Sex-related differences in mechanical nociception and antinociception produced by mu- and kappa-opioid receptor agonists in rats

Previous studies indicate that in antinociceptive procedures employing thermal, chemical and electrical stimuli, opioids are generally more potent in male than female rodents. The purpose of the present study was to examine nociception and opioid antinociception in male and female rats using a mechanical nociceptive stimulus. Results indicated that males had a higher threshold for nociception, and in tests in which a constant pressure was applied to the hindpaw, the paw withdrawal latencies were consistently longer in males. Opioids with activity at the mu receptor, including levorphanol, morphine, dezocine, buprenorphine, butorphanol and nalbuphine, were generally more potent and/or effective in males. In contrast, sex differences were not consistently observed with the kappa-opioid receptor agonists spiradoline, (5,7,8b)-N-methyl-N[2-1(1-pyrrolidinyl),1-oxaspiro[4,5]dec-8-yl benzeneacetamide (U69593), trans-(+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50488), enadoline, ethylketocyclazocine, and nalorphine. These findings suggest that males and females differ in their responsiveness to mechanical nociception and that sex differences in sensitivity to kappa-, but not mu-, opioid receptor agonists are specific to certain nociceptive stimulus modalities.     

Feeding responses to mu-, delta- and kappa-opioid receptor agonists in the meat-type chick

The present study was designed to examine the effect of specific opioid agonists on feeding behavior in neonatal chicks. The food intake of broiler chicks was significantly decreased by intracerebroventricular injection of DAMGO and beta-casomorphin, micro-opioid receptor agonists, at 30-min postinjection. In contrast, both delta-opioid receptor agonists (DADLE and DPDPE) stimulated the food intake of the chick. Similar to the delta-opioid receptor agonists, food intake was elevated by the kappa-opioid receptor agonist (U-50488H and U-62066) in a dose-dependent manner. These results suggest that the endogenous opioid peptides have an important role for feeding behavior in the central nervous system of chicks.     

Influence of temperature on the effects of mu-, delta- and kappa-opioid receptor agonists in the guinea-pig ileum myenteric plexus.

Electrically stimulated guinea-pig ileum myenteric plexus-longitudinal muscle was used to determine if changes in temperature alter the inhibitory effects of DAGO ([D-Ala2,N-MePhe4,Gly5-ol]enkephalin, mu-agonist), DPDPE ([D-Pen2,-Pen5] enkephalin, delta-agonist) and U-50,488H (trans-3,4-dichloro)-N-methyl-N-[2-(1- pyrrolidynyl)cyclohexyl]benzeneacetamide methane sulfonate, kappa-agonist). The potency (expressed as the concentration which produces 50% inhibition, IC50) of DAGO and DPDPE was significantly (P < 0.05) decreased at 30 degrees C (8.8 +/- 2.7 x 10(-9) and 8325.2 +/- 1070 x 10(-9) M), when compared to the potency at 37 degrees C (3.8 +/- 0.3 x 10(-9) and 6298.6 +/- 320 x 10(-9) M). Higher temperature (40 degrees C) did not modify the potency of DAGO or DPDPE compared to that at 37 degrees C. However, the potency of U-50,488H was significantly (P < 0.01) increased at 40 degrees C (0.7 +/- 0.0 x 10(-9) M) versus 37 degrees C (2.4 +/- 0.9 x 10(-9) M) or 30 degrees C (2.5 +/- 0.3 x 10(-9) M). The kappa-agonist was more potent than DAGO or DPDPE at 30 or 40 degrees C. These data demonstrate that changes in temperature can alter the potency of opioid agonists.     

Effects of mu- and kappa-opioid receptor agonists on urinary output in mice

The effects of ethylketazocine, morphine, bremazocine and naloxone were determined on urinary output and weight loss in Cox mice. Morphine and fentanyl were also studied in Harlan mice. Bremazocine, ethylketazocine and morphine markedly increased urinary output and weight loss within 5 hr after injection. Naloxone antagonized the diuretic actions of morphine (5 mg/kg) and bremazocine (0.06 mg/kg) over a similar dose range (0.3--10 mg/kg). By comparison with the other agonists, fentanyl had little effect on urinary output or weight loss. These results suggest that kappa agonist activity increases urinary output in mice just as reported for rats. The data also suggest that in mice morphine has some kappa agonist activity, whereas fentanyl does not.     

Differential effects of K+ channel blockers on antinociception induced by alpha 2-adrenoceptor, GABAB and kappa-opioid receptor agonists.

1. The effects of several K+ channel blockers (sulphonylureas, 4-aminopyridine and tetraethylammonium) on the antinociception induced by clonidine, baclofen and U50,488H were evaluated by use of a tail flick test in mice. 2. Clonidine (0.125-2 mg kg-1, s.c.) induced a dose-dependent antinociceptive effect. The ATP-dependent K+ (KATP) channel blocker gliquidone (4-8 micrograms/mouse, i.c.v.) produced a dose-dependent displacement to the right of the clonidine dose-response line, but neither 4-aminopyridine (4-AP) (25-250 ng/mouse, i.c.v.) nor tetraethylammonium (TEA) (10-20 micrograms/mouse, i.c.v.) significantly modified clonidine-induced antinociception. 3. The order of potency of sulphonylureas in antagonizing clonidine-induced antinociception was gliquidone > glipizide > glibenclamide > tolbutamide, which is the same order of potency as these drugs block KATP channels in neurones of the CNS. 4. Baclofen (2-16 mg kg-1, s.c.) also induced a dose-dependent antinociceptive effect. Both 4-AP (2.5-25 ng/mouse, i.c.v.) and TEA (10-20 micrograms/mouse, i.c.v.) dose-dependently antagonized baclofen antinociception, producing a displacement to the right of the baclofen dose-response line. However, gliquidone (8-16 micrograms/mouse, i.c.v.) did not significantly modify the baclofen effect. 5. None of the K+ channel blockers tested (gliquidone, 8-16 micrograms/mouse; 4-AP, 25-250 ng/mouse and TEA, 10-20 micrograms/mouse, i.c.v.), significantly modified the antinociception induced by U50,488H (8 mg kg-1, s.c.). 6. These results suggest that the opening of K+ channels is involved in the antinociceptive effect of alpha 2 and GABAB, but not kappa-opioid, receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analgesic effect of mu- and kappa-opioid agonists in beige and CXBK mice.

The analgesic effects of mu- and kappa-opioid agonists, including morphine, FK33,824, U50,488H, tifluadom and bremazocine, have been determined in C57BL/6J-bgJ (beige) and CXBK mice which are hyporesponsive to mu-opioid receptor-mediated analgesia compared with those of control mice (C57BL/6J (C6J), C57BL/6By (C6By), BALB/cBy (BALB] using an abdominal constriction assay. The analgesic effect of subcutaneously administered morphine and FK33,824 in both beige and CXBK mice was significantly reduced compared with the controls and the analgesic effect of U50,488H and tifluadom in beige mice was significantly reduced compared with the wild strain (C6J). No reduction of analgesic effect of U50,488H and tifluadom was seen in CXBK compared with its progenitor strains, C6By and BALB, except for a reduction of the effect of tifluadom in CXBK compared with C6By. There was no strain difference in the bremazocine-induced analgesia. These results suggest that the beige mouse has a deficit in analgesia mediated by both mu- and kappa-opioid receptors, whereas the CXBK is deficient only in the mu-opioid receptor-mediated analgesia.     

Contribution of supraspinal mu- and delta-opioid receptors to antinociception in the rat.

This study evaluated the contribution of supraspinal opioid receptors to the production of antinociception, in the rat. I.c.v. administration of a selective mu- (DAMGO) and a selective delta- (DPDPE), but not a selective kappa- (U50,488H) opioid receptor agonist, produced significant dose-dependent increase in mechanical nociceptive thresholds. ICI 174,864, a delta-opioid receptor antagonist, completely blocked the antinociceptive effects produced by DPDPE ([D-Pen2,D-Pen5]enkephalin) at a dose that had no effect on the increases in nociceptive thresholds produced by DAMGO ([D-Ala2,N-MePhe4,Gly5-ol]enkephalin). The simultaneous i.c.v. administration of a low-antinociceptive dose of DAMGO or DPDPE given in combination with sequentially increasing doses of the other opioid agonist, produced synergy (i.e., a more than additive antinociceptive effect), at the lower doses tested. The results of these experiments provide evidence to support the suggestion that both supraspinal mu- and delta-opioid receptors contribute to the production of antinociception, in the rat.     

Effect of insulin hypoglycemic stress on nociceptive responses to mu- and kappa-opioid receptor agonists at LH-surge in female rats

In a randomized, prospective, controlled and crossover study, the effects of insulin hypoglycemic stress on nociceptive responses to mu- and kappa-opioid receptor directed drugs during steroid-induced preovulatory LH-surge were seen in ovariectomized female rats. Ovariectomized rats were equally distributed in two groups of 10. In group 1 rats, LH-surge was induced by sequential treatment with estradiol benzoate 7.5 micro g/rat s.c. and progesterone 5 mg/rat s.c., whereas in group 2 rats, vehicles of estradiol benzoate and progesterone were given in a sequential manner. A third group consisted of sham-operated rats, which received no treatment. Rats were exposed to insulin-induced hypoglycemic stress 1 h before the peak of LH-surge. Antinociceptive responses of morphine, buprenorphine and pentazocine were observed at peak LH-surge during hypoglycemic stress. Increased nociceptive responses to noxious stimulus and decreased percent maximal possible effect for morphine, buprenorphine and pentazocine at LH-surge were significantly (p < 0.01) reversed during insulin hypoglycemic stress. There was a significant (p < 0.01) decrease in the ED(50) values of morphine, buprenorphine and pentazocine during hypoglycemic stress. The present study indicates that insulin hypoglycemic stress is responsible for increased antinociceptive activities of morphine, buprenorphine and pentazocine and decreased sensitivity to noxious stimulus in ovariectomized rats with or without steroid-induced LH-surge.     

Modification of kappa-opioid receptor agonist-induced antinociception by diabetes in the mouse brain and spinal cord

The supraspinal and spinal antinociceptive effects of several kappa-opioid receptor agonists were examined in diabetic and non-diabetic mice using the tail-flick assay. The antinociception induced by intrathecal (i.t.), but not intracerebroventricular (i.c.v.), CI-977, a highly selective kappa(1)-opioid receptor agonist, in diabetic mice was less than that in non-diabetic mice. The antinociceptive effects of ICI-199,441 and R-84760, high potency kappa(1)-opioid receptor agonists, given i.c.v., but not i.t., were attenuated in diabetic mice compared to those in non-diabetic mice. On the other hand, the antinociceptive effects of the new kappa-opioid receptor agonist TRK-820, which has high affinity for kappa(2)- and/or kappa(3)-opioid receptors, injected both i.c.v. and i.t. in diabetic mice were markedly less than those in non-diabetic mice. These results indicate that the antinociceptive effects of those kappa-opioid receptor agonists in diabetic mice are altered in a region-specific manner in the central nervous system (CNS). The dysfunction of kappa-opioid receptor subtypes in diabetic mice may underlie this CNS region-specific variation in the effects of these kappa-opioid receptor agonists.     

Differential antagonism of the rate-decreasing effects of kappa-opioid receptor agonists by naltrexone and norbinaltorphimine.

Eight kappa-opioid receptor agonists were examined for their effects in squirrel monkeys responding under a fixed interval 3-min schedule of stimulus termination. Six of these kappa-opioid receptor agonists decreased dose-dependently the total number of responses and with an order of potency consistent with kappa-opioid receptor interaction. Three of these kappa-opioid receptor agonists, bremazocine, U69,593 [[(5a,7a,8b)-(+)-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)] benzeneacetamide] and enadoline, were evaluated following pretreatment with 1.0 mg/kg of naltrexone or 3.0 mg/kg of norbinaltorphimine. The effects of the three agonists were antagonized significantly by naltrexone, but only those of bremazocine and U69,593 were antagonized significantly by norbinaltorphimine. Statistical analysis of the data averaged over six monkeys revealed that naltrexone was significantly more potent than norbinaltorphimine at antagonizing enadoline and U69,593, but naltrexone and norbinaltorphimine were equipotent at antagonizing bremazocine. Moreover, naltrexone was 8-fold more potent at antagonizing U69,593 and enadoline than at antagonizing bremazocine. These results suggest that under these conditions the effects of U69,593 and enadoline may be mediated, in part, by a different receptor population, perhaps a subtype of kappa-opioid receptors, from the one that mediates the effects of bremazocine.     

Antinociceptive interactions of mu- and kappa-opioid agonists in the colorectal distension assay in rats

Interactions of opioid agonists, fentanyl and oxymorphone (mu-selective) and spiradoline and enadoline (kappa-selective), were examined for additive, sub-additive, or supra-additive antinociception in the colorectal distension (CRD) assay. Single-dose values (mg/kg, 0.006-0.016 for fentanyl, 0.25-1.26 for spiradoline, etc.) were summed to formulate theoretical additive-dose plots for comparison with actual combined-dose effects. Combined fentanyl and spiradoline yielded additive (low-dose levels) or supra-additive (high-dose levels) effects. Single and combined doses of fentanyl (0.012 mg/kg) and spiradoline (0.3 mg/kg) were tested after pretreatment with saline, beta-funaltrexamine (b-FNA, mu-selective antagonist), or nor-binaltorphimine (n-BNI, kappa-selective antagonist). Supra-additive effects of combined agonists were attenuated by either antagonist (greater with n-BNI). But paradoxical patterns of antagonism of single-dose effects occurred: the fentanyl antinociception was not antagonized by b-FNA, whereas the spiradoline antinociception was. The results indicate complex interactions of agonists in this visceral pain model and potential for combined agonists to improve pain relief with decreased side effects.     

Effect of the selective kappa-opioid receptor antagonist JDTic on nicotine antinociception, reward, and withdrawal in the mouse

Rationale  

Several lines of evidence support a role for the endogenous opioid system in mediating behaviors associated with drug dependence. Specifically, recent findings suggest that the kappa-opioid receptor (KOR) may play a role in aspects of nicotine dependence, which contribute to relapse and continued tobacco smoking.     

A microiontophoretic study of the actions of mu-, delta- and kappa-opiate receptor agonists in the rat brain.

The actions of mu-, delta- and kappa-opiate receptor agonists have been compared on the activity of single neurones in the brain stem, caudate nucleus and hippocampus of the rat, using the technique of microiontophoresis. In the brain stem and caudate nucleus the predominant effect of all the opiate agonists tested was depression of neuronal activity which was antagonized by naloxone. The selectivity of naloxone as an opiate receptor antagonist was indicated by its lack of effect on gamma-aminobutyric acid (GABA)-induced responses. In the hippocampus both mu- and delta-agonists mainly caused an increase in neuronal firing rates, though some neurones were depressed. In contrast, all the kappa-agonists, including the proposed endogenous ligand for the kappa-receptor, dynorphin, caused depression of neuronal activity. All of these effects were antagonized by naloxone. There was a clear distinction in the areas within the hippocampus in which the mu- and delta-agonists produced different effects. Neurones in the pyramidal cell layer were always excited by these drugs, whereas neurones in the granule cell layer of the dentate gyrus were always depressed by the same drug.     

Up-regulation of RGS4 mRNA by opioid receptor agonists in PC12 cells expressing cloned mu- or kappa-opioid receptors.

The regulators of G-protein signaling (RGS) proteins have been shown to modulate the function of some heterotrimeric G-proteins by stimulating the GTPase activity of G-protein alpha subunits. In this study, by northern blotting analysis, we investigated the regulation of RGS4 mRNA by opioid receptor agonists in PC12 cells stably expressing either cloned mu- or kappa-opioid receptors. Treatment with respective opioid receptor agonists (mu: morphine) and [D-Ala(2), MePhe(4), Gly(ol)(5)] enkephalin (DAMGO), kappa: (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-(4,5)dec-8-y1]benzeneacetamide (U69,593)) for 0.5-24 h significantly and transiently increased the expression of RGS4 mRNA by 140-170% of the control level in a concentration-dependent manner which peaked when treated for 2 h, while treatment of non-transfected PC12 cells with opioid receptor agonists did not. The up-regulation of RGS4 mRNA was significantly blocked by co-treatment with respective opioid antagonists (mu: naloxone, kappa: norbinaltorphimine) or pretreatment with pertussis toxin. These results suggest that the activation of mu- or kappa-opioid receptors increases RGS4 mRNA level, which might contribute to opioid desentilization.     

Differential effects of micro-opioid, delta-opioid and kappa-opioid receptor agonists on dopamine receptor agonist-induced climbing behavior in mice

Interactions between the dopaminergic system and opioids have not been adequately clarified. The present study was designed to investigate the effects of micro-opioid (morphine), delta-opioid (SNC80) and kappa-opioid (U50 488H) receptor agonists on dopamine receptor agonist-induced climbing behavior in mice. Apomorphine (dopamine-receptor agonist) increased stereotyped climbing behavior, unlike methamphetamine, morphine, U-50 488H and (+/-)7-hydroxy-N,N-di-n-propyl-2-aminotetralin hydrobromide (D2-like receptor agonist). Furthermore, SKF81297 (D1 receptor agonist) and SNC80 caused climbing behavior. In addition, while morphine (20 mg/kg), but not U50 488H or SNC80, significantly attenuated high-dose apomorphine (2.0 mg/kg)-induced climbing behavior, it significantly potentiated low-dose apomorphine (0.5 mg/kg)-induced climbing behavior. These results suggest that morphine may have dual effects on the behavioral effects induced by apomorphine. Furthermore, we interestingly showed that the combination of apomorphine or SKF81297 and SNC80 enhanced frequent nonstereotypic climbing behavior, suggesting that delta/D1 interactions may play a prominent role in the expression of certain types of behavior in mice. Thus, micro-opioid, delta-opioid and kappa-opioid receptor agonists induce possible differential effects on the dopaminergic system in mice.     

Antinociceptive and adverse effects of mu- and kappa-opioid receptor agonists: a comparison of morphine and U50488-H

Although mu-opioids such as morphine are undoubtedly effective in the treatment of acute and postoperative pain, kappa-opioids are of interest for the modulation of visceral pain. In the present study, we compared a kappa-opioid agonist (U50488-H; 0.63-40 mg/kg) with a mu-opioid agonist (morphine; 0.63-40 mg/kg) in different pain models (tail withdrawal, writhing, formalin and plantar test) to represent acute, peritoneovisceral and inflammatory pain states in rats. The effects of the respective receptor agonists on gastrointestinal motility, muscle rigidity and abuse liability were also studied in appropriate animal models (charcoal, castor oil, rotarod and drug discrimination learning). Morphine was highly efficacious in all the nociceptive models employed, but also elicited a potent inhibition of gastric motility, caused severe muscle rigidity and locomotor disturbances and displayed a potential for abuse liability at the higher doses tested (> or =10 mg/kg morphine). In contrast, U50488-H was inactive in the tail withdrawal test, but was more effective in visceral and inflammatory pain settings. Although U50488-H did not elicit any gastrointestinal inhibition, a loss of muscle tone following administration of the compound led to detrimental effects on rotarod performance. The findings presented here indicate that kappa-opioids possess antinociceptive efficacy in visceral and inflammatory pain settings, but their administration can lead to a loss of muscle tone. In contrast, mu-opioids are highly active as analgesics against a range of nociceptive stimuli, but also concomitantly elicit strongly adverse effects.     

Activity profiles of dalargin and its analogues in mu-, delta- and kappa-opioid receptor selective bioassays.

1. To elucidate the structural features ensuring action of [D-Ala2, Leu5]-enkephalyl-Arg (dalargin), a series of dalargin analogues were tested for their effectiveness in depressing electrically-evoked contractions of the guinea-pig myenteric plexus-longitudinal muscle preparations (mu- and kappa-opioid receptors) and the vasa deferentia of the hamster (delta-opioid receptors), mouse (mu-, delta- and kappa-opioid receptors), rat (similar to mu-opioid receptors) and rabbit (kappa-opioid receptors). The naloxone KB values in the myenteric plexus were also obtained. 2. [L-Ala2]-dalargin was 19 times less potent than dalargin, and its pharmacological activity was peptidase-sensitive. The ratio of delta-activity to mu-activity for [L-Ala2]-dalargin was 6.78, and KB was 7.9 nM. This emphasizes the role that D-configuration of Ala2 plays in determining the active folding of dalargin molecule as well as in conferring resistance to peptidases. 3. [Met5]-dalargin was equipotent to dalargin in the myenteric plexus, but was more potent in the vasa deferentia of hamster and mouse (KB=5.5 nM). Leu5 and the interdependence of Leu5 and D-Ala2 are of importance for the selectivity of dalargin for mu-opioid receptors. 4. Dalarginamide was more potent and selective for mu-opioid receptors than dalargin, whilst dalarginethylamide, though equipotent to dalarginamide in the myenteric plexus, was more potent at delta-opioid receptors (KB=5.0 nM). [D-Phe4]-dalarginamide and N-Me-[D-Phe4]-dalarginamide were inactive indicating the contribution of L-configuration of Phe4 to the pharmacological potency of dalargin. 5. N-Me-[L-Phe4]-dalarginamide possessed the highest potency and selectivity for mu-opioid receptors (the ratio of delta-activity to mu-activity was 0.00053; KB=2.6 nM). The CONH2 terminus combined with the N-methylation of L-Phe4 increased the potency and selectivity of dalargin for mu-opioid receptors.     

Dextromethorphan and ketamine potentiate the antinociceptive effects of mu- but not delta- or kappa-opioid agonists in a mouse model of acute pain

Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available NMDA antagonists in combination with classical morphine, mu-selective fentanyl-like opioids, the delta-opioid agonist SNC80 and the kappa-opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of ketamine or dextromethorphan. All compounds were administered intraperitoneally ED(50) values were calculated from the proportion of animals failing to exhibit any response within a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED(50) values for morphine, fentanyl and sufentanil but exerted no effect on the potency of SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive potency of morphine, fentanyl and sufentanil but not SNC80 or U50,488H. In summary, these results support the use of mu-opioid agonists in combination with NMDA antagonists, but suggest that there may be no advantage in combining dextromethorphan or ketamine with delta- or kappa-opioids in the management of acute pain.     

Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists.

1. The antinociceptive activity of a range of opioid agonists and agonist-antagonist analgesics was determined in mice by use of the 55 degrees C hot plate and abdominal constriction assays. 2. Opioid agonists were approximately 10 times more effective in the abdominal constriction assay. 3. The agonist-antagonists produced analgesia only in the abdominal constriction assay, and antagonized the antinociceptive action of opioid agonists in the 55 degrees C hot plate test. 4. These differences were shown to be attributable to the different levels of stimulus employed in the two tests. 5. By comparing the antagonist potencies of the agonist-antagonists in the 55 degrees C hot plate test with their antinociceptive ED50 values in the abdominal constriction assay, an index of intrinsic activity was calculated.     

Effect of mu-, kappa-, and delta-selective opioid agonists on thermoregulation in the rat.

The effect of selective mu-, kappa-, and delta-agonists on brain surface temperature (Tb), oxygen consumption (Vo2), and heat exchange (Q) was studied in unrestrained, male Sprague-Dawley rats using whole-body calorimetry. Hyperthermia, produced by PL-017 (1.86 nM) given ICV, resulted from increased Vo2 and reduced Q during the first 15-45 min postinjection. Tb returned to control levels due to a combination of increased Q and reduced Vo2. PL-017-induced hyperthermia was abolished by the mu-selective antagonist CTAP (0.75 nM). Dynorphin A1-17 (4.65 nM), a kappa-selective agonist, reduced both Vo2 and Q, resulting in hypothermia that was blocked by the kappa-selective antagonist nor-binaltorphimine (25 nM). The delta-selective agonist DPDPE (4.64 nM) caused no significant changes in Tb, Vo2, or Q. The data indicate that central stimulation of the mu- and kappa-opioid receptors affects both oxidative metabolism and heat exchange, which result in a change in Tb. These alterations can be prevented with selective opioid antagonist pretreatment.