Peripherally acting NMDA receptor/glycineB site receptor antagonists inhibit morphine tolerance⋆
Introduction
Over the last decade research has provided compelling evidence that glutamate receptors are crucially involved in phenomena related to opioid tolerance (see Mao, 1999, Price et al., 2000 for reviews). Antagonists of the ionotropic N-methyl-d-aspartate (NMDA) receptor complex, including memantine, the moderate affinity and highly voltage-dependent clinically used NMDA channel blocker (Parsons et al., 1999) inhibit the development of morphine tolerance (Trujillo and Akil, 1991, Marek et al., 1991, Popik et al., 2000a) (see Bespalov and Trujillo, 2002 for the recent review).
One obstacle to the introduction of NMDA receptor antagonists into clinical practice is undesired “phencyclidine side-effects” profile, that is centrally mediated (Parsons et al., 1999). In turn, NMDA receptor antagonists which weakly penetrate to the brain might have a more favorable profile. However, such compounds may not be applicable to the inhibition of tolerance to morphine-induced antinociception which is believed to be primarily of central origin (McNally and Westbrook, 1998, McNally, 1999, Ueda and Inoue, 1999). On the other hand, recent data reported by Kolesnikov and colleagues demonstrated that local (topical) application of uncompetitive NMDA receptor antagonists, (+)MK-801 or ketamine, inhibited tolerance to topically applied morphine (Kolesnikov et al., 1996, Kolesnikov and Pasternak, 1999b, Kolesnikov and Pasternak, 1999a), suggesting a peripheral component of antinociceptive morphine tolerance. Since systemic rather than local administration of compounds is more favorable from the therapeutic perspective, the aim of the present study was to investigate whether antagonism of NMDA receptors in the peripheral nervous system (PNS) would inhibit tolerance to the antinociceptive effects of systemically administered morphine. As pharmacological tools we used recently developed NMDA receptor antagonists acting at the NMDA receptor/glycineB site. These compounds reach relatively low brain levels after systemic application as compared to plasma values (MRZ 2/576: ∼2% (Hesselink et al., 1999b), MDL 105,519: 0.01–0.08% (Opackajuffry et al., 1998)) or seem to be lacking CNS activity as was the case with MRZ 2/596 (see Sections 3.1.3 BBB permeability studies, 4 Discussion). In contrast, the free brain levels of memantine are over 50% of plasma concentration (Hesselink et al., 1999a).
Section snippets
Receptor binding
Tissue preparation was performed according to Foster and Wong (1987) with some modifications. Male Sprague-Dawley rats (200–250 g, Janvier, Le Genest-Isle, France) were decapitated and their brains were removed rapidly. Tissue was then processed as described previously (Parsons et al., 1997). The amount of protein in the final membrane preparation was determined according to Hartfree (1971) and adjusted to 250–500 μg/ml.
Membranes were suspended and incubated in 50 mM Tris–HCl, pH 8.0 for 45 min at 4
Receptor binding
In Scatchard analysis [3H]MDL 105,519 had a Kd of 6.03 ± 0.14 nM and a Bmax of 4.03 pmol/mg protein. MRZ 2/576 and MRZ 2/596 displaced [3H]MDL-105,519 binding to rat cortical membranes with Kis of 126 and 160 nM, respectively (Table 1, IC50 corrected according to the Cheng-Prussoff relationship for 2 nM [3H]MDL 105,519). MDL-105,519 displaced its own binding with a Ki of 11.6 nM. Non-specific binding determined with glycine 100 μM was only 15–20% and standard compounds displaced binding to non-specific
Discussion
NMDA receptor binding and patch clamp studies confirmed that MRZ 2/576 and MRZ 2/596 bind with moderate (nanomolar) affinity to NMDA receptor/glycineB site whereas MDL 105,519 was some 5–10-fold more potent. Because of the use of glycine (1 μM) in the patch clamp studies, IC50 values obtained in these experiments were 4–9-fold higher than the Ki values obtained in binding experiments. However, correction of these IC50 values to Kbs taking into account a Kd for glycine in these patch clamp
Acknowledgements
The study was supported in part by Institute of Pharmacology Statutory Activity.
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The referees of the present paper suggested to assess brain penetration of MRZ 2/596 using brain microdialysis. It was not possible at the time of manuscript preparation but such opportunity appeared after manuscript acceptance. The study revealed, that in rats after application of MRZ 2/596 at the dose of 30 mg/kg ip maximal concentrations in brain reach c.a. 100 nM (N=3) concentrations corrected for in vitro recovery. Thus, it is unlikely that dose used in the present study (0.05–1 mg/kg) resulted in brain levels of MRZ 2/596 that would affect NMDA receptors assuming lack of differences in blood brain barrier between rat and mice.