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BEHAVIORAL PHARMACOLOGY
Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Received for publication
August 11, 2003
Accepted
March 25, 2004.
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Abstract |
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agonists spiradoline and U50,488 [trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate], the nonopioid d-amphetamine, and saline produced predominantly saline-key responding. Naltrexone and nalbuphine dose dependently reversed the morphine-key responding produced by the training dose of morphine. Together, these data suggest that the discriminative-stimulus effects of the low-efficacy µ agonist nalbuphine in morphine-treated pigeons are similar to those of other low-efficacy agonists, naltrexone, and the termination of daily morphine treatment.
; Selley et al., 1998; Walker et al., 1998) are substituted for morphine in animals that have been trained in this manner, they respond on the morphine-appropriate key or lever (Shannon and Holtzman, 1977; Morgan and Picker, 1998). Similar effects have been reported in rats trained to discriminate fentanyl from saline (Colpaert et al., 1980; Zhang et al., 2000).
The discriminative stimulus effects of compounds possessing intrinsic efficacy lower than fentanyl or morphine are particularly interesting. For example, low-efficacy compounds such as cyclazocine, nalbuphine, or nalorphine (Traynor and Nahorski, 1995; Alt et al., 2001), only produce morphine or fentanyl-appropriate responding when lower training doses of fentanyl or morphine are used to establish the discriminations (Shannon and Holtzman, 1979; Colpaert et al., 1980; Young et al., 1992; Zhang et al., 2000). Interestingly, the same dose of nalbuphine that substitutes for a low dose of fentanyl or morphine can antagonize the discriminative stimulus effects of high training doses of fentanyl or morphine, demonstrating that nalbuphine produces both agonist and antagonist effects through similar, presumably µ opioid receptors (Young et al., 1992; Zhang et al., 2000).
The pattern of substitution is less complicated when low-efficacy agonists such as nalbuphine and butorphanol are trained as discriminative stimuli. Under these conditions, both high- and low-efficacy agonists produce full substitution for nalbuphine or butorphanol, generally independent of the training dose (Walker and Young, 1993; Gerak and France, 1996; Picker et al., 1996). Moreover, the discriminative stimulus effects of nalbuphine (Walker and Young, 1993; Gerak and France, 1996), butorphanol (Picker et al., 1996), and dezocine (Picker, 1997) are blocked by µ, but not or 
opioid receptor antagonists, indicating that the effects are mediated through µ opioid receptors.
When pigeons are trained to discriminate among morphine, nalbuphine, and saline in a three-choice discrimination procedure, low-efficacy compounds such as butorphanol, nalorphine, and levallorphan produce predominantly nalbuphine-appropriate responding (Walker et al., 2001). Low doses of morphine, fentanyl, etorphine, buprenorphine, and dezocine also produce nalbuphine-appropriate responding, whereas high doses of these compounds produce morphine-appropriate responding.
A different pattern is observed in opioid-dependent subjects. Under these conditions, low-efficacy agonists such as nalbuphine generally precipitate withdrawal or produce withdrawal-like stimulus effects. For example, nalbuphine precipitates withdrawal signs in methadone-dependent human subjects (Preston et al., 1989; Preston et al., 1990) and morphine-dependent rhesus monkeys (Villarreal and Karbowski, 1974). Similarly, in opioid-dependent rats (Young et al., 1991), pigeons (France and Woods, 1990), and rhesus monkeys (France and Woods, 1989), nalbuphine produces saline or naltrexone-appropriate responding in drug discrimination assays. These data suggest that under some conditions of opioid dependence, nalbuphine produces effects similar to opioid antagonists such as naltrexone.
The present study uses a three choice discrimination procedure to examine further the discriminative stimulus effects of the low-efficacy agonist nalbuphine in morphine-treated pigeons. The following questions are addressed. First, can pigeons be trained to discriminate among a low-efficacy agonist, such as nalbuphine; a high-efficacy agonist, such as morphine; and saline under conditions of daily morphine treatment? Second, what patterns of substitution will a range of high- and low-efficacy agonists and opioid antagonists produce under these conditions? Finally, how are the discriminative stimulus effects of nalbuphine and morphine altered during morphine withdrawal?
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Materials and Methods |
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Apparatus. Seven operant conditioning chambers were used. Each chamber contained three response keys that were 2.5 cm in diameter and located 23 cm from the bottom of the intelligence panel and centered approximately 12 cm apart. An opening located on the intelligence panel centered 8 cm above the floor of the chamber allowed access to a hopper filled with mixed grain when the hopper was raised. A 7-W white bulb illuminated the opening when the hopper was raised. A house light mounted 33 cm above the chamber floor provided ambient illumination. Each chamber was equipped with an exhaust fan and white noise. A microcomputer with software and interfacing (MED Associates, Georgia, VT) was used for scheduling of experimental events and data collection.
Discrimination Training and Testing. Six hours after the morning morphine injections, pigeons were injected with 10 mg/kg morphine, saline, or 1.0 mg/kg nalbuphine and placed in the darkened operant chambers. Fifteen minutes later, the three response lights were illuminated, and the pigeons were trained to respond on either the right, center, or left key on a continuous reinforcement schedule for food delivery (3-s access to mixed grain) for 15 min. Responses on the injection-inappropriate keys were counted but had no programmed consequences. The number of responses required for food delivery was increased to 30 (fixed ratio, FR30) over several experimental sessions. Morphine, saline, and nalbuphine training sessions were conducted randomly with the restriction that a given training drug was not administered for more than two consecutive sessions. Training conditions continued until an individual pigeon met the following conditions: 1) the first 30 responses completed were made on the correct training key; 2) less than 60 responses were made before the first reinforcer; 3) the percentage of responses emitted on the appropriate key during the entire session was 
80%; and 4) the above-mentioned conditions were met for nine of 12 consecutive days. In addition, the pigeon needed to meet criteria 1 to 3 for three saline training days, three nalbuphine training days, and three morphine training days. After initial testing criteria were met, tests were performed whenever pigeons met the above-mentioned criteria for each of the three training conditions for three consecutive days.
Test sessions were conducted using a multiple-trial, cumulative-dosing procedure (Walker et al., 2001). Each trial consisted of a 15-min pretreatment period and a testing component that ended after 10 reinforcers or 5 min, whichever came first. During the testing component, completion of an FR30 on any key produced food. For cumulative dosing, the dose of drug administered before each trial increased the total dose by 0.25 to 1.0 log10 unit. Each test consisted of five to eight trials. For repeated saline tests, an injection of saline was administered at the beginning of every trial for five trials. In the naltrexone and nalbuphine reversal tests, the training dose of morphine was administered to the pigeons and was followed by cumulative doses of naltrexone or nalbuphine. In the morphine withdrawal study, the daily 10 mg/kg morphine injection was replaced by saline and the pigeons were tested 6 h later with saline. After the saline injection, cumulative doses of morphine were tested. The next day, the morning morphine injections were reinstated.
At the end of the experiment, the morning morphine injection was replaced with saline for 23 consecutive days. Six hours later, on days 1, 3, 8, 15, 18, and 23, the pigeons were injected with saline again and placed into the experimental chambers for a single trial test. Fifteen minutes later, the three stimulus lights were illuminated for 15 min and completion of an FR30 on any key produced food. Under similar testing conditions, the training doses of 10 mg/kg morphine and 1.0 mg/kg nalbuphine were tested on days 16 and 17 and 3.2 mg/kg morphine and 10 mg/kg nalbuphine were examined on days 19 and 22, respectively. On those days on which the pigeons were not tested, they received saline injections in the morning and 6 h later they were fed in their home cage.
Surgery. To deliver drugs centrally, a permanent in-dwelling cannula (Plastics One, Roanoke, VA) was placed into the lateral ventricle of each pigeon with a stereotaxic instrument (Stoelting Co., Wood Dale, IL) and a Rezvin adapter (Karten and Hodos, 1967) using methods described previously (France et al., 1985; Jewett et al., 1996). Briefly, each pigeon was anesthetized with 8 mg/kg ketamine and 2.5 to 2.75 ml/kg chloropent (chloral hydrate and pentobarbital; Fort Dodge Laboratories, Fort Dodge, IA). After surgery, a removable 28-gauge dummy cannula was inserted into the guide cannula. Patency of each cannula was tested by injecting 17.2 µg of 2-amino-5-phosphonovalerate (Sigma-Aldrich, St. Louis, MO) and observing catalepsy (Koek et al., 1986). These tests occurred once before, during, and after the i.c.v. experiments to ensure cannula patency over the 5-month i.c.v. testing period.
Data Analyses. Drug discrimination data are presented as the mean percentage of morphine- or nalbuphine-appropriate responding to total responding of all pigeons during the test session. Rate of responding was calculated as a percentage of the rate of responding during the saline training session conducted before the test session. Data were determined for all pigeons tested at a given dose and plotted as mean values. S.E.M. is used to express variance. Data from pigeons responding less than 30 times during a trial were included in the response rate figures but not the discrimination figures. The dose required to produce 50% drug-appropriate responding (ED50 value), reduce drug-appropriate responding to 50% (ID50 value), and reduce response rates to 50% (ED50 value) and 95% CL were calculated by nonlinear regression analysis using unconstrained maximum and minimum values for the logistic equations (GraphPad Prism version 3.0; GraphPad Software Inc., San Diego, CA).
Drugs. The following compounds were used: buprenorphine HCl, etorphine HCl, morphine sulfate, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), [D-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin, U50,488 [trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate] (generously supplied by National Institute on Drug Abuse, Rockville, MD), butorphanol tartrate, sodium pentobarbital (Sigma-Aldrich), nalbuphine HCl, nalorphine HCl, naltrexone HCl, spiradoline mesylate (Sigma/RBI, Natick, MA), levallorphan tartrate (Hoffman-LaRoche, Nutley, NJ), fentanyl citrate (Janssen Pharmaceuticals, Beerse, Belgium), SNC80 (Tocris Cookson Inc., Ellisville, MO), and dezocine HCl (Dalgen; Astra Pharmaceutical, Westborough, MA). Nalbuphine, morphine, etorphine, U50,488, butorphanol, buprenorphine, nalorphine, spiradoline, levallorphan, fentanyl, SNC80, and naltrexone were dissolved in distilled water. Dezocine was purchased as a solution and diluted with distilled water. Solutions were generally prepared to deliver each injection in a volume of 0.1 to 0.7 ml into the breast muscle. Doses are expressed as the forms listed above. Saline was injected in a volume of 1 ml/kg b.wt. As observed in a previous study (Walker et al., 2001), 10 mg/kg buprenorphine disrupted training performance for 1 to 4 weeks. Therefore, higher doses of buprenorphine were not examined.
Nalbuphine and the peptides CTAP and DAMGO were administered i.c.v. using a cumulative-dosing procedure (Jewett et al., 1996). For cumulative dosing, the drugs were dissolved in filtered sterile water and were prepared to deliver each injection in a volume of 3 to 5 µl. The dose of drug administered before each trial increased the total i.c.v. dose by 0.25 to 1.0 log10 unit. Using a hand-held 50-µl Hamilton syringe outfitted with polyethylene-50 tubing and a 28-g injector (Plastics One, Roanoke, VA), 3 to 5 µl of solution was infused slowly for 30 s into the lateral ventricle. The injector remained in place for an additional 30 s to allow the solution to absorb into the tissue. A maximum total volume of 30 µl (five to six trials) was injected during an experiment.
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Results |
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80% nalbuphine-key responding in all pigeons (Fig. 1, left; Table 1). Low doses of morphine produced saline-key responding and higher doses of morphine (10 mg/kg morphine or higher) produced morphine-key responding in all pigeons (Fig. 1, right; Table 1). Five trials of repeated saline injections produced predominantly 80% saline-key responding (Table 1). Doses of 100 mg/kg nalbuphine and morphine decreased response rates to 25 and 0% of saline control values, respectively. Doses of 32 and 100 mg/kg nalbuphine produced vomiting in three pigeons. ED50 values and 95% C.L. are reported in Table 1.
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Substitution Experiments with Other Compounds. Etorphine and fentanyl produced a pattern of substitution similar to morphine in that low and high doses of etorphine and fentanyl produced saline- and morphine-key responding, respectively. Etorphine (Fig. 2, left) and fentanyl (Fig. 2, left middle) produced 80% morphine-key responding in most pigeons (Table 1). Buprenorphine, dezocine (Fig. 2, right middle and right) and butorphanol (Fig. 3, left) produced a combination of saline-, nalbuphine-, and morphine-key responding in the morphine-treated pigeons (Table 1). The lower efficacy agonists nalorphine and levallorphan (Fig. 3, left middle, right middle) as well as the opioid antagonists naltrexone (Fig. 3, right) and CTAP (i.c.v.) produced predominantly nalbuphine-key responding in a majority of pigeons (Table 1). The agonists U50,488 and spiradoline, the agonist SNC80, and the nonopioid d-amphetamine produced predominantly saline-key responding (Table 1). Nalbuphine (i.c.v.) and DAMGO (i.c.v.) produced 50 to 100% nalbuphine- or morphine-key responding, respectively, in four of the five pigeons tested.
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All compounds with the exception of buprenorphine were examined at doses up to those that decreased rates of responding to less than 25% of saline control values (Figs. 1, 2, 3, bottom; Table 1). Because a dose of 10 mg/kg buprenorphine disrupted training performance for 1 to 4 weeks, higher doses were not examined. A dose of 10 mg/kg naltrexone reduced rates to approximately 20% of control levels and produced vomiting in two pigeons. Rate of responding was reduced by 10 to 32 µg of CTAP, 10 to 320 µg of nalbuphine, and 10 to 560 µg of DAMGO. The large degree of intersubject variability observed for the i.c.v. dose of nalbuphine and DAMGO to suppress response rates limited the testing of higher doses.
Reversal Experiments. In the reversal experiments, a single injection of the training dose of 10 mg/kg morphine produced approximately 80% morphine-key responding. Doses of both nalbuphine and naltrexone reversed the stimulus effects of the training dose of morphine in a dose-dependent manner (Fig. 4, left and left middle, respectively). As morphine-key responding decreased, there was a concomitant increase in nalbuphine-key responding as the dose of nalbuphine or naltrexone was increased. In these experiments, the ID50 values for nalbuphine and naltrexone to block morphine-key responding were 0.25 and 0.0017 mg/kg, respectively. In the presence of the training dose of morphine, the ED50 value for nalbuphine increased from 0.96 to 5.4 mg/kg (Fig. 4, left), and the ED50 value for naltrexone increased from 0.0034 to 0.025 mg/kg (Fig. 4, middle left). Therefore, nalbuphine and naltrexone are approximately 5- and 7-fold less potent in producing nalbuphine-key responding in the presence of the training dose of morphine. Similarly, nalbuphine and naltrexone reduced rates of responding with ED50 values of 11 and 0.082 mg/kg, respectively, under these conditions, indicating that nalbuphine and naltrexone are approximately 3- and 4-fold more potent in producing rate-decreasing effects in the presence of the training dose of morphine. Time course studies revealed that an injection of 10 mg/kg morphine followed by six trials of saline injections produced 60 to 100% morphine-key responding for 140 min. In general, response rates were not altered in saline control tests (Fig. 4, right middle).
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Single and Daily Morphine Withdrawal Experiments. When saline was substituted for the morning 10 mg/kg morphine injection, a saline injection 6 h later produced approximately 80% nalbuphine-key responding. This nalbuphine-key responding was reversed by morphine (Fig. 4, right; Table 1). However, the potency of morphine was not altered in the absence of the morning morphine injection (Table 1).
After the completion of the above-mentioned experiments, the morning morphine injection was replaced with saline for 23 days, and the pigeons were tested 6 h later on various days with saline, morphine, or nalbuphine (Table 2). On days 1, 3, 8, 15, and 23, morphine-withdrawn pigeons responded predominantly on the nalbuphine key after a 15-min pretreatment of saline in a single-trial test. Although response rates were very low, the training dose of 10 mg/kg morphine produced morphine-key responding on day 16. The training dose of 1.0 mg/kg nalbuphine produced 71% nalbuphine-key responding on day 17. On day 19, a lower dose of 3.2 mg/kg morphine evoked 64% morphine-key responding. A higher dose of 10 mg/kg nalbuphine was injected on day 22 and produced 29% nalbuphine-key responding and 71% saline-key responding. On the final day of the experiment, saline injection before the test session produced 70% nalbuphine-key responding.
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Discussion |
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Interestingly, substitution tests with high-efficacy opioid agonists in the present study revealed that the nalbuphine discriminative stimulus no longer reflects agonist actions in morphine-treated pigeons, whereas the nalbuphine discriminative stimulus clearly reflects agonist actions in nontreated pigeons. For example, when nontreated pigeons are trained to discriminate a low dose of morphine from a high dose, high-efficacy agonists produce responding on the key appropriate to a low-dose of morphine followed by responding on the key appropriate to a high-dose of morphine (Vanecek and Young, 1995). Similarly, in nontreated pigeons trained to discriminate among morphine, nalbuphine, and saline, high-efficacy agonists produce nalbuphine-key responding at low doses and morphine-key responding at higher doses (Walker et al., 2001). In contrast, data collected in the present study indicate that the high-efficacy agonists etorphine, morphine, and fentanyl do not produce nalbuphine-key responding at any dose in morphine-treated pigeons (Fig. 2). Instead, etorphine, fentanyl, and morphine produce a greater proportion of saline-key responding in morphine-treated pigeons compared with nontreated pigeons (Walker et al., 2001). However, in both studies, etorphine, fentanyl, and morphine produced morphine-key responding.
In the present study, substitution tests with intermediate-efficacy agonists buprenorphine, dezocine, and butorphanol revealed a variable pattern of responding across the morphine, saline, and nalbuphine keys in morphine-treated pigeons. Generally, in morphine-treated pigeons, these intermediate-efficacy agonists produced a greater proportion of saline-key responding than either morphine- or nalbuphine-key responding in comparison with previous results from nontreated pigeons (Walker et al., 2001). For example, buprenorphine produced morphine-key responding in greater than 75% of the nontreated pigeons (Walker et al., 2001), whereas buprenorphine only produced morphine-key responding in 25% of the morphine-treated pigeons (Fig. 2). Similarly, butorphanol produced nalbuphine-key responding in greater than 75% of the nontreated pigeons, whereas butorphanol only produced nalbuphine-key responding in 25% of the morphine-treated pigeons (Fig. 3).
Interestingly, both nalorphine and levallorphan produced high levels of nalbuphine-key responding in both nontreated (Walker et al., 2001) and morphine-treated pigeons (present study) trained to discriminate among morphine, nalbuphine, and saline. In studies using two-choice discriminations, nalorphine, levallorphan, and nalbuphine produce morphine- or fentanyl-appropriate responding as long as the training doses of morphine or fentanyl are low (Holtzman, 1985; Young et al., 1992; Zhang et al., 2000). Similarly, nalorphine and levallorphan produce nalbuphine-appropriate (Walker and Young, 1993), butorphanol-appropriate (Picker et al., 1996), or dezocine-appropriate (Picker, 1996) responding when the discriminative stimuli are lower efficacy agonists (e.g., nalbuphine, butorphanol, or dezocine). In morphinetreated pigeons, as in previous studies in nontreated pigeons and rats (Walker et al., 2001; Walker and Young, 1993) nalorphine and levallorphan retained the capacity to produce nalbuphine-key responding supporting the notion that these compounds all possess very low efficacy at µ opioid receptors.
The discriminative stimulus effects of the and agonists observed in morphine-treated pigeons in the present study were different from those observed previously in nontreated pigeons. The agonists U50,488 and spiradoline have been shown to produce some nalbuphine-appropriate responding in nontreated pigeons (Walker et al., 2001). However, in the present study, U50,488 and spiradoline did not produce nalbuphine-appropriate responding in pigeons treated daily with 10 mg/kg morphine and trained to discriminate a lower dose of nalbuphine. Similarly, the agonists failed to produce morphine- or nalbuphine-key responding under these conditions. Therefore, these observations provide further confirmation that neither the nor the opioid receptor play a prominent role in the morphine, nalbuphine, and saline discrimination in morphine-treated pigeons (France and Woods, 1993; Picker, 1994; Picker and Cook, 1997, 1998).
The opioid antagonist naltrexone and the µ-selective peptide antagonist CTAP both produced nalbuphine-key responding in morphine-treated pigeons. Previous studies have shown that both nalbuphine and naltrexone can reverse the stimulus effects of morphine with potencies indicative of µ receptor blockade in morphine-treated subjects (France et al., 1990; Walker et al., 1996). In the present study, pigeons respond on the nalbuphine key when saline injections were substituted for the morning morphine injections, and increasing doses of morphine reversed responding on the nalbuphine key. Both of these observations are in keeping with findings from other studies with naltrexone (France and Woods, 1987, 1990; France and Woods, 1989). In previous studies, this kind of evidence was used to support the notion that the stimulus effects of naltrexone represent a state of opioid withdrawal in rats, pigeons, and rhesus monkeys (Gellert and Holtzman, 1979; Holtzman, 1985; France and Woods, 1989, 1990). ED50 values for naltrexone to produce either naltrexone- or nalbuphine-key responding in pigeons treated daily with 10 mg/kg were approximately 0.0056 mg/kg (France and Woods, 1990) and 0.0034 mg/kg (present study), respectively. This observation demonstrates the similar degrees of morphine withdrawal between the two studies despite the fact that naltrexone or nalbuphine were trained as the discriminative stimuli in morphine-treated pigeons. Together, these data suggest that the discriminative stimulus effects of nalbuphine in morphine-treated pigeons parallel the discriminative stimulus effects of morphine withdrawal. Indeed, high doses of nalbuphine and naltrexone produced vomiting in some pigeons, a sign indicative of physical withdrawal.
Despite these similarities between naltrexone and nalbuphine, it should be noted that nalbuphine and naltrexone do not always produce similar stimulus effects. For example, naltrexone fails to substitute for nalbuphine and actually blocks the stimulus effects of nalbuphine in nontreated rats, pigeons, and rhesus monkeys trained to discriminate nalbuphine from saline (Walker and Young, 1993; Gerak and France, 1996; Walker et al., 2001). In morphine-treated pigeons trained to discriminate naltrexone from saline, nalbuphine produces approximately equal saline and naltrexone responding (France and Woods, 1990). Yet, in morphinetreated pigeons trained to discriminate between nalbuphine and saline, naltrexone substitutes fully for nalbuphine. This asymmetrical substitution suggests that under some morphine treatment conditions, nalbuphine is able to reverse the discriminative effects produced by naltrexone; however, under other morphine treatment conditions, nalbuphine's discriminative stimulus effects are similar to those of naltrexone. Together, these observations suggest that nalbuphine may represent a withdrawal stimulus similar to a lower training dose of naltrexone.
It is also the possible that nalbuphine produces a discriminative stimulus that represents the absence of morphine in pigeons that have been treated with morphine. For example, pigeons treated with morphine may be discriminating among high-dose morphine (10 mg/kg morphine in the AM plus 10 mg/kg morphine in the PM), low-dose morphine (10 mg/kg morphine in the AM plus saline in the PM), and absence or reversal of morphine (10 mg/kg morphine in the AM and 1.0 mg/kg nalbuphine in the PM). Substituting saline for the morning morphine injection could produce nalbuphine-key responding by evoking a morphine withdrawal state or by just representing the absence of morphine. In either case, these effects would be reversed by increasing doses of morphine (Fig. 4).
The results from the daily morphine withdrawal study may support the notion that nalbuphine-key responding in morphine-treated pigeons represents the absence of morphine. Saline produced predominantly nalbuphine-key responding for as long as 23 days in morphine-withdrawn pigeons. Indeed, a low dose of nalbuphine (1.0 mg/kg) in morphine-withdrawn pigeons produced predominantly nalbuphine-key responding, whereas a higher dose of 10 mg/kg nalbuphine produced 70% saline-key responding and 29% nalbuphine-key responding. These data are in agreement with the suggestion that saline key responding may represent a low dose of morphine under conditions of daily morphine treatment. Morphine withdrawal did not seem to alter the discriminative stimulus effects of morphine with the exception that the pigeons became more sensitive to the rate-decreasing effects of 10 mg/kg morphine. When the morphine test dose was lowered to 3.2 mg/kg, the pigeons distributed their responding relatively evenly between the morphine (proposed high-dose) and saline (proposed low-dose morphine) keys.
One feature of the nalbuphine discrimination in the present experiments, however, does not agree with the hypothesis that the nalbuphine stimulus represents the absence of morphine, whereas the saline stimulus represents a low dose of morphine. Studies in nontreated subjects have firmly established that high doses of nalbuphine evoke generalization with low-dose morphine training stimuli (Holtzman, 1985; Young et al., 1992; Vanecek and Young, 1995; Walker et al., 1996; Morgan and Picker, 1998). Therefore, if the above-mentioned hypothesis is true, as the nalbuphine dose is increased, responding should move from the nalbuphine key (proposed absence of drug stimuli) to the saline key (proposed low-dose morphine stimulus). This did not occur, however. In contrast, increasing the dose of nalbuphine above the training dose produced only nalbuphine-key responding and occasional vomiting, suggesting the presence of a mild state of withdrawal. This outcome lends strong support to the alternate hypothesis that the nalbuphine stimulus comprised a withdrawal cue. It is possible that the discriminative stimulus effects of nalbuphine observed in the present study resemble the stimuli produced in models of acute dependence, in which animals are treated with morphine, followed 4 h later by naltrexone (Easterling and Holtzman, 1999; Holtzman, 2003; White and Holtzman, 2003). This acute dependence model produces a pattern of discrimination that is unique from that observed when naltrexone is administered without morphine pretreatment. In the present study, 6-h pretreatment of morphine followed by nalbuphine may also produce a different set of interoceptive stimuli. Moreover, the data collected here suggest that these interoceptive stimuli are shared with opioid antagonists, low-efficacy µ agonists, and single or daily morphine withdrawal.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: FR, fixed ratio; CL, confidence limits; CTAP, D-Phe-Cys-Tyr-D-Tryp-Lys-Thr-Pen-Thr-NH2; DAMGO, [D-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin; SNC80, (+)-4-[(
R)--[2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-methoxybenzyl]-N,N-diethylbenzamide; U50,488, trans-3,4-di-chloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate.
Address correspondence to: Dr. Ellen A. Walker, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad St., Philadelphia, PA 19140. E-mail: ellen.walker{at}temple.edu
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