Chronic psychostimulant exposure to adult, but not periadolescent rats reduces subsequent morphine antinociception

Abstract

Preweanling methylphenidate (MPH) exposure produces a long lasting enhanced sensitivity to opioids. Two important questions are whether this enhancement is specific to the age of psychostimulant exposure and the type of psychostimulant. To answer these questions periadolescent (PD 35) and adult (PD 55) rats received daily injections of saline, MPH, or methamphetamine (METH) for 10 consecutive days. Two weeks later, acute morphine antinociception was assessed on the hot plate using a cumulative dose response procedure. Following acute antinociceptive testing, morphine tolerance was induced in half the animals by administering morphine twice a day over two days. Rats pretreated with MPH and METH during the periadolescent period of ontogeny showed no change in acute morphine antinociception, but rats exposed to a relatively high METH dose (3 mg/kg) displayed enhanced morphine tolerance compared to saline pretreated controls. MPH and METH pretreatment during adulthood led to a reduction in morphine antinociceptive potency and an apparent reduction in morphine tolerance. When combined with our previously published findings, these data indicate that the developmental stage during which MPH and METH exposure occurs differentially alters adult morphine responsiveness. That is, psychostimulant exposure to preweanling rats enhances morphine antinociception and facilitates the development of tolerance, whereas psychostimulant exposure to adult rats reduces subsequent morphine antinociception and tolerance. These alterations indicate that it could be important for physicians to know about prior psychostimulant use when prescribing opioids for pain relief.

1. Introduction

Psychostimulants such as methylphenidate (MPH) and methamphetamine (METH) are commonly used for extended periods of time. Such long-term use, whether prescribed as medication or used illegally, increases the likelihood of long-lasting neural changes. For example, chronic exposure to psychostimulants has been shown to cause long-term changes to brain transcription factors and second messenger molecules (Carlezon and Konradi, 2004, Crawford et al., 2011, Yano and Steiner, 2007). These molecular changes correlate with behavioral changes such as psychostimulant-induced locomotor sensitization (Dafny and Yang, 2006, Martin-Iverson and Burger, 1995, Vezina, 2004), enhanced psychostimulant self-administration (Brandon et al., 2001, Schenk and Partridge, 1997, Vezina, 2004), and an increase in psychostimulant place preference (Lett, 1989, Meririnne et al., 2001). Although many psychostimulants such as MPH, cocaine, amphetamine, and METH exert their effects via the dopamine transporter (DAT), an important question is whether these drugs impact other transmitter systems.

The frequent use of psychostimulants such as MPH to treat ADHD in children, raises questions about the long term effects of MPH exposure during ontogeny (Kollins et al., 2001). Chronic MPH treatment can enhance or attenuate psychostimulant drug seeking behavior in adulthood, but the direction of these effects appears to be dependent upon the age of the rat during MPH pretreatment (Achat-Mendes et al., 2003, Brandon et al., 2001, Crawford et al., 2007). Chronic MPH administration to preweanling rats (PD 11–20) enhances both the rewarding (Crawford et al., 2007) and antinociceptive (Cyr and Morgan, 2009, Halladay et al., 2009) effects of subsequent administration of an opioid such as morphine.

MPH-induced changes in pain modulation are particularly interesting because morphine antinociception is not directly related to the dopamine (DA) reward system activated by psychostimulants. That is, the ventral tegmental area and nucleus accumbens are part of the DA reward pathway (Maldonado, 2003), whereas morphine produces antinociception primarily by binding to mu-opioid receptors in the periaqueductal gray, rostral ventromedial medulla, and spinal cord (Yaksh, 1997). Because the period of ontogeny during which MPH exposure occurs can dictate the direction of later psychostimulant response, it is possible that developmental age also affects later morphine-induced antinociception and tolerance. Moreover, if adaptations to the DAT underlie the long-term changes in morphine responsiveness, then the different interactions with the DAT produced by MPH (prevents DA reuptake) and METH (stimulates DA release and prevents reuptake) could produce different effects. The effects of METH were included because use of this drug is common in adolescents and adults, whereas MPH is more commonly used in children. Thus, the present experiments will test two hypotheses: a) The age of chronic psychostimulant exposure will determine the long-term effects of morphine; and b) These effects will be similar whether rats are treated with MPH or METH. These hypotheses were tested by comparing morphine antinociception and tolerance in adult rats pretreated with MPH and METH during periadolescence or early adulthood.

2. Materials and Methods

2.1. Animals

Subjects were periadolescent and adult male Sprague-Dawley rats, purchased from Harlan Laboratories (Livermore, CA). Rats were group housed (4 – 6 per cage) with littermates throughout the experiments to reduce stress from housing rats individually. A subset of rats in each cage were treated with saline and MPH or METH. The colony room was kept on a reverse 12 L: 12 D cycle and maintained at 22°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. Compounds

MPH hydrochloride and METH (Sigma Aldrich, St. Louis, USA) were dissolved in saline and injected i.p. in a volume of 2 ml/kg for periadolescents and 1 ml/kg for adults. A larger volume was used in the smaller periadolescent rats to provide accurate dosing. Morphine sulfate (a gift from NIDA) was dissolved in saline and injected s.c. in a volume of 1 ml/kg.

2.3. Pretreatment

Starting at PD 35 (n = 71) or PD 55 (n = 73) rats were randomly assigned to one of four pretreatment groups distinguished by daily i.p. injections of SAL, METH (1 or 3 mg/kg), or MPH (5 mg/kg). The dose of 1 mg/kg METH was chosen because it is the lowest dose shown to consistently produce behavioral sensitization (Bevins and Peterson, 2004; Hall et al., 2008). Because animals were group housed and higher doses of METH can elicit aggressive behavior, a moderate dose of 3 mg/kg was chosen to detect possible dose response effects. Daily injections occurred between 10:00 and 13:00 and continued for 10 consecutive days at which time rats were left undisturbed for 2 weeks except for handling several times a week. At the end of this 2-week period, the acute antinociceptive effects of morphine were assessed. Although strict blind testing procedures were not used, the 2-week delay prevented knowledge of the pretreatment condition on the test day.

2.4. Acute morphine-induced antinociception

The effects of periadolescent and adult psychostimulant pretreatment on acute morphine antinociception were assessed at 60 and 80 days of age, respectively. A quarter log cumulative dosing procedure was used, wherein cumulative doses of morphine were injected every 20 minutes resulting in quarter log doses of 1.8, 3.2, 5.6, 10.0, and 18 mg/kg. This procedure allows the generation of complete dose-response curves from a relatively small number of rats (Morgan et al., 2006). Nociception was assessed using the hot plate test 15 min after each injection. The hot plate test consisted of measuring the latency to lick the hind paw when placed on a 52.5°C plate. The rat was removed from the hot plate if no response occurred within 50 s.

2.5. Morphine tolerance

Following the assessment of acute morphine-induce antinociception, rats were divided into tolerance treatment groups. Half the animals in each age group (periadolescent and adult exposure) and from each pretreatment group (MPH, METH, or SAL) were injected with either SAL or morphine (5 mg/kg, s.c.) twice daily for two consecutive days (Table 1). Morphine tolerance was assessed 16 hrs after the last injection. Tolerance to morphine was assessed using the same cumulative dose procedure described above (Section 2.4).

Table 1.

Outline of the experimental procedure showing the 8 groups tested acutely with morphine and the 16 groups tested for morphine tolerance.

Age	10-Day Treatment	Acute Test Sample Size	Tolerance Treatment	Tolerance Test Sample Size
			Saline	9
	Saline	18
			Morphine	8
			Saline	9
	MPH (5 mg/kg)	18
			Morphine	9
Periadolescent
			Saline	8
	METH (1 mg/kg)	16
			Morphine	8
			Saline	9
	METH (3 mg/kg)	19
			Morphine	8
			Saline	11
	Saline	22
			Morphine	11
			Saline	8
	MPH (5 mg/kg)	17
			Morphine	9
Adult
			Saline	9
	METH (1 mg/kg)	17
			Morphine	8
			Saline	9
	METH (3 mg/kg)	17
			Morphine	8

Note: Morphine responses were assessed both before (Acute: Section 2.4) and after the tolerance treatment procedure (Tolerance: Section 2.5). The sample size for each “Tolerance Test” of saline and morphine treated rats should add to the sample size for the “Acute Test” except when it was not possible to test a rat in both conditions.

2.6. Data analysis

Adolescent and adult rats were tested at different times of the year. Thus, the effects of psychostimulant pretreatment was compared to saline pretreated controls within each age and not across ages. Baseline nociceptive hot plate latency was analyzed using a one-way ANOVA with psycholstimulant pretreatment as the between group factor. Following the induction of tolerance, baseline hot plate latency was analyzed using a 4 × 2 ANOVA with psychostimulant pretreatment and tolerance treatment as the between group factors. Post hoc comparisons for baseline assessments were conducted using Tukey HSD tests. Morphine dose-response curves and the dose of half maximal antinociception (D₅₀) were calculated for all groups using non-linear regression (GraphPad Prism 5). The lower limit for calculating D₅₀ values was set at the mean baseline hot plate response. The upper limit was set at the mean response produced by the highest dose of morphine (18 mg/kg). Changes in D₅₀ values were assessed using ANOVA (GraphPad Prism 5) and 99% confidence intervals.

3. Results

3.1. Acute morphine-induced antinociception

Baseline hot plate latencies for rats pretreated with MPH, METH 1 mg/kg, and METH 3 mg/kg as periadolescents and tested 2 weeks later as adults were similar to SAL pretreated rats (F (3, 64) = 1.74, p = 0.17; Table 2). Morphine dose-dependently produced antinociception in all pretreatment groups (Figure 1A). There was a significant main effect of periadolescent pretreatment on acute morphine-induced antinociception in adulthood, (F (3, 347) = 2.912, p = 0.034), but none of the psychostimulant pretreated groups differed from saline treated controls as revealed by overlapping 99% confidence intervals (Table 3). Statistical significance was driven by enhanced acute morphine-induced antinociception in MPH compared to METH (1 mg/kg) pretreated animals.

Table 2.

Mean (± SEM) baseline hot plate test latency two weeks after psychostimulant pretreatment

Pretreatment	Periadolescent	Adult
SAL	12.5 ± 0.7	11.8 ± 0.7
MPH	15.0 ± 1.0	13.8 ± 1.1
METH (1 mg/kg)	13.3 ± 0.8	11.0 ± 0.5
METH (3 mg/kg)	13.0 ± 0.8	11.8 ± 0.8

Figure 1.

Acute morphine antinociception. (A) Acute adult morphine antinociceptive potency following periadolescent pretreatment with SAL, MPH, or METH. Pretreatment with psychostimulants from PD 35–44 had no effect on morphine-induced antinociception when measured by the hot plate test on PD 60. (B) Acute adult morphine antinociceptive potency following adult pretreatment with SAL, MPH, or METH. Pretreatment with psychostimulants from PD 55–64 reduced morphine-induced antinociception compared to SAL pretreated controls when measured by the hot plate test on PD 80.

Table 3.

Comparison of morphine D₅₀ values in rats pretreated as periadolescents

		Following Tolerance Procedure
Pretreatment	Acute	Saline	Morphine	% Shift
Saline	6.2 ± 1.1	8.4 ± 1.3	11.1 ± 1.9#	179%
MPH	5.4 ± 1.0	8.0 ± 1.1	10.1 ± 1.6#	187%
METH 1	7.2 ± 1.1	8.9 ± 1.5	12.6 ± 2.5#	175%
METH 3	6.4 ± 1.0	7.7 ± 1.4	14.3 ± 1.8‡#	223%

D₅₀ ± 99% confidence interval is in mg/kg. % Shifts were calculated as D₅₀ morphine ÷ D₅₀ acute × 100, within each pretreatment group.

^‡denotes statistical significance from saline pretreated rats

^#denotes statistical significance from tolerance controls

A small difference in baseline hot plate latencies was evident in rats that received different pretreatments during adulthood (F (3, 65) = 2.81, p < 0.05) (Table 2). Post hoc analysis indicated that the difference in baseline responding existed between rats pretreated with MPH and 1 mg/kg of METH (p < 0.05), but none of the groups differed from saline pretreated controls. Subsequent morphine administration produced a dose-dependent antinociception in all groups (Figure 1B). Rats pretreated with MPH and METH (1 and 3 mg/kg) during adulthood were less sensitive to the acute antinociceptive effects of morphine as indicated by a significant rightward shift in the morphine dose response curve compared to saline pretreated controls, (F (3, 357) = 12.40, p < 0. 01; Figure 1B). The D₅₀ values for acute morphine antinociception in all three of the psychostimulant pretreated groups were outside the 99% confidence interval for morphine antinociception in the saline pretreated animals (Table 4).

Table 4.

Comparison of morphine D₅₀ values in rats pretreated as adults

	Following Tolerance Procedure
Pretreatment	Acute	Saline	Morphine	% Shift
Saline	5.0 ± 0.8	9.0 ± 1.3	10.2 ± 2.0	204%
MPH	7.5 ± 1.0‡	8.1 ± 1.5	11.4 ± 2.4#	152%
METH 1	7.3 ± 1.0‡	9.6 ± 2.0	13.8 ± 3.1#	189%
METH 3	7.8 ± 1.3‡	10.6 ± 1.6	12.1 ± 3.2	155%

D₅₀ ± 99% confidence interval is in mg/kg. % Shifts were calculated as D₅₀ morphine ÷ D₅₀ acute × 100, within each pretreatment group.

^‡denotes statistical significance from saline pretreated rats

^#denotes statistical significance from tolerance controls

3.2. Morphine tolerance

Morphine tolerance was induced with repeated injections of morphine (saline was injected as a control) on the two days following the acute antinociceptive test (Table 1). Neither periadolescent psychostimulant pretreatment (F (3, 64) = 0.20, p = 0.90), nor tolerance treatment (F (1, 64) = 2.84, p = 0.10) altered hot plate latency immediately prior to tolerance assessment (Figure 2A). Repeated administration of morphine for 2 days caused a rightward shift in the morphine dose response curve compared to rats injected with saline for two days as would be expected with the development of tolerance. This shift was evident whether rats were pretreated with saline (F (1, 82) = 11.49, p = 0.0001), MPH (F (1, 86) = 7.657, p = 0.007), 1 mg/kg of METH (F (1, 77) = 7.708, p = 0.007), or 3 mg/kg of METH (F (1, 71) = 57.51, p < 0.0001) as periadolescents (Table 3; Figure 3). The magnitude of morphine tolerance was the greatest in periadolescent animals pretreated with 3 mg/kg of METH (F (3, 157) = 2.678, p < 0.05). The D₅₀ in rats pretreated with 3 mg/kg of METH shifted from 7.7 mg/kg in control rats to 14.3 mg/kg in morphine tolerant rats (See Table 3).

Figure 2.

Hot plate latency in adult rats following pretreatment with psychostimulants and morphine. (A) Baseline hot plate latencies did not differ between periadolescent pretreatment or tolerance treatment groups on PD 63 following the induction of tolerance (n = 8 – 9 per group). (B) Baseline hot plate latencies did not differ between adult pretreatment or tolerance treatment groups on PD 83 following the induction of tolerance (n = 8 – 12 per group).

Figure 3.

Assessment of morphine tolerance following periadolescent psychostimulant pretreatment. Administration of morphine caused a rightward shift in the morphine dose-response that was comparable in rats pretreated as adolescents with saline (A), MPH (B), and 1 mg/kg of METH (C). Rats pretreated with 3 mg/kg of METH (D) showed a significantly greater rightward shift in the dose response curve in morphine compared to saline treated rats (e.g., greater tolerance) than the other groups (Figures A–C). Rats injected with saline instead of morphine twice a day for two days also showed a rightward shift in the morphine dose response curve compared to the acute morphine dose-response data collected prior to the tolerance induction procedure. This finding suggests that administration of morphine during the acute test caused a small degree of tolerance.

In rats pretreated as adults, neither psychostimulant pretreatment (F (3, 71) = 0.34, p = 0.80) nor tolerance treatment (F (3, 71) = 0.16, p = 0.70) altered baseline hot plate latencies following the induction of tolerance (Figure 2B). MPH (F (1, 82) = 25.99, p < 0.0001) and METH 1 mg/kg (F (1, 82) = 7.008, p = 0.0097) pretreated rats given morphine for 2 days showed a reduction in morphine potency compared to similarly pretreated rats given saline for 2 days (Figure 4). Saline (F (1, 112) = 0.681, p = 0.410) and METH 3 mg/kg (F (1, 81) = 0.633, p = 0.428) pretreated rats had a much smaller, and non-significant, shift in morphine potency as a result of repeated morphine injections (Figure 4). Following the induction of tolerance, there was no significant difference in morphine potency between psychostimulant pretreated groups (F (3, 177) = 2.296, p = 0.079). Unfortunately, this comparison is compromised by the greater morphine potency in saline pretreated rats during the acute antinociception test. Comparison of morphine potency before and after the induction of tolerance reveals a large shift (204%) in the D₅₀ value of rats pretreated with saline. In contrast, rats pretreated with 1 mg/kg of METH showed a 189% shift in D₅₀ value, and MPH and METH 3 mg/kg pretreated animals showed a 152% and 155% D₅₀ shift, respectively (Table 4).

Figure 4.

Assessment of morphine tolerance following adult psychostimulant pretreatment. Administration of morphine caused a significant rightward shift in the morphine dose-response curve in rats pretreated as adults with MPH (B) or 1 mg/kg of METH (C). There was no significant shift in the morphine dose response curves in rats pretreated with saline (A) or 3 mg/kg of METH (D). Rats injected with saline instead of morphine twice a day for two days also showed a rightward shift in the morphine dose-response curve compared to the acute morphine dose-response data collected prior to the tolerance induction procedure. This finding suggests that administration of morphine during the acute test caused a small degree of tolerance.

4. Discussion

The present data show that chronic pretreatment with psychostimulants produced long-lasting effects on morphine antinociception and tolerance. These effects varied based on the compound used for pretreatment and the age at which pretreatment occurred. Rats pretreated with MPH and METH during the periadolescent period of ontogeny showed no change in acute morphine-induced antinociception, but the same pretreatment in adult rats reduced morphine potency measured two weeks later. The effects of psychostimulant pretreatment on tolerance to morphine antinociception is less clear. Tolerance was enhanced in rats exposed to 3 mg/kg of METH as adolescents, whereas minimal tolerance was evident in rats pretreated with psychostimulants as adults.

Previous research in our lab found that preweanling pretreatment with 2 and 5 mg/kg of MPH enhanced acute morphine-induced antinociception and tolerance in adulthood (Cyr and Morgan, 2009). That is, morphine potency was greater initially, but repeated morphine administration resulted in greater tolerance (e.g., a rightward shift in the dose response curve) in rats pretreated with MPH compared to saline. This effect was not replicated in the current study when chronic MPH pretreatment was administered during the periadolescent period. The lack of enhancement of morphine antinociception in periadolescent rats suggests that there is a critical period for enhancement that requires exposure early in life. In both studies, hot plate assessments began at PD60, so the amount of elapsed time between pretreatment and testing was shorter (2 weeks) in the present study. Previous research has shown that a 2-week withdrawal period following periadolescent MPH exposure was sufficient to produce a robust enhancement of cocaine-induced locomotion and cocaine self-administration (Brandon et al., 2001).

Chronic MPH exposure has been shown to cause alterations in later psychostimulant responsiveness (Achat-Mendes et al., 2003, Brandon et al., 2001, Crawford et al., 2007). Sometimes these alterations are consistent regardless of what age MPH exposure occurred, but often these changes in drug responsiveness are dependent upon the age of the rat during MPH pretreatment. For example, exposing rats to MPH during the preweanling (Crawford et al., 2011), periadolescent (Brandon et al., 2001), and adult (Schenk and Izenwasser, 2002) stages of ontogeny enhanced later cocaine self-administration regardless of the developmental pretreatment period. In contrast, preweanling MPH exposure had no effect on later cocaine place preference (Crawford et al., 2011), but MPH exposure during the preadolescent period (PD 20–PD 35) reduced cocaine place preference (Andersen et al., 2002, Carlezon et al., 2003). It is not surprising then that the developmental stage during which MPH exposure occurs could affect subsequent morphine responsiveness as well. Moreover, as the DA system develops during early ontogeny, responsiveness to DA agonists could vary, and subsequently, long-term changes induced by chronic administration of these drugs would vary depending on when exposure occurred.

Adult animals pretreated with either MPH or METH showed a very different behavioral profile than preweanling (Cyr and Morgan, 2009) and periadolescent pretreated animals. Adult pretreated animals showed a reduction in acute morphine antinociceptive potency instead of enhanced antinociception in preweanlings and no effect in periadolescent rats. The effect of adult psychostimulant pretreatment on tolerance to the antinociceptive effects of morphine are less clear. The difference in acute morphine antinociception across the four pretreatment groups makes it impossible to compare these groups against each other following the induction of morphine tolerance. Moreover, the high D₅₀ values in control rats injected repeatedly with saline suggest that morphine administration during the acute test was sufficient to induce tolerance as has been reported previously (Melief et al., 2010; personal observation). That is, there was a shift in D₅₀ between the first and second test for morphine antinociception even in rats injected repeatedly with saline. Although there was a further reduction in antinoccieptive potency in rats given repeated morphine injections, the magnitude of this tolerance was relatively small. These data suggest two patterns. First, drug treatments that enhance antinociception also enhance the development of tolerance (Cyr and Morgan, 2009), and treatments that attenuate antinociception appear to attenuate the development of tolerance. Second, there is an inverse correlation between age of psychostimulant exposure and the magnitude of morphine antinociception. Rats pretreated with psychostimulants as preweanlings showed the greatest morphine antinociception and rats pretreated as adults had the least antinociception.

This age-related difference may be caused by pruning of synapses and receptors in adult animals. An overproduction of synapses and receptors from infancy to pubertal onset is followed by a pruning to adult levels during the transition from adolescence to adulthood (Huttenlocher, 1979). Specifically, a peak in striatal, accumbal, and cortical DA receptor density seems to occur at around PD 40 before declining to adult levels (Andersen et al., 2002, Levant et al., 2011). It is possible that these developmental changes in DA receptor numbers could be responsible for the differences in behavioral outcomes observed between rats pretreated during the preweanling (Cyr and Morgan, 2009), periadolescent, and adult periods of ontogeny.

Even though both MPH and METH increase DA content in the synapse in different ways, the effects on morphine antinociception and tolerance are consistent. MPH binds to DAT and subsequently prevents DA from being cleared from the synapse, whereas METH is transported by DAT and stimulates release of DA through DAT. It has been shown that DAT blockers (MPH) but not DA releasers (METH) induce much greater dopamine efflux in PD 28 relative to PD 70 rats (Walker et al., 2010). This finding suggests that during development, the way a psychostimulant acts at DAT to increase DA content in the synapse may be important to later behavioral outcomes.

Both antinociceptive potency and μ-opioid receptor desensitization have been suggested to influence the expression of tolerance to the antinoceceptive effects of morphine (Ingram et al., 2008). It follows that greater acute antinociception would lead to enhanced tolerance and less acute antinociception would lead to decreased tolerance. It is not surprising then that exposure to MPH and METH (1 and 3 mg/kg) during adulthood reduced acute morphine-induced antinociception and seemed to also reduce morphine tolerance. A similar, but opposite relationship was evident in preweanling rats treated chronically with MPH, since MPH pretreated rats showed enhanced morphine-induced antinociception and tolerance (Cyr and Morgan, 2009). Moreover, compared to saline pretreated animals, rats pretreated with MPH and 1 mg/kg of METH during periadolescence showed no change in antinociception or tolerance. Only periadolescent rats pretreated with 3 mg/kg of METH seem to follow this pattern. Thus, most of the data suggest that acute morphine antinociceptive potency is positively correlated with the expression of tolerance to morphine.

While it is obvious that chronic MPH and METH exposure have enduring effects on morphine responsiveness, the underlying mechanisms and brain areas responsible are unknown. Given the popularity of MPH use clinically and METH abuse illicitly, future research in this area is important to elucidate where and how these changes are occurring. It is possible that alterations in gene transcription factors and/or second messenger molecules in DA-rich areas in the brain may be involved. Specifically, areas involved in both opioid reward and pain modulation warrant further investigation. Finally, if these findings extrapolate to humans it could be important for physicians to know about prior psychostimulant use when prescribing opioid drugs for pain relief.

5. Conclusion

These data demonstrate that chronic psychostimulant exposure during adulthood changes later morphine antinociceptive responsiveness. Moreover, the compound used and the developmental stage during which psychostimulant exposure occurs seems to alter the direction and magnitude of these effects.

Highlights.

The main finding is that chronic administration of the psychostimulants methylphenidate or methamphetamine to adult, but not periadolescent rats attenuates morphine antinociception measured two weeks later.

Abbreviations

DA

Dopamine

DAT

Dopamine transporter

METH

Methamphetamine

MPH

Methylphenidate