Vol. 284, Issue 2, 455-459, February 1998

Lack of Morphine and Enkephalin Tolerance in 129/SvEv Mice: Evidence for a NMDA Receptor Defect

The Cotzias Laboratory of Neuro-Oncology (Y.K., G.W.P.) and the Department of Anesthesiology (Y.K., S.J., R.W.), Memorial Sloan-Kettering Cancer Center, and The Departments of Neurology and Neuroscience and Pharmacology, Cornell University Medical College (G.W.P.), New York, New York

	Abstract

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In contrast to the rapid development of tolerance to morphine in CD-1 mice, tolerance is not seen in 129/SvEv mice implanted with morphine pellets or given daily morphine injections for 5 days. Similarly, the progressive and complete loss of analgesia in CD-1 mice seen with repeated dosing of the delta ligand [D-Pen²,D-Pen⁵]enkephalin is not observed in 129/SvEv mice. In contrast, tolerance develops normally to both the kappa₁ drug U50,488H and the kappa₃ agent naloxone benzoylhdrazone. N-methyl-D-aspartate (NMDA) given alone attenuates morphine analgesia in CD-1 mice and accelerates the development of tolerance in CD-1 mice when given daily with morphine. In contrast, NMDA has no significant effect in the 129/SvEv mice in either paradigm. Activation of NMDA receptors can lead to the production of nitric oxide, which also is involved with morphine tolerance. Sodium nitroprusside and L-arginine increase nitric oxide levels and decrease morphine analgesia in both the control CD-1 and 129/SvEv mice. Thus, the defect in the NMDA/nitric oxide cascade responsible for the loss of morphine tolerance in the 129/SvEv mice rests at the level of the NMDA receptor itself or in the steps up to the activation of nitric oxide synthase.

	Introduction

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Morphine tolerance can be readily demonstrated in mice using a variety of experimental paradigms. Although repeated administration of morphine almost certainly leads to biochemical changes at the level of the receptor and possibly its transduction systems, some of the most interesting aspects of morphine tolerance have come from studies implicating both the NMDA and nitric oxide systems (Bhargava, 1994; Pasternak et al., 1995). The development of morphine tolerance is effectively prevented by noncompetitive or competitive NMDA antagonists (Ben-Eliyahu et al., 1992; Bhargava and Matwyshyn, 1993; Dunbar and Yaksh, 1996a; Elliott et al., 1994, 1995; Gutstein and Trujillo, 1993; Kolesnikov et al., 1993a; Manning et al., 1996; Tiseo and Inturrisi, 1993; Trujillo and Akil, 1991, 1994), or even agents acting at the glycine site (Kolesnikov et al., 1994; Lutfy et al., 1995). NMDA activation leads to increases in NO production. Inhibition of NOS, the enzyme that generates NO, also blocks the appearance of morphine tolerance (Babey et al., 1994; Bhargava and Zhao, 1996; Dunbar and Yaksh, 1996b; Kolesnikov et al., 1992, 1993b, 1997; London et al., 1994; Vaupel et al., 1995). These insights into modulatory circuits mediating morphine tolerance has opened new potential therapeutic targets.

Variations among strains of mice have provided valuable models with which to explore opioid function. The demonstration that different strains vary markedly in their sensitivity to opioid analgesics has played a large role in the identification and characterization of the various opioid receptor subtypes. For example, morphine is not an effective analgesic when given either systemically or supraspinally in CXBK mice (Baron et al., 1975; Elmer et al., 1995; Pick et al., 1993; Raffa and Schupsky, 1993; Reith et al., 1981; Vaught et al., 1988). This insensitivity to morphine analgesia contrasts sharply with the normal potency of heroin, its active metabolite 6-acetylmorphine and morphine-6-glucuronide in this mouse strain (Rossi et al., 1996), indicating the existence of distinct receptors for the two classes of drugs. The development of knockout mice lacking various proteins, including opioid receptors, provides important new tools in the exploration of opioid pharmacology. Because many of these genetically altered animals are derived from 129/SvEv mice, it is important to determine the pharmacology of opioids in this strain. We now describe the differences in the development of morphine tolerance between CD-1 and 129/SvEv mice.

	Materials and Methods

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Morphine sulfate, U50,488H and DPDPE were gifts from the Research Technology Branch of the National Institute on Drug Abuse (Rockville, MD). Halothane was obtained from Halocarbon Laboratory (Hackensack, NJ). NalBzoH was synthesized as described previously (Luke et al., 1988). All other chemicals were purchased from Sigma Chemical (St. Louis, MO).

Male CD-1 (24-32 g; Charles River Laboratories, Raleigh, VA) and 129/SvEv mice (Taconic, Germantown, NY) were housed in groups of five with food and water available ad libitum. Animals were maintained on a 12-hr light/dark cycle. Single morphine pellets (75 mg; Research Technology Branch, NIDA) were implanted subcutaneously on the back with the animals under light halothane anesthesia. Compounds were administered intracerebroventricularly with the animals under light halothane anesthesia as reported previously (Haley and McCormick, 1957), and analgesia was assessed with the tail-flick assay. Response latencies were determined by the radiant heat tail-flick assay (D'Amour and Smith, 1941), with base-line latencies between 2 and 3 sec, which did not differ between the two strains. After drug administration, we used a maximum cutoff score of 10 sec to minimize tissue damage. Antinociception was defined quantally as a doubling or greater of base-line tail-flick scores, as reported previously (Pan et al., 1995; Rossi et al., 1995; Standifer et al., 1994). For convenience, the term "analgesia" is used synonymously with antinociception. Time actions were performed for all drugs and peak times determined. All subsequent testing was then performed at peak effect, which was 30 min after systemic drug and 15 min after centrally administered agent. Tolerance was induced using approaches previously reported by our laboratory (Kolesnikov et al., 1993b). Morphine pellets (75 mg free base) were placed subcutaneously in the back with the animals under halothane anesthesia. Daily injections also were used in which the animals received a single injection each day. Animals receiving multiple injections always received morphine 15 min after the other agent.

All groups contained a minimum of 10 mice; most comprised at least 20. Single doses were compared using the Fisher Exact Test. Dose-response curves were generated from at least three doses of drug. Each dose was tested in at least 10 mice, which were examined only once. Data were analyzed to generate ED₅₀ values and 95% confidence limits using the BLISS-20 program, which maximizes the log-likelihood function to fit a parallel set of gaussian normal sigmoid curves to the dose response of quantal data (Umans and Inturrisi, 1981).

	Results

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Morphine tolerance in CD-1 and 129/SvEv mice. First, we examined the development of morphine tolerance in both the CD-1 and 129/SvEv strains of mice. Pelleting mice with morphine produced analgesia in all the mice, followed within a few days by the rapid development of tolerance in CD-1 mice (fig. 1a). In contrast, the analgesic response in the 129/SvEv mice did not diminish over the 6 days examined. The analgesic response was 100% for 4 days; the limited decline after that was not significant. We observed a similar effect with daily subcutaneous injections of equianalgesic morphine doses (fig. 1b). As reported previously (Elliott et al., 1994; Kolesnikov et al., 1993a, 1993b, 1994), tolerance developed quite rapidly in the CD-1 mice, with the analgesic response declining from 60% to 0% within 5 days. In contrast, 129/SvEv mice receiving equianalgesic dose of morphine daily did not develop tolerance. The analgesic response remained constant at 60% over the full 5 days. Finally, we examined the effects of daily supraspinal injections of morphine (fig. 1c). Again, the morphine analgesia seen on the first day was virtually lost by the fifth day in the CD-1 but not in the 129/SvEv, mice.

View larger version (12K): [in this window] [in a new window]   Fig. 1.   Effects of daily morphine dosing in CD-1 and 129/SvEv mice. A, Groups of mice (n  10) were implanted with a morphine pellet (75 mg free base s.c.) on day 1 and the analgesia due to the single pellet determined at the indicated time after implantation. After 4 days, no CD-1 mice were analgesic (P < .0001) whereas the 129/SvEv mice showed no significant change in their analgesic response over the entire period. B, Groups of mice (n  10) received daily equianalgesic injections of morphine (CD-1: 4 mg/kg s.c.; 129/SvEv: 2.5 mg/kg s.c.), and analgesia was assessed on the indicated day 30 min after the injection. After 5 days, none of the CD-1 mice were analgesic (P < .01), whereas the 129/SvEv mice showed no significant change in their analgesic sensitivity. C, Groups of mice (n  10) received daily injections of morphine (100 ng i.c.v.) and analgesia was assessed on the indicated day 15 min after the injection. After 5 days, the CD-1 mice were significantly less responsive (P < .01), whereas the 129/SvEv mice showed no significant change in their analgesic sensitivity.

Delta and kappa tolerance in CD-1 and 129/SvEv mice. Prior studies have shown many similarities in the pharmacological sensitivity of tolerance to both delta and mu analgesia (Babey et al., 1994; Kolesnikov et al., 1992, 1993a, 1993b, 1994; Pasternak et al., 1995). With daily intrathecal injections, the analgesic activity of the delta ligand DPDPE rapidly declined from 60% to zero by 5 days in the CD-1 mice (fig. 2). In contrast, the response in the 129/SvEv mice remained relatively constant over the same period (P < .01).

View larger version (11K): [in this window] [in a new window]   Fig. 2.   Effects of daily DPDPE dosing in CD-1 and 129/SvEv mice. Groups of mice (n  10) received DPDPE (0.5 µg i.t.) daily, and analgesia was determined on the indicated day 15 min after injection. After 5 days, none of the CD-1 mice were analgesic (P < .01), whereas the 129/SvEv mice showed no significant change in their analgesic sensitivity.

View larger version (14K): [in this window] [in a new window]   Fig. 3.   Effects of daily kappa drugs in 129/SvEv mice. Groups of 129/SvEv mice (n  10) received daily injections of either the kappa1 drug U50,488H (5 mg/kg s.c.) or the kappa3 agent NalBzoH (50 mg/kg s.c.). Analgesia was determined on the indicated day 30 min after injection. None of the mice were analgesic after 4 days on NalBzoH or 5 days on U50,488H (P < .01).

Earlier work suggested that kappa tolerance was not mediated through the same NMDA/NO cascade as mu and delta drugs (Babey et al., 1994; Elliott et al., 1994; Kolesnikov et al., 1992, 1993a, 1993b, 1994). We therefore examined tolerance to the kappa₁ agent U50,488H and the kappa₃ drug NalBzoH in the 129/SvEv mice (fig. 3). Prior studies have repeatedly demonstrated that repeated daily dosing with either U50,488H or NalBzoH leads to a loss of analgesia within 5 days in CD-1 mice (Babey et al., 1994; Elliott et al., 1994; Kolesnikov et al., 1992, 1993b, 1994). We observed a similar loss of kappa analgesic sensitivity in the 129/SvEv mice. Using this same daily injection paradigm, the analgesic activity of U50,488H and NalBzoH in 129/SvEv mice seen on the first day, 70% and 60%, respectively, was completely lost by the fifth day. Thus, tolerance to both kappa₁ and kappa₃ drugs developed in the 129/SvEv mice at a rate similar to that previously reported in CD-1 mice (Babey et al., 1994; Kolesnikov et al., 1992, 1993a, 1993b, 1994).

NMDA receptors and NO actions on morphine analgesia. We next assessed the location along the NMDA/NO cascade responsible for the loss of morphine and DPDPE tolerance. Because blockade of NMDA receptors prevents the development of morphine tolerance, we administered NMDA in an effort to induce a lowered morphine response. Treating mice with NMDA alone for 5 days significantly lowered the response to a single morphine dose in CD-1 mice, whereas 129/SvEv mice treated in the same manner retained their analgesic sensitivity toward morphine, as demonstrated by full dose-response studies (table 1). The analgesic ED₅₀ value for morphine in the CD-1 mice was shifted 4-fold, whereas the response in the 129/SvEv mice was not significantly affected.

View this table: [in this window] [in a new window]   TABLE 1 Effect of NMDA, L-arginine and nitroprusside on morphine analgesia in CD-1 and 129/SvEv mice Animals were assessed for morphine aalgesia after receiving no treatment (naive), L-arginine (50 mg/kg i.p. for 3 days), sodium nitroprusside (5 mg/kg s.c. for 3 days) or NMDA (1 mg/kg s.c. for 5 days). On the last day of treatment, ED50 values with 95% confidence limits were determined from dose-response curves with morphine administered 15 min later. The doses for the control CD-1 mice were 2.5, 5 and 10 mg/kg s.c., with n = 10 for each dose. The treated CD-1 mice received doses of 5, 10 and 20 mg/kg s.c. (NMDA) or 4, 10 and 20 mg/kg s.c. (nitroprusside), with n = 10 for each dose. The doses for the control 129/SvEv mice were 1, 2.5 and 5 mg/kg s.c., with n = 20 for each dose. The doses for the treated 129/SvEv mice were 3, 6 and 10 mg/kg s.c. (nitroprusside); 1, 5 and 10 mg/kg s.c. (L-arginine); or 1, 3 and 6 mg/kg s.c. (NMDA), with n = 20 for each dose. L-Arginine values for CD-1 mice are from the literature (Babey et al., 1994). Saline treatment of 129/SvEv mice did not significantly alter the ED50 value (1.9 mg/kg; 95% CL, 1.1, 3.0) compared with untreated mice (2.0 mg/kg; 95% CL, 1.4, 2.8). Base-line latencies in the CD-1 (2.8 ± 0.2 sec) and 129/SvEv mice (2.5 ± 0.2 sec) were not influenced by NMDA (2.9 ± 0.1 and 2.4 ± 0.2 sec, respectively). Base-line latencies in the CD-1 (2.3 ± 0.1 sec) and 129/SvEv mice (2.1 ± 0.1 sec) were not influenced by sodium nitroprusside (2.4 ± 0.1 and 2.2 ± 0.2 sec, respectively). Base-line latencies in the CD-1 (2.5 ± 0.1 sec) and 129/SvEv mice (2.3 ± 0.1 sec) were not influenced by L-arginine (2.3 ± 0.1 and 2.2 ± 0.1 sec, respectively).

We then examined the effects of NMDA given along with morphine. Concurrent daily administration of NMDA along with morphine accelerated the development of morphine tolerance in CD-1 mice (fig. 4a). After 3 days of treatment, all analgesic activity in the CD-1 mice receiving both drugs was lost, a result that was significantly different from the response in the morphine-alone group (P < .05). NMDA coadministered with morphine had no significant effect on the analgesic activity of morphine over time in the 129/SvEv mice, even when the treatment period was extended to 10 days (fig. 4b). This inability of NMDA itself to overcome the lack of tolerance development in these mice suggested that the defect was at the level of the NMDA receptor or further downstream in the pathway.

View larger version (15K): [in this window] [in a new window]   Fig. 4.   Effect of NMDA on morphine tolerance in CD-1 and 129/SvEv mice. A, Groups of CD-1 mice (n  10) received daily injections of morphine (4 mg/kg s.c.) alone (Control) or with daily injections of NMDA (1 mg/kg s.c.). After 3 days, the response in the group receiving NMDA was significantly lower than controls (P < .05). B, Groups of 129/SvEv mice (n  10) received daily injections of morphine (2.5 mg/kg s.c.) alone (Control) or with daily injections of NMDA (1 mg/kg s.c.). Base-line latencies in the 129/SvEv (2.8 ± 0.2 sec) were not influenced by NMDA (2.9 ± 0.1 sec).

To explore the potential role of the NO system, we used both L-arginine and sodium nitroprusside. Both agents, which increase NO levels, significantly lowered the analgesic sensitivity of mice to morphine (table 1). Sodium nitroprusside works directly as a NO donor while L-arginine requires its enzymatic conversion to NO by NOS. Activity by nitroprusside implies that the downstream pathway activated by NO is intact. The ability of L-arginine to modulate morphine actions ensures the presence of enzymatically active NOS.

Sodium nitroprusside significantly shifted the dose-response curve for morphine 2.7-fold in CD-1 mice and 2.5-fold shift in the 129/SvEv mice. L-Arginine, the substrate for NOS, is converted enzymatically to NO. Treating mice with L-arginine for 3 days significantly lowered morphine analgesia in both the CD-1 and 129/SvEv strains to a similar degree (table 1).

We then examined the effect of concurrent administration of morphine and L-arginine in 129/SvEv mice (fig. 5). Given daily for 5 days, morphine maintained a constant analgesic response, consistent with the previous result in which daily morphine injections did not significantly change over 10 days (fig. 4b). After 5 days, we added L-arginine to the regimen. Coadministering L-arginine with morphine rapidly induced a dramatic decline in analgesic responsiveness, eliminating the analgesic response within an additional 5 days. The rate of decline of analgesic sensitivity was similar to that seen with morphine alone in CD-1 mice (fig. 1b).

View larger version (12K): [in this window] [in a new window]   Fig. 5.   Effect of L-arginine on the development of morphine tolerance in 129/SvEv mice. A group of 129/SvEv mice (n = 10) received morphine (2.5 mg/kg s.c.) alone for 5 days and then continued to receive the same morphine dose in conjunction with a daily dose of L-arginine (50 mg/kg i.p.) for an additional 5 days. After 5 days on L-arginine, analgesia was significantly decreased compared with the response before the addition of L-arginine (P < .01).

	Discussion

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Opioid tolerance is a complex series of biochemical events leading to a reduction in sensitivity (Reisine and Pasternak, 1996). Although it is likely that many factors play a role, numerous studies have documented the importance of NMDA receptors (Ben-Eliyahu et al., 1992; Bhargava and Matwyshyn, 1993; Dunbar and Yaksh, 1996a; Elliott et al., 1994, 1995; Gutstein and Trujillo, 1993; Kolesnikov et al., 1994, 1993a; Lutfy et al., 1995; Manning et al., 1996; Tiseo and Inturrisi, 1993; Trujillo and Akil, 1991, 1994) and the NOS cascade (Babey et al., 1994; Bhargava and Zhao, 1996; Dunbar and Yaksh, 1996b; Kolesnikov et al., 1992, 1993b, 1997; London et al., 1994; Vaupel et al., 1995) in morphine and enkephalin tolerance. The generation of various knockout animals has greatly facilitated studies that explore the molecular biology of behavior. However, the use of these animals requires a sound understanding of the pharmacology of the mouse strains used to generate the mutants, including the 129/SvEv mouse strain. Initially considered simple control studies, we quickly observed very unusual results in the 129/SvEv mice.

In contrast to the CD-1 strain, 129/SvEv mice did not develop tolerance to morphine regardless of whether it was administered by pellet or daily injections given subcutaneously or intracerebroventricularly. This does not appear to simply reflect a slower rate of tolerance development. The analgesic activity of morphine in the 129/SvEv mice remained similar to naive levels even after 10 days of treatment, twice the time needed to completely lose morphine analgesia in the CD-1 mice. Prior work has suggested that delta tolerance is similar to that of morphine, as indicted by the similar sensitivity toward NMDA antagonists and NOS inhibitors (Babey et al., 1994; Elliott et al., 1994; Kolesnikov et al., 1993a, 1993b, 1994; Pasternak et al., 1995). As in these earlier studies, the activity of the delta ligand DPDPE mimicked that of morphine. DPDPE maintained its analgesic potency in the 129/SvEv mice over 5 days despite the complete loss of an equianalgesic DPDPE dose in CD-1 mice in the same period of time. Yet, tolerance develops to both kappa₁ and kappa₃ drugs in the 129/SvEv mice at rates indistinguishable from those in the CD-1 mice (Kolesnikov et al., 1993b), dissociating mu and delta tolerance in the 129/SvEv mice from that involved with kappa agents. Thus, the deficit present in these 129/SvEv mice is limited to mu and delta systems. These results are consistent with prior work from our laboratory in which NMDA antagonists and NOS inhibitors selectively modulated mu and delta, but not kappa, systems (Babey et al., 1994; Elliott et al., 1994; Kolesnikov et al., 1993a, 1993b, 1994; Pasternak et al., 1995).

In an attempt to identify the defect responsible for absence of mu and delta tolerance, we focused on the NMDA/NO cascade. It is generally believed that occupation of NMDA receptors leads to the activation of nNOS, which in turn leads to the development of tolerance. We examined the role of NMDA receptors and NOS. Although NMDA effectively lowered morphine analgesia in CD-1 mice, it was inactive in the 129/SvEv mice. After 5 days, NMDA treatment shifted the morphine dose-response curve in CD-1 mice 4-fold without significantly changing the response in the 129/SvEv mice. This observation implied that the difficulty arose from the NMDA receptor itself or from a downstream step in the pathway.

The NO pathway does not appear to be impaired. The NO donor nitroprusside effectively lowered the analgesic potency of morphine as effectively in both the 129/SvEv and the CD-1 mice, implying that the targets for NO needed to diminish the activity of morphine and the downstream pathways are intact. The ability of L-arginine to shift the morphine dose-response to a similar degree in both strains suggests that the enzymatic activity of NOS also is not impaired.

Together, these results imply that the defect in the 129/SvEv mice may lie at the NMDA receptor itself. Alternatively, it might involve steps in the pathway between the NMDA receptor and the initiation of the NO cascade. Additional studies are now needed to explore these possibilities. Clearly, the 129/SvEv mice provide a unique model to further explore the mechanisms mediating opioid tolerance and illustrate the strength of genetic models in the exploration of opioid function.

	Acknowledgments

This work was supported in part by a research grant (DA07242) and a Research Scientist Award (DA00220) to G.W.P. and a core grant to Memorial Sloan-Kettering Cancer Center (CA08748).

	Footnotes

Accepted for publication September 29, 1997.

Received for publication April 14, 1997.

Send reprint requests to: Dr. Gavril W. Pasternak, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail: pasterng{at}mskmail.mskcc.org.

	Abbreviations

NalBzoH, naloxone benzoylhydrazone; DPDPE, [D-Pen²,D-Pen⁵]enkephalin; NMDA, N-methyl-D-aspartate; NOS, nitric oxide synthase; NO, nitric oxide.

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