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Selective Modulation of Morphine Anfinocicepfion, but Not Development of Tolerance, by 8 Receptor Agonists

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Selective Modulation of Morphine Anfinocicepfion, but Not Development of Tolerance, by 8 Receptor Agonists European Journal of Pharmacology, 186 (1990) 137-141 137 Elsevier EJP 20693 Short communication Selective modulation of morphine anfinocicepfion, but not development of tolerance, by 8 receptor agonists Qi Jiang, Henry I. Mosberg 1 and Frank Porreca Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724. U.S.A. and I College of Pharmacy. University of Michigan, Ann Arbor, Mi 48109, U.S.A. Received 2 July 1990, accepted 10 July 1990 Co-administration of 8 opioid agonists at doses which do not produce measurable antinociception were demon- strafed to produce an increase in the antinociceptive potency of morphine in the mouse tail-flick test. In contrast, co-administration of equi-antinociceptive combinations of a 8 agonist plus morphine for three days resulted in the development of less tolerance to morphine antinociceptive actions. The data indicate that while acute antinociceptive effects of opioid It agonists are modulated by 8 agonists, the development of antinociceptive tolerance is not. Antinociception; Morphine; 8-Opioid receptor agonists; Tolerance 1. Introduction Ocomplexed (¢~cx) receptors to designate their ex- istence within the/t-~ receptor complex (Rothman Previous reports from our laboratory (Heyman et al., 1989) while those /t and 8 receptors not et al., 1989a,b; Jiang et al., in press; Porreca et al., interacting were termed the ~non-complexed (~tncx) 1990) and others have shown that 8 opioid agonists and 8,on-complcx~ (8,cx)receptors. can modulate the potency and efficacy of opioid p The possibility that occupation of the opioid agonists such as morphine. The modulatory action Sex site could increase the potency (Heyman et al., (i.e. increases or decreases in potency and/or ef- 1989a,b; Porreca et al., 1990) and efficacy (Jiang ficacy), but not the direct antinociceptive effect of et al., in press) of opioid ~t agonists was of inter- morphine, was blocked by pretreatment with the est, for example, in using /~ agonists of lower selective 8 opioid antagonist, ICI 174,864 (Cotton efficacy to produce equi-effective pain relief clini- et al., 1984), and this compound given alone did cally. Such a possibility was particularly interest- not produce antinociception nor modulation of ing in that the route of administration of the morphine effects. These studies, and others (see modulating 8 agonist seemed to be umimportant. Rothman et al., 1989 for review) have supported In this regard, i.c.v, administration of the highly the hypothesis that some opioid/t and 8 receptors selective 8 agonist, [D-Pen2,D-PenS]enkephalin may exist in a functionally associated state. In this (DPDPE) (Mosberg et al., 1983) or i.p. adminis- hypothesis, opioid receptors thought to function- tration of [LeuS]enkephalin produced an increase ally interact have been termed ~complexed (~cx) and in the antinociceptive potency of morphine given by the same route. In spite of these findings, however, it remained unclear whether all of the pharmacological actions Correspondence to: F. Porreca, Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ of morphine would be similarly subjected to mod- 85724, U.S.A. ulation by O opioid agonists, or whether selective 0014-2999/90/$03.50 © 1990 Elsevier Science Pubfishers B.V. (Biomedical Division) 138 modulation of specific effects could be achieved. 1989a,b; Jiang et al., in press), while morphine The present study has addressed whether DPDPE and [LeuS]enkephalin were given i.po and testing or [LeuS]enkephalin would increase the rate of took place after 20 min, a time shown to result in development of tolerance to morphine antinoci- a maximal response for the combination (Porreca ceptive actions following chronic administration et al., 1990). of equi-antinociceptive combinations. We now re- A cutoff time of 15 s was employed; if the port that although these compounds increase mouse failed to respond within this time, the tail morphine antinociceptive potency, the rate of de- was removed from the water and that animal was velopment of antinociceptive tolerance depends assigned a maximum score. Mice not responding only on the amount of morphine administered. within 5 s in the initial control trial were eliminated from the experiment. Antinociception at each time point was calculated according to the following 2. Materials and methods formula: ~ antinociception ffi 100 y (test latency- control latency)/(15-control latency). 2.1. Animals 2.4. Induction of antinociceptive tolerance Male, ICR mice (20-30 g) were used for all experiments. Animals were kept in groups of five in a temperature-controlled room with a 12 h In the tolerance experiments, mice were in- light-dark cycle (lights on 7 : 00 a.m. to 7: 00 p.m.). jected twice daily (8:00 a.m. and 5:p.m.) for 3 Food and water were available ad libitum until days, alid testing took place on the morning of the time of the experiment. day 4. For the DPDPE/morphine experiments, animals received i.c.v, saline, morphine alone (1.2 2.2. Injection techniques or 6 nmol), DPDPE alone (1.55 nmol) or morphine plus DPDPE (1.2 and 1.55 nmol), respectively. I.c.v. administrations were made directly into This combination of i.c.v, morphine plus DPDPE the lateral ventricle as previously described (Hey- was shown to produce an equivalent degree of man et al., 1989a,b). The mouse was tightly antinociception as i.c.v, morphine given at the 6 anesthetized with ether, an incision was made in nmol dose. After each i.c.v, injection, the scalp the scalp, and the injection was made 2 mm lateral incision was closed using wound clips. No signs of and 2 mm caudal to bregma at a depth of 3 mm distress were noted in these animals over the 3 using a 10/~l Hamilton microliter syringe with a days (six injections) period. In the [LeuS]enkepha- 26-gauge needle. I.c.v. injections were made at a lin/morphine experiments, mice received i.p. volume of 5/H. saline, morphine alone (9 or 24 ~tmol/kg), [LeuS]enkephalin (18/~mol/kg) or morphine plus 2.3. Taii flick assay [LeuS]enkephalin (9 and 18 /tmol/kg), respec- tively. The combination of i.p. morphine plus The thermal nociceptive stimulus was 55°C [LeuS]enkephalin was shown to produce an equiv- warm water with the latency to tail-flick or alent degree of antinociception as i.p. morphine withdrawal taken as the endpoint (Heyman et al., given at the 24/~mol/kg dose. 1989a, b). After the determination of control latencies, the mice received graded i.c.v, doses of 2.5. Chemicals vehicle, morphine, or concurrent combination of morphine plus DPDPE or [LeuS]enkephafin. Morphine sulfate was purchased from Mal- Morphine and DPDPE were given by the i.c.v. linckrodt Chemical Co. (St. Louis, MO) while route and testing took place after 10 min, a time [LeuS]enkephalin was purchased from Sigma previously shown to result in a maximal response Chemical Company (St. Louis, MO). DPDPE was for both compounds (Heyman et al., 1987; synthesized as previously described (Mosberg et 139 al., 1983). All compounds were dissolved in dis- 100 tilled water just before using. QO 80 2.6. Statistics ,H 70 I10 o') SO Regression lines, As0 values (i.e. the dose pro- td 40 ducing a 50~ antinociception response) and 95~; < confidence limits (C.L.) were determined with each Z<l: individual data point using the computer program described by Tallarida and Murray (1986) (proce- 0 ....... " ................. I I dure 8). For the fitting of regression lines and 02 1 10 I00 180 calculation of the As0 values, only the linear por- DOSE MORPHINE(nmol, i.c.v.) tion of the dose-effect curve was used. Relative Fig. 1. Dose-response fines for i.c.v morphine in mice pre- potencies were calculated by comparison of the treated with saline (circles), DPDPE (1.55 nmol, inverted trian- regression line As0 values. All data points shown gles), morphine (1.2 nmol, triangles), morphine (6 nmol, are the mean of 10 mice and error bars represent squares) and morphine (1.2 nmol) plus DPDPE (1.55 nmol) the S.E. (diamonds). 3. Results resulted in a slight tolerance to the antinociceptive actions of morphine as shown by the 1.85-fold I.c.v. morphine produced a dose-related anti- rightward displacement of the dose-response line; nociceptive effect in the mouse tail-flick test with the As0 for morphine in animals pretreated with an As0 value of 0.92 (0.65-1.3) nmol. When morphine at 1.2 nmol was calculated to be 2.13 morphine and DPDPE were co-administered i.c.v., (1.44-3.15) nmol (fig. 1). Pretreatment with i.c.v. the morphine dose-response line was displaced to morphine at 6 nmol produced a locater degree of the left; the As0 of this combination was calcu- tolerance resulting in approximately a 12.84-fold lated as 0.21 (0.12-0.34) indicating an approxi- rightward displacement of the i.c.v, morphine mately 4.4-fold increase in potency. Similarly, i.p. dose-response line. Additionally, the maximum morphine produced a dose-related antinociceptive antinociceptive effect of i.c.v, morphine in animals repsonse with an As0 value of 15.3 (12.99-18.02) pretreated with this higher dose of morphine was ~tmol/kg and when co-administered with i.p. shown to be approximately 60~;; the calculated [LeuS]enkephalin the dose-response line for the As0 value for these pretreated mice was 14.77 combination was to the left of that for morphine (9.21-23.68) nmol, indicating severe antinocicep- alone, with an As0 of 4.25 (3,41-5.31) ~tmol/kg, a tive tolerance (fig.
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