preschool-aged children (Vitiello, 2001; Zito et al., 2000) and children who do not meet the criteria for ADHD diagnosis
* Corresponding author. Tel.: þ1 360 546 9726; fax: þ1 360 546 9038. E-mail address: [email protected] (M.C. Cyr). 0028-3908/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2009.07.030
(Marshall, 2000). Thus, a better understanding of the long-term consequences of early MPH treatment is needed. Several studies have found that early MPH exposure alters the reinforcing potential of cocaine, but the direction of these effects is dependent upon the age of the rat during MPH pretreatment. For example, exposing rats to MPH during the periadolescent period (post-natal day (PD) 35–PD 45) (Andersen, 2003) increases drug responsiveness (Brandon et al., 2001), while MPH exposure during the earlier preadolescent period (PD 20–PD 35) (Andersen, 2003) reduces responsiveness to later psychostimulant administration (Andersen et al., 2002; Carlezon et al., 2003). MPH exposure during the pre-weanling stage of development (PD 11–PD 20), analogous to preschool age in children (Andersen, 2003) also increases morphine conditioned place preference and propensity to work for sucrose in adulthood (Crawford et al., 2007). More recently, MPH exposure during this time in ontogeny has been shown to potentiate the antinociceptive effects of morphine (Halladay et al., 2008). Changes in pain modulation are particularly interesting because morphine antinociception in not directly related to the dopamine reward system activated by MPH. The objective of this study is to determine whether the enhanced morphine antinociception produced by prior MPH treatment (Halladay et al., 2008) alters the
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M.C. Cyr, M.M. Morgan / Neuropharmacology 57 (2009) 673–677
development of morphine tolerance. It is hypothesized that rats exposed to MPH during the pre-weanling period will show enhanced responsiveness to morphine-induced antinociception initially and will show greater morphine tolerance. Moreover, given that morphine antinociception tends to be greater in male compared to female rats (Craft, 2008), MPH enhancement of morphine antinociception is expected to be greater in male rats.
group (MPH 0, 2, or 5 mg/kg) for HP and TW tests using non-linear regression (GraphPad Prism 5 software). The lower limit for calculating D50 values was set at the baseline response. The upper limit was the mean response produced by the highest dose of morphine (18 mg/kg). Differences in D50 values between groups were compared using ANOVA. Statistical significance was defined as probability of less than 0.05.
2. Materials and methods
3.1. Experiment 1: acute morphine antinociception
2.1. Animals Subjects were 102 male and female Sprague–Dawley rats, born and raised at Washington State University Vancouver. Rats were housed with their littermates and dam until weaned (PD 25) and were then moved to separate cages and housed with same sex littermates. The colony room was kept under a reverse 12L:12D cycle and was maintained at 22–24 C. Rats were given continuous access to food and water throughout the experiment except during testing. Experiments were conducted in accordance with the guidelines of the Committee for Research and Ethical Issues of the International Association for the Study of Pain. This experiment was approved by the Animal Care and Use Committee at Washington State University. 2.2. Drugs Methylphenidate hydrochloride (MPH) (Sigma Aldrich, St. Louis, USA) was dissolved in saline and injected intraperitoneally (i.p.) at a volume of 5 ml/kg. Morphine sulfate (a gift from NIDA) was dissolved in saline and injected subcutaneously (s.c.) at a volume of 1 ml/kg. 2.3. MPH pretreatment Starting at PD 11 rats were randomly assigned to one of three pretreatment groups and received daily i.p. injections of saline or MPH (2 or 5 mg/kg). Efforts were taken to ensure that within a given litter each of the three dose conditions were represented within both sexes to control for possible litter effects. These daily injections continued for 10 consecutive days at which time rats were left undisturbed except for twice weekly handling until PD 60. 2.4. Experiment 1: acute morphine antinociception At 60 days of age (analogous to adulthood in humans) (Andersen, 2003), morphine-induced antinociception was assessed using a within-subjects cumulative dosing procedure (for a more in depth description of this procedure see Wenger, 1980). This within-subjects procedure reduces the amount of animals needed for experimentation and yields comparable results to between subjects designs (Morgan et al., 2006). Rats were tested on the tail withdrawal (TW) and hot plate (HP) tests with increasing cumulative doses of morphine (0, 1.8, 1.4, 2.4, 4.4, and 8 mg/kg s.c. injections) resulting in quarter log doses of 0, 1.8, 3.2, 5.6, 10.0, and 18 mg/kg. Injections of morphine occurred every 20 min and rats were tested 15 min after each injection of morphine. Rats were tested on the HP and TW tests in rapid succession.
3. Results
Pretreatment with MPH had no effect on baseline HP latency when rats were tested as adults. Baseline responding was consistent across pretreatment groups on the HP test, (F (2, 96) ¼ 1.15, ns) (Fig. 1). Females (12.3 0.5) had a significantly higher mean baseline latency compared to males (10.7 0.5) (F (1, 96) ¼ 5.11, p < 0.05). This difference was consistent across conditions as indicated by the lack of a sex pretreatment interaction (F (2, 96) ¼ 1.01, ns). Morphine caused a dose dependent increase in HP latency in both male and female rats. There was no overall effect of sex on morphine HP antinociception, (F (1, 602) ¼ 0.1849, ns) (Fig. 2). Pretreatment with MPH during the pre-weanling stage of development altered acute morphine-induced antinociception on the HP test in adulthood, (F (2,606) ¼ 13.25, p < 0.0001). Specifically, rats pretreated with both 2 and 5 mg/kg showed a leftward shift in the dose response curve compared to saline pretreated controls (Fig. 3). D50 values for the MPH2 and MPH5 groups were 6.7 mg/kg and 6.9 mg/kg respectively, whereas saline pretreated animals had a D50 value of 8.4 mg/kg. Rats pretreated with 5 mg/kg MPH had a higher mean baseline TW latency (3.8 0.2) than rats pretreated with 2 mg/kg MPH (3.2 0.2) and saline (3.0 0.2) (F (2,96) ¼ 3.25, p < .05). Males had a higher mean baseline TW latency (3.9 0.2) than females (2.9 0.2) (F (1, 96) ¼ 16.02 p < 0.0001), but there was no significant sex by pretreatment interaction (F (2, 96) ¼ 2.58, ns). Administration of morphine caused an increase in TW latency for all groups, but there was no effect of pretreatment on acute morphine-induced antinociception on the TW test (F (2, 606) ¼ 0.90, ns). D50 values for saline, MPH2, and MPH5 groups were 3.5 mg/kg, 3.2 mg/kg, and 3.3 mg/kg respectively. Male rats (D50 ¼ 2.8 mg/kg) showed greater antinociception on the TW test compared to females (D50 ¼ 3.9 mg/kg) (F (1, 602) ¼ 14.05, p < 0.0001).
2.5. Experiment 2: morphine tolerance At 61 days of age rats were matched based on MPH pretreatment, sex and latency to lick their hind paw following morphine administration on the previous test day. They were then assigned to one of two groups to assess tolerance to morphine antinociception. Rats received two daily injections of either saline or morphine (5 mg/kg) at 09:00 and 15:00 for two consecutive days. At 63 days of age the cumulative-morphine-dose procedure described in Experiment 1 was repeated. 2.6. Measurement of antinociception The HP test consisted of placing the rat on an enclosed hot plate (52.5 C) and measuring the latency to lick a hind paw or attempt to jump out of the apparatus. If no response occurred within 50 s the rat was removed from the hot plate. The TW test consisted of placing the posterior 8–10 cm of the tail in hot water (52.5 C) while the rat rested on the arm of the researcher. The latency to flick the tail was measured. If no response occurred within 12 s the rat’s tail was removed from the water. 2.7. Data analysis Group means SEM were calculated for raw HP and TW latencies. Differences in baseline responding between sexes and pretreatment groups were determined using a 2 3 ANOVA. Morphine dose response curves and the half maximal antinociceptive effect (D50) (Tallarida, 2000) were calculated for each pretreatment
Fig. 1. Mean (SEM) baseline hot plate latency of rats pretreated with saline (SAL), MPH 2 mg/kg (MPH2), and MPH 5 mg/kg (MPH5) from PD 11 to 20 and tested on the HP on PD 60. Saline pretreated animals performed similarly to animals pretreated with 2 and 5 mg/kg of MPH on baseline HP measures (n ¼ 33–35 per group). Female rats had slightly higher baseline latencies than male rats (n ¼ 50–52 per group) across conditions.
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Fig. 2. Comparison of morphine dose–response curves for male and female rats. Pretreatment groups were collapsed to determine whether there was a sex difference in morphine antinociception. Morphine dose response curves were calculated for male and female rats pretreated with saline (SAL), MPH 2 mg/kg (MPH2), and MPH 5 mg/kg (MPH5) from PD 11 to 20 and tested on the HP on PD 60 (n ¼ 16–19 per group). There was no effect of sex on acute morphine antinociception.
3.2. Experiment 2: morphine tolerance Rats treated with morphine for 2 days showed a reduction in morphine potency on the HP test compared to rats treated with saline for 2 days. This difference in morphine potency was significantly different for each pretreatment group (see Table 1). The magnitude of the rightward shift in tolerant animals varied according to pre-weanling pretreatment. Saline animals showed a 120% shift in D50, MPH2 animals showed a 140% shift in D50, and MPH5 exposed animals showed a 190% shift in D50 (see Fig. 4). 4. Discussion In the present study, pretreatment with the dopamine agonist MPH (2 and 5 mg/kg) from PD11 to 20 enhanced acute morphineinduced antinociception and tolerance on the HP test in adult rats. More specifically rats pretreated with MPH showed a leftward shift in the acute morphine dose response curve compared to saline pretreated controls, indicating enhanced sensitivity to morphine antinociception as adults following chronic MPH exposure during development. Repeated morphine administration to these rats caused an MPH dose dependent enhancement of morphine tolerance. There is a growing literature linking chronic MPH treatment during development to changes in responsiveness to common drugs of abuse (Andersen et al., 2002; Brandon et al., 2001; Crawford et al., 2007). For example, it has been shown that MPH pretreatment can both increase (Brandon et al., 2001) and decrease (Andersen et al., 2002) the rewarding properties of cocaine depending on the age at which rats are exposed to MPH. Adult rats given MPH during the pre-weanling period of ontogeny spend
Table 1 Change in morphine potency (D50) following morphine tolerance.
Saline MPH2 MPH5
Saline
Morphine
F
p
9.41 8.27 7.51
11.5 11.55 14.53
31.67 24.97 121.00
<0.01 <0.01 <0.01
Note: Sample sizes were 16–18 per condition.
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Fig. 3. Early MPH administration enhances morphine antinociception. Morphine dose response curves were calculated for rats pretreated with saline (SAL), MPH 2 mg/kg (MPH2), and MPH 5 mg/kg (MPH5) from PD 11 to 20 and tested on the HP on PD 60 (n ¼ 33–35 per group). Pretreatment with 2 and 5 mg/kg MPH produced a leftward shift in the morphine dose response curve compared to saline pretreated controls.
more time in a morphine-paired compartment compared to saline pretreated animals, indicating an enhanced response to the rewarding properties of morphine (Crawford et al., 2007). This change in morphine responsiveness does not appear to be specific to the reward system because MPH exposure from PD11 to20 also potentiates morphine-induced locomotor activity, hyperthermia, and antinociception in adulthood (Halladay et al., 2008). In particular, Halladay et al. (2008) found that female rats pretreated with MPH displayed a persistent increase in morphine-induced locomotor activity as adults. In this same study, following adult morphine administration, male and female rats exposed to MPH during development were shown to have higher rectal temperatures and HP latencies compared to saline controls. The results of the present study are in agreement with this previously reported enhancement of morphine-induced antinociception as measured by the HP test. Moreover, the demonstration of a leftward shift in the morphine dose response curve extends the work of Halladay et al. (2008). Importantly, the current study adds to the MPH literature by showing that early exposure to this compound also enhances the development of morphine tolerance. Past research reveals sex differences in the antinociceptive properties of acute morphine administration on the HP and TW tests (Candido et al., 1992; Craft, 2008; Kavaliers and Innes, 1987; Lipa and Kavaliers, 1990). A similar sex difference in morphine antinociception has been reported in rats pretreated with MPH early in life (Halladay et al., 2008). Specifically Halladay et al. (2008) found that regardless of MPH pretreatment male rats showed an enhancement of morphine antinociception on both the TW and HP tests compared to female rats. Sex differences were observed on the TW test in the present study, but it is unlikely that these sex differences were a result of MPH pretreatment given the absence of a sex by pretreatment interaction. Moreover, previous research indicates that biological differences between the sexes, such as estrodial levels, may account for the sex dependent differences in morphine antinociception in adult rats (Craft, 2008). Morphine dose dependently produced antinociception on the TW test, but there were no differences in overall tail flick responding between pretreatment groups. This finding is consistent with Halladay et al. (2008) who found effects of MPH on morphine antinociception measured by the HP, but not the TW test. Since the tail flick response is a spinal reflex it is possible that MPH
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involved since it has been shown to be integral in both the rewarding (Flores et al., 2006; Olmstead and Franklin, 1997) and acute antinociceptive properties of opiates (Flores et al., 2004). Specifically, 6-hydroxydopamine (6-OHDA)-induced lesions of the PAG (Olmstead and Franklin, 1997) and infusions of dopaminergic D2 antagonists into the PAG, (Flores et al., 2006) respectively abolished morphine and heroine CPP. Similarly 6-OHDA-induced lesions of large PAG neurons and infusions of dopaminergic D1 antagonists into the PAG, attenuated acute opiate-induced antinociception on the HP test (Flores et al., 2006). When microinjected into the PAG, the dopamine agonist apomorphine produced robust antinociception (Meyer et al., 2009) further demonstrating a relationship between the PAG and dopamine in antinociception. Additionally, acute spinal nociceptive pain reactions, as measured by the TW test, seem not to be affected after PAG manipulation (Flores et al., 2004). Increased acute responsiveness to morphine should lead to greater desensitization of morphine neurons during the induction of tolerance, so it is not surprising that exposure to MPH during the pre-weanling stage of development enhanced morphine tolerance in adulthood. In concordance with the acute effect, this enhanced expression of tolerance also implies the involvement of PAG neurons, since the PAG has been shown to be an important site in the development of tolerance to morphine (Jacquet and Lajtha, 1976; Morgan et al., 2005; Siuciak and Advokat, 1987; Tortorici et al., 1999). Moreover, selective blockade of opioid receptors in the PAG have been shown to prevent tolerance to the antinociceptive effect of systemically administered morphine (Lane et al., 2005). Interestingly, administration of D2 receptor agonists and antagonists have been shown to attenuate the development and expression of morphine tolerance (Zarrindast et al., 2002). Further studies will determine whether MPH pretreatment enhances morphine antinociception and tolerance following morphine microinjection into the PAG. While the underlying mechanisms by which pre-weanling MPH exposure exerts its effects on behavioral output in mature animals is still unclear, it is obvious that treatment with this compound early in life causes global changes in neural mechanisms that persist into adulthood. The ability of MPH to change drug responsiveness, in drugs with different mechanisms of action (psychostimulants and opioids) and across very different behavioral phenomenon (reward and antinociception), is unsettling considering the number of children, including many under age 5, currently taking MPH (Vitiello, 2001). More research in this area is necessary to determine the long-term impact of MPH treatment on ADHD and non-ADHD children. Specifically, further investigation looking at possible molecular changes in PAG dopamine receptors is needed. Fig. 4. Early MPH administration enhanced the development of morphine tolerance. Morphine dose response curves were calculated for rats that were pretreated with saline (SAL), MPH 2 mg/kg (MPH2), and MPH 5 mg/kg (MPH5) from PD 11 to 20 and later received saline (SAL) or morphine (MOR) twice daily from PD 61–62. Data shown is from rats tested on the HP on PD 63 (n ¼ 16–18 per group). Rats who received morphine from PD 61 to -62 showed an MPH dose dependant enhancement of morphine tolerance. (a) Tolerant rats pretreated with saline (SAL/MOR) showed a 120% rightward shift in the dose response curve compared to saline controls (SAL/SAL). (b) Tolerant rats pretreated with 2 mg/kg MPH (MPH2/MOR) showed a 140% rightward shift in the dose response curve compared to saline controls (MPH2/SAL). (c) Tolerant rats pretreated with 5 mg/kg MPH (MPH5/MOR) showed a 190% rightward shift in the dose response curve compared to saline controls (MPH5/SAL).
exposure during this pretreatment regimen is exerting its effects in an exclusively supraspinal manner. The central mechanisms underlying the behavioral changes associated with early exposure to MPH have not been elucidated. It is possible that the periaquiductal gray (PAG) dopamine network is
Acknowledgements Supported by NIDA grant DA015498.
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