Calcium channel antagonists attenuate cross-sensitization to the rewarding and/or locomotor effects of nicotine, morphine and MK-801

The present study focused on the evaluation of behavioural cross-sensitization, particularly in locomotor activities and conditioned rewarding effects, between nicotine and morphine, cocaine, amphetamine or MK-801. Nicotine (0.5 mg kg(-1))-experienced mice manifested an enhanced locomotor response to morphine (5 mg kg(-1)) or MK-801 (0.3 mg kg(-1)). No cross-sensitization was observed between nicotine and amphetamine (2 mg kg(-1)) or cocaine (15 mg kg(-1)). Additionally, the L-type voltage-dependent calcium-channel antagonists, nimodipine and verapamil, but not diltiazem, at a dose of 20 mg kg(-1) injected before morphine or MK-801 challenge, blocked the expression of this cross-sensitization. In the second test, an enhancement of morphine place conditioning in rats pre-exposed to nicotine (0.5 mg kg(-1), injected daily for 5 days) was demonstrated. After two conditioning sessions, morphine (5 mg kg(-1)) induced a clear place preference only in animals that had previously received nicotine injections. The administration of nimodipine (10 and 20 mg kg(-1)), verapamil (10 and 20 mg kg(-1)) and diltiazem (10 and 20 mg kg(-1)) prior to nicotine dose-dependently prevented this sensitization to the rewarding effect of morphine produced by prior injections of nicotine. These findings support the hypothesis that similar neural calcium-dependent mechanisms are involved in the appetitive effects of nicotine and morphine and in the sensitized locomotor stimulant effects of nicotine and morphine or MK-801.     

Varenicline and mecamylamine attenuate locomotor sensitization and cross-sensitization induced by nicotine and morphine in mice

The present study focused on the evaluation of behavioural sensitization and cross-sensitization induced by nicotine and morphine in mice. First, we revealed that after 9 days of nicotine administration (0.175 mg/kg, free base), every other day and following its 7-day withdrawal, challenge doses of nicotine (0.175 mg/kg) and morphine (5 mg/kg) induced locomotor sensitization in mice. When we examined the influence of varenicline, a partial alpha4beta2 nicotinic receptor agonist (0.5, 1 and 2 mg/kg) and mecamylamine (0.5, 1 and 2 mg/kg), a non-selective nicotinic receptor antagonist, we found that both agents attenuated the acquisition and expression of nicotine sensitization as well as locomotor cross-sensitization between nicotine and morphine. Our results indicate similar cholinergic mechanisms involved in the locomotor stimulant effects of nicotine and morphine in mice, and as such these data may suggest that nicotinic neurotransmission could be a potential target for developing pharmacotherapeutic strategies to treat and prevent nicotine and/or opioid addiction.     

Accentuating effects of nicotine on ethanol response in mice with high genetic predisposition to ethanol-induced locomotor stimulation

BackgroundCo-morbid use of nicotine-containing tobacco products and alcohol is prevalent in alcohol dependent individuals. Common genetic factors could influence initial sensitivity to the independent or interactive effects of these drugs and play a role in their co-abuse.MethodsLocomotor sensitivity to nicotine and ethanol, alone and in combination, was assessed in mice bred for high (FAST) and low (SLOW) sensitivity to the locomotor stimulant effects of ethanol and in an inbred strain of mouse (DBA/2J) that has been shown to have extreme sensitivity to ethanol-induced stimulation in comparison to other strains.ResultsThe effects of nicotine and ethanol, alone and in combination, were dependent on genotype. In FAST and DBA/2J mice that show high sensitivity to ethanol-induced stimulation, nicotine accentuated the locomotor stimulant response to ethanol. This effect was not found in SLOW mice that are not stimulated by ethanol alone.ConclusionsThese data indicate that genes underlying differential sensitivity to the stimulant effects of ethanol alone also influence sensitivity to nicotine in combination with ethanol. Sensitivity to the stimulant effects of nicotine alone does not appear to predict the response to the drug combination, as FAST mice are sensitive to nicotine-induced stimulation, whereas SLOW and DBA/2J mice are not. The combination of nicotine and ethanol may have genotype-dependent effects that could impact co-abuse liability.     

Calcium channel antagonists suppress nicotine-induced place preference and locomotor sensitization in rodents

The influence of calcium channel antagonists on the behavioral sensitization to nicotine-induced hyperlocomotion and place preference was investigated. Locomotor sensitization in mice was produced by injecting nicotine (0.5 mg/kg, i.p.) for 5 consecutive days before placement in an apparatus in which locomotor activity was evaluated for 1 h. One week later, activity of mice was recorded after challenge with the same dose of nicotine. The L-type voltage-dependent calcium channel antagonists: nimodipine (5, 10 and 20 mg/kg, i.p.), verapamil (5, 10 and 20 mg/kg, i.p.) and diltiazem (5, 10 and 20 mg/kg, i.p.) were injected 15 min before each injection of nicotine (induction of sensitization) or acutely 15 min before a challenge nicotine injection (expression of sensitization). It was shown that the calcium channel blockers attenuated both the induction and expression of nicotine-induced locomotor sensitization in a dose-dependent manner. In the place preference paradigm, nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.5 mg/kg, i.p., 4 drug sessions). Pretreatment with nimodipine (10 mg/kg, i.p.), verapamil (10 mg/kg, i.p.) and diltiazem (10 mg/kg, i.p.) blocked nicotine-induced place conditioning. These results suggest the common calcium-dependent mechanisms of nicotine-induced behavioral sensitization and place preference.     

Behavioral sensitization to ethanol does not result in cross-sensitization to NMDA receptor antagonists

Rationale Fluoxetine is used to treat unipolar depression and is thought to act by increasing the concentration of serotonin (5-HT) in the synaptic cleft, leading to increased serotonin signaling. The 5-HT_2A/2C receptor subtypes are coupled to a phospholipase A₂ (PLA₂). We hypothesized that chronic fluoxetine would increase the brain activity of PLA₂ and the turnover rate of arachidonic acid (AA) in phospholipids of the unanesthetized rat.Materials and methods To test this hypothesis, rats were administered fluoxetine (10 mg/kg) or vehicle intraperitoneally daily for 21 days. In the unanesthetized rat, [1-¹⁴C]AA was infused intravenously and arterial blood plasma was sampled until the animal was killed at 5 min and its brain was subjected to chemical, radiotracer, or enzyme analysis.Results Using equations from our fatty acid model, we found that chronic fluoxetine compared with vehicle increased the turnover rate of AA within several brain phospholipids by 75–86%. The activity and protein levels of brain cytosolic PLA₂ (cPLA₂) but not of secretory or calcium-independent PLA₂ were increased in rats administered fluoxetine. In a separate group of animals that received chronic fluoxetine followed by a 3-day saline washout, the turnover of AA and activity and protein levels of cPLA₂ were not significantly different from controls. The protein levels of cyclooxygenases 1 and 2 as well as the concentration of prostaglandin E₂ in rats chronically administered fluoxetine did not differ significantly from controls.Conclusion The results support the hypothesis that fluoxetine increases the cPLA₂-mediated turnover of AA within brain phospholipids.     

Naloxone does not attenuate the locomotor effects of ethanol in FAST,SLOW, or two heterogeneous stocks of mice

Rationale Previous studies suggest that some behavioral effects of ethanol and morphine are genetically correlated. For example, mice bred for sensitivity (FAST) or insensitivity (SLOW) to the locomotor stimulant effects of ethanol differ in their locomotor response to morphine. Objective To evaluate a possible common mechanism for these traits, we examined the effect of naloxone, an opioid receptor antagonist, on ethanol- and morphine-induced locomotion in FAST and SLOW mice, as well as on ethanol-induced locomotion in two heterogeneous stocks of mice. Method In experiments 1 and 2, naloxone was given to FAST and SLOW mice 30 min prior to 2 g/kg ethanol or 32 mg/kg morphine, and locomotor activity was measured for 15 min (ethanol) or 30 min (morphine). In experiments 3 and 4, naloxone was administered 30 min prior to 1.25 g/kg ethanol, and locomotor activity was assessed in FAST mice and in a heterogeneous line of mice [Withdrawal Seizure Control (WSC)]. Experiment 5 assessed the effect of naloxone on ethanol-induced stimulation in outbred National Institutes of Health (NIH) Swiss mice. Results There was no effect of naloxone on the locomotor response to ethanol in FAST, SLOW, WSC, or NIH Swiss mice. However, naloxone did significantly attenuate the locomotor effects of morphine in FAST and SLOW mice. Conclusions These results suggest that a common opioidergic mechanism is not responsible for the correlated locomotor responses to ethanol and morphine in FAST and SLOW mice, and that activation of the endogenous opioid system is not critical for the induction of ethanol-induced alterations in activity.     

Environment-specific cross-sensitization between the locomotor activating effects of morphine and amphetamine

Groups of eight rats each were preexposed on four occasions to 10 or 20 mg/kg morphine sulfate, IP, either in activity boxes where activity was measured for two hours (COND, conditioning groups) or in their home cages (UNPAIRED groups). On alternate days these groups were administered saline in the other environment. Two groups of eight rats each served as CONTROL groups (one for each preexposure dose) and were administered saline in both environments. On the day following morphine preexposure, all animals were administered 0.5 mg/kg d-amphetamine sulfate, IP, prior to being tested in the activity boxes. On this test, the COND group preexposed to 10 mg/kg morphine showed higher levels of activity than either of its respective UNPAIRED or CONTROL groups. The COND group preexposed to 20 mg/kg morphine was significantly more active than its unpaired group, but not more active than its CONTROL group. The implications of such environment-specific cross-sensitization between the activity effects of opiate and stimulant drugs are discussed.     

Methylphenidate enhances the abuse-related behavioral effects of nicotine in rats: intravenous self-administration, drug discrimination, and locomotor cross-sensitization.

Stimulant drugs, including D-amphetamine, cocaine, and methylphenidate, increase cigarette smoking in controlled human laboratory experiments. Although the mechanism(s) underlying this effect are unknown, it is possible that stimulants may enhance directly the abuse-related effects of nicotine. In the present study, we characterized the behavioral pharmacological interactions between methylphenidate and nicotine in the intravenous self-administration, drug discrimination, and locomotor cross-sensitization procedures. Adult male Sprague-Dawley rats were trained to respond for intravenous nicotine (0.01 or 0.03 mg/kg/infusion) or sucrose, and the acute effects of methylphenidate (1.25-10 mg/kg) were determined; in addition, separate groups of rats were treated with methylphenidate (2.5 mg/kg) or saline before 12 consecutive nicotine (0.03 mg/kg/infusion) self-administration sessions. Next, the discriminative stimulus effects of nicotine (0.03-0.3 mg/kg) and methylphenidate (1.25-10 mg/kg), alone and in combination with a low nicotine dose (0.056 mg/kg), were tested in nicotine-trained rats. Finally, the locomotor effect of repeated methylphenidate (2.5 mg/kg) was tested in rats previously treated with nicotine (0.2-0.8 mg/kg). Results indicated that acute methylphenidate increased the rate of nicotine self-administration at doses that reduced sucrose-maintained responding; furthermore, tolerance to this effect was not apparent following repeated methylphenidate. Methylphenidate, while not substituting for nicotine alone, dose-dependently enhanced the discriminative stimulus effect of a low nicotine dose. In addition, repeated nicotine exposure promoted the development of locomotor sensitization to methylphenidate. Taken together with recent clinical findings, these results suggest that methylphenidate may enhance the abuse-related behavioral effects of nicotine, perhaps increasing vulnerability to tobacco dependence.     

The interactive effects of methylphenidate and ethanol on ethanol consumption and locomotor activity in mice

The concomitant use of alcohol (EtOH) and the psychotherapeutic agent dl-methylphenidate (MPH) has risen as a consequence of an increase in ADHD diagnoses within the drinking age population. It was recently found that the combination of MPH and EtOH increases the self-report of pleasurable feelings relative to MPH alone. This finding raises concerns regarding the combined abuse liability for these two widely used drugs. The present behavioral study reports on the development of an adult male C57BL/6J (B6) mouse model to further characterize this MPH-EtOH interaction. We examined the effects of MPH on EtOH consumption in a limited access paradigm and EtOH stimulation of locomotor activity. B6 mice consumed about 2 g/kg EtOH daily and MPH dose-dependently reduced drinking. The most effective dose of MPH was 1.25 mg/kg, which produced a 41% decrease in drinking and had no effect on locomotor activity. However, when the 1.25 mg/kg dose of MPH was combined with a stimulatory dose of ethanol (1.75 g/kg) by intraperitoneal injection, there was a significantly enhanced stimulation of locomotor activity. The drug combination increased activity compared to the vehicle or MPH injections by 45% and increased the activity relative to EtOH alone by an additional 25%. The results of the EtOH and MPH interactions observed with the mouse model appear to be behaviorally relevant and suggest several converging mechanisms that may underlie MPH-EtOH interactions.     

Lack of cross-sensitization of the locomotor effects of morphine in amphetamine-treated rats.

Repeated exposure to morphine and amphetamine induces long-lasting sensitization of their psychomotor stimulant properties, whereas pretreatment with morphine causes cross-sensitization of the locomotor effects of amphetamine. Here, we investigated whether pre-exposure to amphetamine also results in cross-sensitization to morphine. Rats pretreated with amphetamine (5 x 2.5 mg/kg, i.p.) displayed neither short-term (3 days post-treatment) nor long-term (3 weeks post-treatment) cross-sensitization of the locomotor effects of morphine (2 or 5 mg/kg, s.c.). Two other amphetamine pretreatment protocols (1 x 5 mg/kg, i.p. and 14 x 2.5 mg/kg, i.p.) also failed to induce cross-sensitization to morphine. In contrast, all amphetamine pretreatment regimens induced sensitization of the locomotor effects of amphetamine (1 mg/kg, i.p.) and pretreatment with morphine (14 x 10 mg/kg, s.c.) induced both short- and long-term sensitization of the locomotor effects of both morphine and amphetamine. These data suggest that the expression of sensitization of the locomotor effects of morphine and amphetamine, at least partially, involves distinct neuroadaptive phenomena.     

Influence of calcium channel antagonists on nonsomatic signs of nicotine and d-amphetamine withdrawal in mice

BackgroundNonsomatic signs of psychostimulant withdrawal, difficult to demonstrate in animal paradigms, may appear to promote drug seeking and drug relapse in humans; thus, it is important to understand the mechanisms that mediate this kind of behaviors. The present study was undertaken to examine the calcium-dependent mechanism of negative nonsomatic and anhedonia-related symptoms of acute and protracted withdrawal of nicotine and d-amphetamine.MethodsMice were chronically treated with nicotine (seven days, three times daily, 3.35 mg/kg, sc) or d-amphetamine (14 days, once daily, 2.5 mg/kg, ip). Then, at the first, seventh or 14th day of withdrawal, anxiety- or depression-related effects, as well as cognition or nociception were studied.ResultsOur results demonstrated that, at the seventh or 14th day of d-amphetamine or nicotine withdrawal, respectively, mice exhibited increased anxiety and depression-like effects, memory impairment and hyperalgesia. Further, major findings showed that calcium channel antagonists, i.e., nimodipine, verapamil and flunarizine (10 and 20 mg/kg, ip), injected before the test, attenuated above-mentioned signs of drug withdrawal.ConclusionsAs an outcome, these findings support the hypothesis that similar calcium-dependent mechanisms are involved in an aversive nonsomatic component, associated with nicotine or d-amphetamine withdrawal. We can suggest that calcium channel blockers have potential to alleviate drug withdrawal and may thus be beneficial as pharmacotherapy of drug cessation and relapse.     

Rimonabant attenuates sensitization, cross-sensitization and cross-reinstatement of place preference induced by nicotine and ethanol

The present study focused on the evaluation of behavioral sensitization, cross-sensitization, and cross-reinstatement processes induced by nicotine and ethanol in rodents. First, we showed that nicotine (0.175 mg/kg, base, intraperitoneally, ip) produced a conditioned place preference in rats. When the nicotine place preference was extinguished, nicotine-experienced animals were challenged with nicotine (0.175 mg/kg, ip) or ethanol (0.5 g/kg, ip), which reinstated a preference for the compartment previously paired with nicotine. In the second series of experiments, we demonstrated that after 9 days of nicotine administration (0.175 mg/kg, subcutaneously, sc) every other day and following its 7-day withdrawal, challenge doses of nicotine (0.175 mg/kg, sc) and ethanol (2 g/kg, ip) induced locomotor sensitization in mice. Finally, when we examined the influence of rimonabant (0.5, 1 and 2 mg/kg, ip), we found that this cannabinoid CB₁ receptor antagonist attenuated reinstatement effect of ethanol priming as well as nicotine sensitization and locomotor cross-sensitization between nicotine and ethanol. Our results indicate that similar endocannabinoid-dependent mechanisms are involved in the locomotor stimulant and reinforcing effects of nicotine and ethanol in rodents, and as such these data may provide further evidence for the use of cannabinoid CB₁ receptor antagonists in treatment of tobacco addiction with or without concomitant ethanol dependence.     

Acute tolerance to the locomotor stimulant effects of nicotine in the rat

Studies of peripheral nicotinic receptors have revealed that, after an initial agonist action, the receptors remain inhibited either through continued depolarization blockade due to continued presence of the agonist or through a brief inactivation of the receptor following its activation. If a similar phenomenon occurs at central nervous system nicotinic receptors, then behavioral responses to nicotine should exhibit an acute tolerance (tachyphylaxis). Groups of rats were given either saline or 0.2 mg/kg nicotine injections at 20-min intervals in photocell activity cages. A progressive decline in the locomotor responsiveness to nicotine was observed. The time course of this acute tolerance was observed in other rats given initial 0.2 mg/kg nicotine injections followed at differing time intervals by second 0.2 mg/kg nicotine test injections. The secondary antagonism to nicotine's locomotor stimulant effects was maximal at 45–60 min and recovered by 90–120 min. The locomotor response to 0.2 mg/kg nicotine test injections was observed in other rats following exposure to 1.8 mg/kg nicotine, and the behavioral response was attenuated for more than 5 h.     

Synergistic interactions between muscarinic antagonists,adrenergic agonists and NMDA antagonists with respect to locomotor stimulatory effects in monoamine-depleted mice

Summary The purpose of the present investigation was to study the effects of simultaneous manipulations of central cholinergic, adrenergic and glutamatergic systems on locomotion in an animal model of Parkinson's disease.Mice were deprived of their monoamine stores by pretreatment with the monoamine depleter reserpine and the catecholamine synthesis inhibitor -methyl-p-tyrosine, given 18 h and 60 min, respectively, before the acute experiment. Traditionally, only dopaminergic agonists have been shown to reverse the akinesia thus produced. However, in the present study it is demonstrated that if a muscarine receptor antagonist (atropine or biperiden) is combined with an -adrenergic agonist/-adrenergic agonist precursor (clonidine or l--methyl-dopa), a marked locomotor stimulation can be achieved, although either agent given alone is ineffective. Adding an NMDA antagonist (MK-801, ketamine or SDZ EAA494) to the combination biperiden+clonidine resulted in further potentiation of the locomotor stimulatory effects. Send offprint requests to M. Carlsson at the above address     

Opposite effects of chlordiazepoxide and serotonin receptor antagonists on morphine-induced locomotor stimulation in mice

Chlordiazepoxide and two serotonin receptor antagonists showed opposite effects when tested for their influence on morphine-induced locomotor stimulation in mice. Chlordiazepoxide enhanced morphine-induced hyperactivity, which was antagonized by cyproheptadine and mianserin. The results indicate that the enhancement of morphine-induced locomotor stimulation is not attributable to an antiserotonergic action of the benzodiazepine compound.     

Decrease in d-methamphetamine sensitivity in mice due to ethanol: apparent inhibitory and stimulatory effects of ethanol on d-methamphetamine-induced locomotor activity

The locomotor activity of mice was recorded after administration of d-methamphetamine-HCl (1.5, 2.5, 5.0 and 7.5 mg/kg body weight) and/or ethanol (0.8 and 1.6 g/kg body weight). Mice injected with lower doses of d-methamphetamine (1.5 or 2.5 mg/kg) showed a marked increase in locomotor activity, while in those with higher doses of d-methamphetamine (5.0 or 7.5 mg/kg), locomotor activity was not further enhanced, but slightly decreased. Administration of ethanol inhibited the stimulated locomotor activity caused by low doses of d-methamphetamine (1.5 or 2.5 mg/kg), while the stimulation of motility after higher doses of d-methamphetamine (5.0 or 7.5 mg/kg) was potentiated by administering ethanol. Although apparent inhibition and stimulation of d-methamphetamine-induced locomotor activity of mice due to ethanol was observed, it is suggested that mice administered ethanol showed the decreased sensitivity to d-methamphetamine by plotting total locomotor activity of mice against doses of d-methamphetamine administered. The half maximum effective dose of d-methamphetamine for locomotor activity was increased from 1.5 mg/kg to 3.0 mg/kg by concomitant administration of 1.6 g/kg ethanol.     

Neonatal ethanol and nicotine exposure causes locomotor activity changes in preweanling animals

Sprague-Dawley rats were used to investigate the effects of neonatal ethanol (ETOH) and nicotine (NIC) exposure on activity levels in preweanling offspring. Male and female pups received daily oral intubations of ethanol ((ETOH) 5 g/kg/day), nicotine ((NIC) 12 mg/kg/day), ethanol and nicotine ((ETOH+NIC) 5 g/kg/day+12 mg/kg/day) or isocaloric maltose (control) on either postnatal days (PND) 1-7 or PND 8-14. A non-treated control group was also included. Peak blood ethanol concentrations (BECs) measured in a separate subset of animals ranged from 167 and 344 mg/dl depending upon neonatal treatment and period of exposure. Subjects were tested in an open field apparatus on PND 19-21. Animals exposed to ETOH or ETOH+NIC on PND 1-7 were hyperactive relative to the other treatment groups. In contrast, animals exposed to NIC or ETOH+NIC during PND 8-14 were hypoactive relative to other treatment groups. Males appeared more sensitive than females on measures of anxiety (distance traveled in the center of the open field) but this also varied dependent on neonatal treatment and period of exposure. These findings suggest that the third trimester is a critical period for ETOH and NIC effects on offspring activity although the pattern of effects on activity are different depending on when drug exposure occurred during the neonatal period.     

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA_B receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA_B receptor agonist baclofen in FAST mice. We hypothesized that GABA_B receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA_B receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA_B receptor activation may instead enhance some of the behavioral effects of morphine.     

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA(B) receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA(B) receptor agonist baclofen in FAST mice. We hypothesized that GABA(B) receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA(B) receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA(B) receptor activation may instead enhance some of the behavioral effects of morphine.