NMDA-Receptor Antagonists and Opioid Receptor Interactions as Related to Analgesia and Tolerance

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Journal of Pain and Symptom Management S7

Proceedings Supplement NDMA-Receptor Antagonists: Evolving Role in Analgesia

NMDA-Receptor Antagonists and Opioid Receptor Interactions as Related to Analgesia and Tolerance Donald D. Price, PhD, David J. Mayer, PhD, Jianren Mao, PhD, and Frank S. Caruso, PhD Departments of Oral and Maxillofacial Surgery and Neuroscience, University of Florida, (D.D.P), Florida; Department of Anesthesiology, Medical College of Virginia, (D.J.M., J.M.), Virginia; and Algos Pharmaceutical Corporation (F.S.C.), Neptune, New Jersey, USA

Abstract A model proposing that N-methyl-D-aspartate (NMDA) receptor and opioid receptor mechanisms overlap and interact within the same dorsal horn nociceptive neurons makes several predictions. First, hyperalgesia should be associated with opioid tolerance. Second, both hyperalgesia and tolerance to opioid-analgesia should be blocked by an NMDA-receptor antagonist. Results from our laboratory and others support these predictions and point to several clinical implications. One is that, in addition to preventing tolerance and dependence, combining NMDA-receptor antagonists with both opioid and nonopioid analgesics may increase their analgesic potency. Preclinical animal studies demonstrate these advantages and underscore the practicality of the combined administration of nontoxic NMDA-receptor antagonists with various types of analgesic drugs. J Pain Symptom Manage 2000;S7–S11. © U.S. Cancer Pain Relief Committee, 2000. Key Words NMDA-Receptor antagonists, hyperalgesia, opioid tolerance, dextromethorphan

Introduction An emerging principle in new pharmacological strategies for treating pain is to combine existing analgesic agents with nontoxic N-methyld-aspartate (NMDA) receptor antagonists to

Address reprint requests to: Donald D. Price, PhD, Claude Denson Pepper Center for Research on Oral Health in Aging, Health Science Center, PO Box 100416, Gainesville, FL 32610-0416, USA. Accepted for publication: September 17, 1999. © U.S. Cancer Pain Relief Committee, 2000 Published by Elsevier, New York, New York

enhance their analgesic effects, extend their duration, and prevent tolerance to their repeated administration. Our contribution to this principle has been the discovery of neurochemical mechanisms by which NMDA-receptor antagonists exert these effects, followed by preclinical tests of combinations of dextromethorphan (DM) with opioid and nonopioid analgesic agents. Here we briefly review the mechanisms by which NMDA-receptor antagonists enhance analgesic effects of these agents, and we note the preclinical studies that have led to human clinical trials. 0885-3924/00/$–see front matter PII S0885-3924(99)00121-9

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Overview of NMDA-Receptor Mechanisms of Pain The mechanisms by which nontoxic NMDAreceptor antagonists such as DM enhance analgesic effects of conventional analgesic agents are likely to take place to a major extent within the spinal cord dorsal horn. Dorsal horn neurons that process pain information have both m-opioid and NMDA-receptors. These neurons are at the origin of ascending pathways subserving “normal” pain and pathophysiological pain. Impulses in primary nociceptive afferents evoke brief high-intensity excitation in dorsal horn nociceptive neurons that is followed by a lower-intensity prolonged impulse discharge.1 Continuous input over C polymodal nociceptive afferents, but not other types of nociceptive afferents, additionally evokes temporal summation by activation of NMDA-receptors.2,3 These mechanisms are thought to provide part of the basis for centrally mediated hyperalgesia that occurs in persistent pain states, such as inflammatory pain that follows tissue injury. This hyperalgesia is a normal consequence of injury and subsides with healing of the injured tissue. Generally similar central mechanisms of hyperalgesia also occur with nerve injury.4,5 Temporal summation of C afferent–evoked responses of dorsal horn nociceptive neurons is likely to be mediated by the release of glutamate/aspartate and their activation of NMDA-receptors, leading to prolonged depolarizations.3,6 NMDAreceptor antagonists have been shown to powerfully block prolonged depolarizations evoked in dorsal horn neurons in in vitro preparations3,6 and to block the temporal summation evoked by electrical stimulation of C afferents in in vivo preparations without reducing the responses of these same neurons to A-fiber stimulation.1–3,6 Temporal summation of C afferent–evoked responses in dorsal horn neurons reflects some of the mechanisms underlying centrally mediated hyperalgesia that occurs after nerve injury or after inflammation.1–6 This happens because both phenomena involve the same NMDAreceptor mechanism and at least some of the same intracellular consequences of NMDAreceptor activation.1–6 Thus, temporal summation has long been considered a central neural mechanism in pathophysiological pain.1,6 That temporal summation of C fiber–medi-

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ated responses of dorsal horn nociceptive neurons directly participates in normal pain is shown in human psychophysical experiments on second pain. If the stimulus that activates the C nociceptive afferents occurs at a frequency greater than once every 3 seconds, both second pain and C afferent–evoked impulse discharges of dorsal horn nociceptive neurons progressively increase in magnitude.1,6,7 If the same NMDA-receptor mechanism underlies both electrophysiological and psychophysical expressions of slow temporal summation, then both phenomena should be antagonized by NMDAreceptor antagonists. In a direct test of this hypothesis, oral doses of DM and a vehicle control were given on a double-blind basis to healthy human subjects who rated intensities of first and second pain in response to repeated brief stimuli.7 DM 30 mg and 45 mg, but not 15 mg, were effective in attenuating temporal summation of second pain, a psychophysical correlate of temporal summation of C afferent–mediated responses of dorsal horn nociceptive neurons that has been termed “windup.” These results further confirm temporal summation of second pain as a psychophysical correlate of windup by providing evidence that DM selectively reduces temporal summation of second pain, as has been shown for windup. Windup is now considered related to the central mechanisms of hyperalgesia.1,4,6 Similar to what occurs following tissue injury, tonic input from nociceptive C afferents is thought to lead to central sensitization of dorsal horn neurons by means of this windup mechanism.1,4,6 Moreover, slow temporal summation, electrophysiological and behavioral indices of hyperalgesia can be blocked by NMDA-receptor antagonists, and windup itself can be enhanced by tissue injury–evoked hyperalgesia.2,3 To a certain extent, windup has come to serve as a predictive model for pharmacological and other manipulations that may be used to modulate central mechanisms of hyperalgesia.1–4

NMDA-Receptor Mechanisms of Hyperalgesia and Narcotic Tolerance/Dependence Within the last few years, several studies have directly or indirectly indicated that narcotic tolerance and narcotic-induced hyperalgesia

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involve some of the same NMDA mechanisms that occur during inflammatory and neuropathic pains.6,8 Of relevant interest is the critically important role that NMDA-receptor activation plays in tolerance to the analgesic effects of narcotics, dependence on narcotics, and narcotic-induced thermal hyperalgesia (see Mao et al.6 for review). The prevention of analgesic tolerance and hyperalgesia by NMDA antagonists suggests a role for excitatory amino acids in these phenomena. The site of the NMDA-receptor action is likely within the spinal cord dorsal horn.1,6 Taken together, data on neurogenic and inflammatory thermal hyperalgesia as well as on morphine tolerance/ dependence suggest that central activation of NMDA-receptors is strategically involved in both thermal hyperalgesia with a variety of pathological etiologies and the development of narcotic tolerance and dependence. Once it has developed, thermal hyperalgesia associated with narcotic tolerance can also be potently reversed by intrathecal treatment with MK-801 (another NMDA-receptor antagonist), indicating that NMDA-receptors are critical for the expression of thermal hyperalgesia in morphine-tolerant rats as well.8 Thermal hyperalgesia develops in association with the development of morphine tolerance and dependence, and NMDA-receptor antagonists potently prevent the appearance of both morphine tolerance and thermal hyperalgesia. Therefore, it is very likely that the origination of morphine tolerance/dependence and the associated thermal hyperalgesia may involve a common NMDA and non-NMDA-receptor mechanism. Protein kinase C (PKC) also is involved in the development of morphine tolerance and dependence in rats. Spinal cord levels of membrane-bound PKC (the translocated form of PKC) increase significantly, specifically within the superficial laminae of the dorsal horn (laminae I–II), following the development of morphine tolerance and dependence. Furthermore, GM1 ganglioside potently attenuates both the increase in membrane-bound PKC and the development of tolerance to the analgesic effect of morphine.9 In addition, GM1 ganglioside effectively prevents the development of thermal hyperalgesia associated with the development of morphine tolerance and dependence.9 Similarly, behavioral studies have indicated that nitric oxide (NO) is in-

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volved in thermal hyperalgesia induced by peripheral nerve injury or intrathecal NMDA administration and in the development of morphine tolerance and dependence (see Mao et al.6 for review). The combination of these observations indicates that intracellular PKC and NO may mediate neurogenic and inflammatory thermal hyperalgesia along with the development of narcotic tolerance and dependence, both of which are known to be associated with NMDA-receptor activation. Thus, these converging lines of evidence strongly suggest that NMDA-receptor-mediated intracellular PKC and NO changes may well be associated with thermal hyperalgesia that occurs following the development of narcotic tolerance and dependence as well as with hyperalgesia that follows nerve injury. Several lines of research from different laboratories have demonstrated that postsynaptic opioid m-receptor occupation by an exogenous ligand such as morphine may initiate the activation of PKC.6 Activation of PKC by opioids then increases the sensitivity of the NMDAreceptor by the same mechanisms that occur during persistent pain states. At the same time, activated PKC may uncouple the G-protein associated with the opioid m-receptor or modulate the m-activated potassium channel. In either case, the net result is reduced responsiveness of the m-receptor to an exogenous opioid and, hence, tolerance. The two major components of this mechanism are a positive feedback loop wherein the NMDA receptor becomes progressively sensitized as a result of repeated opioid administration and a negative feedback loop wherein activation of PKC reduces the sensitivity of the m receptor. The model makes the following predictions: (1) hyperalgesia should be associated with opioid tolerance, and this hyperalgesia should be blocked by an NMDA antagonist; (2) opioid tolerance should be blocked by an NMDA antagonist to some extent; (3) a preexisting hyperalgesic state, such as that brought about by chronic constrictive nerve injury, should be associated with increased resistance to the analgesic effects of morphine (i.e., tolerance). Results from our laboratory and others support these predictions and offer several clinical implications.6 There is experimental support for the longheld impressions that patients with neuro-

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Fig. 1. Oral administration of MS 32 mg/kg with DM 8 to 64 mg/kg twice daily for 8 days. Animals receiving MS alone showed development of tolerance (rapid decline in maximal analgesic effect after day 3), while animals receiving MS:DM in ratios of 2:1, 1:1, and 1:2 remained responsive. In particular, MS:DM 1:1 appeared to be the optimal ratio for prevention of tolerance. Reproduced from Mao et al. (10) with permission.

pathic pain are resistant to opioid analgesics and that hyperalgesia and tolerance develop in some patients who have taken narcotic analgesics for extended periods of time. These problems may be prevented by the co-administration of nontoxic NMDA-receptor antagonists with opioids. Combining NMDA-receptor antagonists with opioid and even nonopioid analgesics may be a way of increasing their analgesic potency in addition to preventing tolerance and dependence. Preclinical animal studies demonstrate the practicality of the combined administration of nontoxic NMDA-receptor antagonists with various types of analgesic drugs.

Use of DM to Enhance Morphine Sulfate (MS) Analgesia and Prevent MS Tolerance In a study specifically designed to evaluate the practical feasibility of the combined oral administration of morphine sulfate (MS) with the NMDA-receptor antagonist DM, several key points were demonstrated. DM prevented the development of tolerance to the antinociceptive effects of MS (15, 24, or 32 mg/kg),10 as shown in Figure 1, and attenuated signs of naloxone-precipitated physical dependence on morphine in rats. A broad range of ratios of MS to DM (2:1, 1:1, and 1:2) was effective. An important feature of this DM-mediated preven-

tion of the development of morphine tolerance is that selective ratios of MS:DM rather than absolute DM seemed effective. The results indicate a wide therapeutic window for potential clinical utility of this MS:DM combination treatment regimen. Finally, DM increased the antinociceptive effects of MS even with a single administration of an MS:DM (1:1) combination (Figure 2). This result has particular relevance to the clinical possibility of combining MS with DM to enhance peak analgesic potency as well as to extend the duration of MS analgesia without enhancing side effects of MS. Thus, it is important that Grass et al.11 replicated and extended the earlier results of Mao et al.10 by demonstrating that intraperitoneal injections of DM (30 mg/kg) greatly enhanced peak analgesia and duration of analgesia produced by subcutaneous injections of 5 mg/kg MS. The combination of results from Mao et al.10 and Grass et al.11 indicates that oral treatment that combines DM with opiate analgesics may be a powerful approach for simultaneously preventing opiate tolerance and dependence while enhancing both peak and duration of opioid analgesia in humans. A critical feature of the study by Mao et al.10 was the demonstration that DM increased the antinociceptive effects of low doses of MS. This result is similar to that obtained using a 48hour delivery of MS and DM through a subcutaneous osmotic pump.12 Although the highest DM dose (64 mg/kg) alone used in the experi-

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research and management. Vol 1. Seattle: IASP Press, 1994:61–84. 2. Dickenson AH, Sullivan AF. Differential effects of excitatory amino acid antagonists on dorsal horn nociceptive neurons in the rat. Brain Res 1990;506: 31–39. 3. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-d-aspartic acid receptor activation; implications for the treatment of postinjury pain hypersensitivity states. Pain 1991;44:293–299. Fig. 2. Potentation of MS analgesia by DM following a single dose of the combination. Maximal analgesia with the combination was significantly greater than MS alone during the first 90 minutes after administration (P , 0.05). Reproduced from Mao et al. (10) with permission.

ments produced some antinociception, no changes in baseline tail-flick latencies were observed in rats receiving lower doses (30 or 15 mg/kg) of DM alone. These results indicate that greater antinociception resulting from a MS:DM combination is not simply an additive effect of MS and DM. Clinically, this would mean that DM might not only be able to prevent morphine tolerance when co-administered with MS but also could enhance morphine analgesia, thereby possibly reducing the dose of opiate analgesics required for pain relief. DM potently facilitates morphine analgesia, at least in part by preventing tolerance. The mechanisms by which morphine analgesia is enhanced and tolerance is prevented are likely to be the same. There is also evidence that DM can reverse morphine tolerance once it is established.13 Finally, oral DM also facilitates analgesia produced by other opioid analgesics (Mao, Price, Caruso, and Mayer, unpublished observations), suggesting the possibility of other combination analgesic products.

4. Dubner R. Neuronal plasticity and pain following peripheral tissue inflammation or nerve injury. In: Bond M, Charlton E, Woolf, CJ, eds. Proceedings of V World Congress on Pain. Pain Research and Clinical Management. Vol 5. Amsterdam: Elsevier, 1991:263–276. 5. Ren K, Hylden JL, Williams GM, Ruda MA, Dubner R. The effects of a noncompetitive NMDA-receptor antagonist, MK-801, on behavioral hyperalgesia and dorsal horn neuronal activity in rats with unilateral inflammation. Pain 1992;50:331–344. 6. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995;62:259–274. 7. Price DD, Mao J, Frenk H, Mayer DJ. The N-methyld-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man. Pain 1994;59:165–174. 8. Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994;14: 2301–2312. 9. Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 1995;61: 365–374. 10. Mao J, Price DD, Caruso F, Mayer DJ. Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats. Pain 1996;67:361–368. 11. Grass S, Hoffman O, Xu X-J, Wiesenfeld-Hallin Z. N-methyl-d-aspartate receptor antagonists potentiate morphine’s anti-nociceptive effect in the rat. Acta Physiol Scand 1996;158:269–273.

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12. Manning B, Mao J, Frenk H, Price DD, Mayer DJ. Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance. Pain 1996;67:79–88.

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