The Effects of Repeated Opioid Administration on Locomotor Activity: I. Opposing Actions of and Receptors

Repeated administration of many addictive drugs leads to a progressive increase in their locomotor effects. This increase in locomotor activity often develops concomitantly with increases in their positive-reinforcing effects, which are believed to contribute to the etiology of substance use disorders. The purpose of this study was to examine changes in sensitivity to the locomotor effects of opioids after their repeated administration and to determine the role of and receptors in mediating these effects. Separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and changes in locomotor activity were measured. Repeated administration of the agonists, morphine and buprenorphine, produced a progressive increase in locomotor activity during the treatment period, and this effect was blocked by coadministration of the opioid antagonist naltrexone. The agonist spiradoline decreased locomotor activity when administered alone and blocked the progressive increase in locomotor activity produced by morphine. The ability of spiradoline to block morphine-induced increases in locomotor activity was itself blocked by pretreatment with the antagonist nor-binaltorphimine. Repeated administration of high doses, but not low or moderate doses, of the mixed / agonists butorphanol, nalbuphine, and nalorphine produced a progressive increase in locomotor activity during the treatment period. Doses of butorphanol, nalbuphine, and nalorphine that failed to produce a progressive increase in locomotor activity when administered alone did so when subjects were pretreated with nor-binaltorphimine. These findings suggest that and receptors have functionally opposing effects on opioid-mediated locomotor activity and sensitization-related processes. Locomotor activity after psychotropic drug administration has long been of interest to behavioral pharmacologists in general and substance abuse researchers in particular. The reasons for this interest can be traced to the fact that the anatomical structures and neurotransmitter systems mediating locomotor activity overlap those that mediate positive reinforcement and reward (for review, see Wise, 1987; Tzschentke, 2001). Because of this overlap, a careful examination of locomotor activity after drug administration can shed light on the neuropharmacological basis of substance abuse and other addictive behaviors. Opioid analgesics produce a stereotypical pattern of locomotor activity that has been well characterized. After systemic administration, -opioid agonists initially produce a transient decrease in locomotor activity that gradually dissipates over the course of 60 to 120 min, which is then followed by an increase in locomotor activity lasting several hours (Babbini and Davis, 1972; Buxbaum et al., 1973). Sensitivity to both the initial decrease and the subsequent increase in locomotor activity changes after the repeated administration of opioids, such that the initial decrease becomes gradually smaller, and the subsequent increase becomes progressively larger (Vasko and Domino, 1978; Brady and Holtzman, 1981). These changes in sensitivity to the locomotor effects of opioids have been termed behavioral sensitization, as opposed to tolerance, because the initial decrease in locomotor activity often disappears entirely and is replaced by an increase in locomotor activity that becomes progressively greater with continued treatment (Vanderschuren et al., 1999b). Similar changes in sensitivity are observed after treatment with other drugs possessing significant abuse and dependence liability (McCreary et al., 1999; Sabeti et al., 2003), and cross-sensitization is often observed between pharmacological classes (Leri et al., 2003; McDaid et al., 2005). Studies examining behavioral sensitization and other sensitization-related processes are particularly important in substance abuse research because sensitization to the posiThis work was supported in part by the National Institutes of Health [Grant DA14255]; the Howard Hughes Medical Institute [Grant 52006292]; the National Science Foundation; the Duke Endowment; and Davidson College. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.150011. ABBREVIATIONS: U69593, ( )-(5 ,7 ,8 )-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; U50488, trans-( )-3,4dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide. 0022-3565/09/3302-468–475$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 330, No. 2 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 150011/3489490 JPET 330:468–475, 2009 Printed in U.S.A. 468 at A PE T Jornals on Sptem er 7, 2017 jpet.asjournals.org D ow nladed from tive-reinforcing and incentive-motivational effects of drugs is believed to contribute to the etiology of substance use disorders (for review, see Robinson and Berridge, 2000; Morgan and Roberts, 2004). There is evidence that and -opioid receptors may play functionally opposing roles in the development of behavioral sensitization. For example, repeated administration of the opioid morphine produces sensitization to its locomotor effects (Powell and Holtzman, 2001) and cross-sensitization to the locomotor effects of cocaine (Cunningham et al., 1997; Vanderschuren et al., 1999a). In contrast, repeated administration of the opioid U69593 does not produce sensitization to its effects but blocks the development of sensitization to the effects of cocaine (Heidbreder et al., 1993; Shippenberg et al., 1996). The full extent of these functionally opposing actions on sensitization-related processes is unknown because only a few studies have coadministered and agonists using a protocol that would be expected to produce a systematic change in their behavioral effects. Complicating matters further, very few studies have examined changes in sensitivity to the behavioral effects of opioids possessing agonist activity at both and receptors, and few have made use of receptor-selective antagonists to tease apart the potential role of these opioid receptor subtypes. The purpose of the present study was to examine changes in sensitivity to the locomotor effects of opioids after their repeated administration and to determine the relative contribution of and receptors in these effects. To this end, separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and changes in locomotor activity were measured. All locomotor activity data were collected during discrete trials conducted 15 min after drug administration. This period of time was chosen because changes in locomotor activity are readily apparent (Székely et al., 1980; Brady and Holtzman, 1981), plasma drug concentrations are approaching their peak (Berkowitz et al., 1975; Melzacka et al., 1985), and drug-drug interactions are easily observed and quantified (Porreca et al., 1981; Morgan et al., 1999). Materials and Methods Animals. Adult male Long-Evans rats, weighing approximately 250 g, were obtained from Charles River Laboratories (Raleigh, NC) and housed individually in polycarbonate cages, with food and drinking water freely available. All rats were housed in a temperatureand humidity-controlled colony room and maintained on a 12-h light/ dark cycle (lights on, 7:00 AM). All subjects were maintained in accordance with the guidelines of the Davidson College Animal Care and Use Committee. A total of 222 rats were divided among 32 groups: saline (three determinations; n 18), 10 mg/kg cocaine (n 6), 0.3 mg/kg naltrexone (n 6), 3.0 mg/kg naltrexone (n 6), 10 mg/kg nor-binaltorphimine (two determinations; n 12), 3.0 mg/kg spiradoline (n 6), 10 mg/kg spiradoline (n 6), 3.0 mg/kg morphine (n 6), 10 mg/kg morphine (two determinations; n 12), 10 mg/kg morphine 0.3 mg/kg naltrexone (n 6), 0.3 mg/kg buprenorphine (n 6), 1.0 mg/kg buprenorphine (n 6), 1.0 mg/kg buprenorphine 0.3 mg/kg naltrexone (n 6), 10 mg/kg morphine 10 mg/kg spiradoline (n 6), 10 mg/kg morphine 10 mg/kg spiradoline 10 mg/kg norbinaltorphimine (n 6), 1.0 mg/kg buprenorphine 10 mg/kg spiradoline (two determinations; n 12), 1.0 mg/kg buprenorphine 10 mg/kg spiradoline 10 mg/kg nor-binaltorphimine (n 6), 3.0 mg/kg butorphanol (n 6), 10 mg/kg butorphanol (n 6), 30 mg/kg butorphanol (n 6), 10 mg/kg butorphanol 10 mg/kg nor-binaltorphimine (n 6), 30 mg/kg butorphanol 10 mg/kg nor-binaltorphimine (n 6), 3.0 mg/kg nalbuphine (n 6), 10 mg/kg nalbuphine (n 6), 30 mg/kg nalbuphine (n 6), 10 mg/kg nalbuphine 10 mg/kg nor-binaltorphimine (n 6), 30 mg/kg nalbuphine 10 mg/kg nor-binaltorphimine (n 6), 3.0 mg/kg nalorphine (n 6), 10 mg/kg nalorphine (n 6), 30 mg/kg nalorphine (n 6), 10 mg/kg nalorphine 10 mg/kg nor-binaltorphimine (n 6), and 30 mg/kg nalorphine 10 mg/kg nor-binaltorphimine (n 6). The effects of 10 mg/kg morphine, 10 mg/kg nor-binaltorphimine, and 10 mg/kg spiradoline 10 mg/kg buprenorphine were determined twice in separate groups of rats tested approximately 12 months apart. In all cases, the effects of these drugs and drug combinations did not differ between the two determinations. As a consequence, data from the two groups were combined for all statistical analyses. The effects of saline were determined in three separate groups of rats tested approximately 18 months apart. Similar to that observed with the other drugs and drug combinations, the effects of saline did not differ across the three determinations, and data from the three groups were combined for all statistical analyses. The entire study was completed over the course of 48 months. Apparatus. All behavioral tests were conducted in a single, openfield, locomotor activity chamber (interior dimensions, 43 43 30 cm) obtained from MED Associates (St. Albans, VT). The chamber consisted of a polyvinyl chloride floor and acrylic sidewalls with aluminum corner supports. Two circuit boards were located on opposite sidewalls 2.5 cm above the floor of the chamber. One board contained 16 infrared photocells spaced 2.5 cm apart; the opposite board contained 16 infrared detectors with identical spacing. All photocells and detectors were interfaced through a computer running a Microsoft Windows operating system and MED Associates software. Testing Procedure. Before behavioral testing, each rat was habituated to the apparatus and testing procedure by being placed into the activity chamber for 5 min a day for 3 consecutive days (Table 1). On the 3rd and final day of habituation, a saline control session was conducted in which each rat received an injection of saline (1.0 mg/kg i.p.) 15 min before being placed in the chamber. During drug treatment and locomotor activity testing, all groups were administered a test drug (or test drugs) every other day for 10 days. On days in which testing was conducted, each rat was brought to the laboratory, administered an intraperitoneal injection of the test drug, and then returned to its home cage. After 15 min, the rat was placed in the activity chamber for 5 min, and photo beam interruptions were recorded. After the testing period, the rat was removed from the chamber and returned to its home cage. For groups in which multiple drugs were administered, separate injections were administered on opposite sides of the peritoneal cavity. Because of its extremely long duration of action, nor-binaltorphimine was administered only once immediately after the saline control session on the 3rd day of habituation. Rats receiving nor-binaltorphimine were then administered saline every other day for the next 10 days, 15 min before being placed into the activity chamber. On days in which