75 25 Analgesics, pain and tolerance: The St John’s discussionColor profile: EMBASSY.CCM - Scitex...
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Analgesics, pain and tolerance: The St John’s discussion Tony L Yaksh PhD F our of the articles in the present issue of Pain Research & Management discuss preclinical issues relevant to under- standing the changes that occur to the analgesic efficacy of opiates over an extended interval of delivery (pages 25 to 57). The articles reflect the extended and interesting discus- sions that transpired at the Canadian Pain Society meeting held in St John’s, Newfoundland, May 14 to 16, 1999. The role of changes in opiate responsiveness in long term opiate exposure in clinical pain states is controversial. While few argue that opiate dosing does not rise over time, it is evi- dent that, with chronic exposure, many patients show a very stable dosing requirement. When the dosing necessary to sustain pain relief rises, the rise may occur by several mecha- nisms, including the appearance of more intense pain and the evolution of opiate-insensitive pain states. Yaksh reviews some of these issues in his contribution (pages 33-39). Nev- ertheless, clinical and preclinical studies aimed at defining specific dose requirements have emphasized that, of the sev- eral mechanisms, pharmacodynamic plasticity can contrib- ute to the ongoing changes in dose requirements. Several of the articles in this issue focus on this component of the pro- cess, with an emphasis on the potential importance of changes in receptor coupling and function. An emerging con- cept is the role of glutamate, and the several ionotropic and metabotropic receptors on which it works. Importantly, such observations are in agreement with the review by Jhamandas and colleagues (pages 25-32) of the potential contributions of a variety of spinal transmitters and second messengers in the development of a reduced response to the chronically de- livered opiate. Fundytus (pages 40-48) considers the poten- tial contribution of several neurotransmitter systems and emphasizes the potential role of metabotropic receptors. She draws parallels between the mechanisms of neuropathic pain states and opioid tolerance. Yaksh discusses the role of spinal glutamate receptors in spinal tolerance to opioid and al- pha 2 -adrenergic agonists, and the contribution of phosphory- lation to spinal tolerance. Cahill and Coderre (pages 49-57) discuss the interactions of nerve growth factor and the ex- pression of cholecystokinin in the opiate insensitivity noted in some neuropathic states. The reviews, thus, strongly fo- cus on the local neuronal network and the cell type on which the opiate receptor is found. Rather than repetitiously detail- ing the conclusions of each article, I will consider some of the implications of the opinions of the author(s) of each paper re- garding the mechanisms responsible for a rise in opiate dos- ing. I hope that my interpretations will be viewed forgivingly by each contributor in the possible event that I erred in my reading of their interpretation. SOME RAMIFICATIONS OF THE MECHANISMS PROPOSED FOR OPIATE TOLERANCE The mechanism by which opiate tolerance occurs has not been clearly identified. Nevertheless, several consequences of the mechanisms that have been proposed may be considered to offer an opportunity to be ‘hoisted by our own petard’. As with any hypothesis, the more counterintuitive the predic- tions are, the better. ‘As required’ medication and glutamate release Because tolerance seems to be, in part, a function of dose and time of agonist receptor exposure, it seems intuitive that re- moval of the opiate should at least slow the process by which the tolerance mechanisms are driven. On the other hand, one observation that appears clear is that opiate withdrawal leads to the release of glutamate. As reviewed by Fundytus, Jha- Pain Res Manage Vol 5 No 1 Spring 2000 19 EDITORIAL Department of Anesthesiology, University of California, San Diego, California, USA Correspondence and reprints: Dr Tony L Yaksh, University of California, San Diego, Department of Anesthesiology, Anesthesiology Research Laboratory, 9500 Gilman Drive, La Jolla, California 92093-0818 USA. Telephone 619-543-3597, fax 619-543-6070, e-mail [email protected]
Transcript of 75 25 Analgesics, pain and tolerance: The St John’s discussionColor profile: EMBASSY.CCM - Scitex...
Analgesics, pain and tolerance:The St John’s discussion
Tony L Yaksh PhD
Four of the articles in the present issue of Pain Research &Management discuss preclinical issues relevant to under-
standing the changes that occur to the analgesic efficacy ofopiates over an extended interval of delivery (pages 25 to57). The articles reflect the extended and interesting discus-sions that transpired at the Canadian Pain Society meetingheld in St John’s, Newfoundland, May 14 to 16, 1999.
The role of changes in opiate responsiveness in long termopiate exposure in clinical pain states is controversial. Whilefew argue that opiate dosing does not rise over time, it is evi-dent that, with chronic exposure, many patients show a verystable dosing requirement. When the dosing necessary tosustain pain relief rises, the rise may occur by several mecha-nisms, including the appearance of more intense pain and theevolution of opiate-insensitive pain states. Yaksh reviewssome of these issues in his contribution (pages 33-39). Nev-ertheless, clinical and preclinical studies aimed at definingspecific dose requirements have emphasized that, of the sev-eral mechanisms, pharmacodynamic plasticity can contrib-ute to the ongoing changes in dose requirements. Several ofthe articles in this issue focus on this component of the pro-cess, with an emphasis on the potential importance ofchanges in receptor coupling and function. An emerging con-cept is the role of glutamate, and the several ionotropic andmetabotropic receptors on which it works. Importantly, suchobservations are in agreement with the review by Jhamandasand colleagues (pages 25-32) of the potential contributionsof a variety of spinal transmitters and second messengers inthe development of a reduced response to the chronically de-livered opiate. Fundytus (pages 40-48) considers the poten-tial contribution of several neurotransmitter systems andemphasizes the potential role of metabotropic receptors. Shedraws parallels between the mechanisms of neuropathic pain
states and opioid tolerance. Yaksh discusses the role of spinalglutamate receptors in spinal tolerance to opioid and al-pha2-adrenergic agonists, and the contribution of phosphory-lation to spinal tolerance. Cahill and Coderre (pages 49-57)discuss the interactions of nerve growth factor and the ex-pression of cholecystokinin in the opiate insensitivity notedin some neuropathic states. The reviews, thus, strongly fo-cus on the local neuronal network and the cell type on whichthe opiate receptor is found. Rather than repetitiously detail-ing the conclusions of each article, I will consider some of theimplications of the opinions of the author(s) of each paper re-garding the mechanisms responsible for a rise in opiate dos-ing. I hope that my interpretations will be viewed forgivinglyby each contributor in the possible event that I erred in myreading of their interpretation.
SOME RAMIFICATIONS OF THE MECHANISMSPROPOSED FOR OPIATE TOLERANCE
The mechanism by which opiate tolerance occurs has notbeen clearly identified. Nevertheless, several consequencesof the mechanisms that have been proposed may be consideredto offer an opportunity to be ‘hoisted by our own petard’. Aswith any hypothesis, the more counterintuitive the predic-tions are, the better.
‘As required’ medication and glutamate releaseBecause tolerance seems to be, in part, a function of dose andtime of agonist receptor exposure, it seems intuitive that re-moval of the opiate should at least slow the process by whichthe tolerance mechanisms are driven. On the other hand, oneobservation that appears clear is that opiate withdrawal leadsto the release of glutamate. As reviewed by Fundytus, Jha-
Pain Res Manage Vol 5 No 1 Spring 2000 19
EDITORIAL
Department of Anesthesiology, University of California, San Diego, California, USA
Correspondence and reprints: Dr Tony L Yaksh, University of California, San Diego, Department of Anesthesiology, Anesthesiology Research Laboratory,
9500 Gilman Drive, La Jolla, California 92093-0818 USA. Telephone 619-543-3597, fax 619-543-6070, e-mail [email protected]
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mandas and Yaksh, activation of glutamate receptors (meta-botropic or ionotropic) appears to lead to processes thatexacerbate tolerance. In that regard, the data reviewed byJhamandas and Yaksh are clear in that, during withdrawal indifferent systems, glutamate release is enhanced. It is reason-able then to hypothesize that loss of effect should be less pro-found with continuous exposure than after bolus opiateexposure. This leads to the speculation that ‘as required’medication is less desirable than establishing a continuedlevel of opiate dosing. To the degree that there is a ‘half-life’of tolerance, it may be speculated that if the pain state re-quires dosing at intervals less than the half-life of tolerance,continuous dosing is preferable to ‘as required’ dosing. Inother words, continued receptor occupation is preferable toperiodic activation and deactivation of the receptor popula-tion (see below). This leads to the paradoxical notion that it isnot the duration and exposure dose that define the magnitudeof loss of effect, but the acute periodicity of exposure, eg, inthis case, less exposure leads paradoxically to more toler-ance.
Chronic pain and clinical versus preclinical opiatetoleranceAs indicated by all of the authors, there is little doubt that, inanimal models, there is a rapid decrement in drug effect dur-ing a defined drug exposure, ie, tolerance, whether the drug isdelivered as a bolus or continuously, or systemically or neu-raxially. In contrast, as reviewed by Yaksh, tolerance in painpatients is less clear and is typically less acute. This differ-ence poses some theoretical embarrassment for those whopromulgate mechanisms based on the preclinical models.Why do humans not show the same rapid and continued in-crementation as seen in animal models? One argument is thatthe preclinical models often involve systems in which con-tinued pain is not present. In contrast, the clinical conditionreflects an ongoing pain condition. This argument, while ap-pealing, may create some dismay among the several authorswho suggest that glutamate release induces activation of re-ceptors, the activation of which leads to the cascade that in-volves events believed to be relevant to the downregulationof the opiate effect (phosphorylation, cholecystokinin, nitricoxide, etc). One interpretation of this cascade that is believedto be important is that chronic pain, far from reversing toler-ance, should make it worse (by enhancing glutamate traffic).Moreover, breakthrough pain may actually drive the toler-ance cascade. It is interesting to note that, in the clinical con-dition, the pain manager often observes the rapidincrementation of opiate requirements in the later stages ofcancer. As Yaksh reviews, there are a number of reasons whythis may be, but the models proposed by the authors are con-sistent with the concept that intensification of the pain statemay lead to a fulminating crisis in which an additional com-ponent of drug escalation is indeed the escalation of pharma-codynamic tolerance. Thus, whatever the difference, it isdifficult to imagine that pain itself prevents tolerance basedon the current thinking. Other relevant issues are discussedfurther below.
Parallels between injuries leading to hyperalgesia and toopiate toleranceAll of the contributors to this issue are quite taken with thesimilarities between mechanisms that lead to tolerance andthose that are related to the loss of opiate reactivity. Duringopiate withdrawal, animals display glutamate release and hy-peralgesia that is diminished by N-methyl-D-aspartate an-tagonism. Fundytus emphasizes that the lack of opiatesensitivity in neuropathic pain may be related to the roleplayed by group I metabotropic glutamate receptors. Shenotes that blockade of these receptors returns the sensitivityof animals to opiates and prevents tolerance. Cahill and Cod-erre note that nerve injury leads to an increase in nervegrowth factor levels that may serve to downregulate the spi-nal expression of cholecystokinin, which itself serves todownregulate opiate sensitivity. The question of interest iswhether the relationships are corollary or causal. As consid-ered above, chronic pain states should enhance glutamate re-lease and initiate the cascade leading to tolerance. Is this whatleads a neuropathic state to be opiate resistant? One canimagine that chronic pain states may lead to a ‘tolerance cas-cade’ and, by an independent mechanism, produce a painstate that is not regulated by opiates. Thus, as reviewed, nerveinjury models, such as the Chung tactile allodynia model, arerelatively resistant to the spinal effects of opiates. This maybe due to the fact that the phenomenon is mediated by largeafferent input that is not regulated by spinal opiate receptors.
If the chronic pain state is responsible for opiate tolerance,it may produce tolerance to the opiate in models that are sen-sitive to spinal opiates, eg, thermal escape. There are few datato suggest that the thermal escape in Chung animals is notblocked by opiates. Indeed, the thermal hyperalgesia in theBennett chronic compression model is clearly opiate in na-ture. An additional implication of this thinking relates toother agents that have a spinal action through G-coupled pro-teins. On example is the alpha2 receptor. As reviewed byYaksh, this system produces a potent antinociception afterspinal delivery and shows tolerance with continued delivery.This tolerance is attenuated by intrathecal N-methyl-D-aspartate antagonism. Yet, unlike opiates, intrathecal alpha2
agonists are active in models of nerve injury-evoked allo-dynia. This suggests that there is at least one dissociation be-tween the neuropathic state and spinal G protein-mediatedreceptor tolerance.
TOLERANCE AND DRUGCHARACTERISTICS
Previous studies have shown that continuous intrathecal infu-sion of DAMGO (a mu opioid peptide), sufentanil or mor-phine in doses that initially produce equianalgesic effectsleads to a parallel loss of effect over a five- to seven-day in-terval. Thus, all drugs show an ongoing loss of effect withcontinued exposure. Nevertheless, measuring the right shiftof the dose-effect curve for the respective toleragen given asa bolus after completion of the infusion reveals that the mag-nitude of tolerance, as measured by the right shift of the probedose-response curve, was least for DAMGO and sufentanil,
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and greatest for morphine (1). Moreover, when the degree ofcross-tolerance was defined, the rank ordering of the magni-tude of the dose-response curve shift was as follows: mor-phine/morphine greater than morphine/sufentanil greaterthan sufentanil/morphine greater than sufentanil/sufentanil(where the first drug is the toleragen and second is the probedrug). This suggests an asymmetry in the cross-tolerance.While it has been only minimally investigated in human con-ditions, instances of asymmetric cross-tolerance have beenreported in opiate-tolerant patients (2). These observationsthus raise the intriguing possibility that tolerance producedby different opiates may be distinguishable. Because theagents are given by continuous infusion, the issue of local ki-netics is probably not relevant. Several possibilities may berelevant; two are considered – receptor internalization andagonist efficacy.
Receptor internalizationOpiate receptors undergo internalization. Coupling studieshave indicated that this phenomenon is mediated by activa-tion of beta-arrestin and by phosphorylation of the cytosolictail of the opiate receptor (3,4). Interestingly, such internali-zation is not uniformly produced by all opiates. Thus, in a va-riety of cell systems transfected with mu receptors,internalization was produced by DAMGO but not by mor-phine (5-8). Studies with receptor chimeras suggest that thisdifference depends on the characteristics of the cytosolic tailof the mu opioid receptor. Increasing the ability of the cyto-solic tail of the chimeric mu receptor to be phosphorylatedsubsequently allowed morphine to induce internalization (7).This dichotomy regarding internalization with two agentsthat display a similar tolerance indicates either that internali-zation plays no role or that there are at least two distinct cel-lular mechanisms. Thus, agents that do not internalize thereceptor (eg, morphine) may result in downstream changesthat inactivate the receptor. On the other hand, the ability ofan agonist to drive internalization of the receptor (eg,DAMGO) may prevent a continuous activation and avoiddownstream changes. Both events may lead independently toa loss of agonist effect. Internalization may be seen as a local‘protective’ mechanism preventing the downstream effectsthat may have profound consequence for cellular function(7).
Agonist efficacyPrevious studies using irreversible spinal mu antagonismhave shown that, for a given degree of spinal mu opioid re-ceptor inactivation, the degree of right shift in the intrathecaldose-response curve is as follows: DAMGO equivalent tosufentanil greater than morphine (9). Such an observation isconsistent with the interpretation that morphine shows lessintrinsic efficacy than either DAMGO or sufentanil, ie, mor-phine requires a higher fraction of the receptor to be occupiedto produce a given effect than the fraction required by eitherDAMGO or sufentanil. Under these conditions, any degreeof receptor inactivation (by either internalization or by somedownstream change in receptor coupling) leads to a greater
right shift in the probe dose-response curve for morphinethan for either sufentanil or DAMGO. Importantly, this ob-servation is consistent with the asymmetric cross-tolerancethat was previously noted between morphine and sufentanil.
Jointly, one may speculate that certain agents such asDAMGO and sufentanil may lead to a transient internaliza-tion of the receptors over time and that this accounts for theirongoing loss of effect. In contrast, morphine, by not resultingin an internalization, may induce downstream changes thatlead to more pronounced changes in receptor function for agiven degree of functional activation. In addition, if mor-phine possesses a receptor occupancy requirement, the de-gree of right shift produced by any mechanism of receptor/coupling downregulation would lead to a greater right shiftthan that observed for sufentanil. An additional intriguingpossibility is that a variety of conditions may alter the rela-tionship between receptor occupancy and internalization thatreflect on the events discussed in the articles in this issue.Thus, consider that the in vitro cell studies cited above sug-gest that morphine may not internalize the receptor, exceptwhere there is an increased opportunity for phosphorylationof the cytosolic tail. Suppose that over time a phosphory-lating function is induced. Will this lead to a condition inwhich morphine develops the ability to induce internaliza-tion? Recent work has shown that chronic opiate exposure in-creases the expression of protein kinase C protein (10). Isthere a triggering level of activation at which morphine be-comes more comparable to the functionality of DAMGO andbegins to induce internalization? As the contributors to thisissue have suggested, chronic afferent traffic leads to en-hanced phosphorylation. Can one imagine a seemingly para-doxical series of events in which pain leads to enhancedphosphorylation of the mu receptor that turns morphine (andother agonists such as buprenorphine) into an agent that inter-nalizes the receptor rather than producing a hypothesizeddownstream regulation? Is it possible that a certain level ofafferent input activating ionotropic or metabotropic recep-tors, or the transport of trophic factors, leads to a change incellular phosphorylating function that results in stabilization(through the mechanism of internalization) in the rate or de-gree to which the receptor will internalize for any given de-gree of receptor downregulation? Whatever the case, theabove reasoning suggests that the characteristics of the toler-ance observed after administration of each of the two classesof mu agonists may have distinct properties. Which one isbetter remains to be seen.
CONCLUSIONSThe phenomenon of tolerance is complex and dynamic. Thecomments made by the authors of these articles reflect the ex-citing discussions held in St John’s.
REFERENCES1. Sosnowski M, Yaksh TL. Differential cross-tolerance between
intrathecal morphine and sufentanil in the rat. Anesthesiology1990;73:1141-7.
2. de Leon-Casasola OA, Parker BM, Lema MJ, Groth RI,Orsini-Fuentes J. Epidural analgesia versus intravenous patient-
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controlled analgesia. Differences in the postoperative course of cancerpatients. Reg Anesth 1994;19:307-15.
3. Ferguson SS, Barak LS, Zhang J, Caron MG. G-protein-coupledreceptor regulation: role of G-protein-coupled receptor kinases andarrestins. Can J Physiol Pharmacol 1996;74:1095-110.
4. Krupnick JG, Benovic JL. The role of receptor kinases and arrestins inG protein-coupled receptor regulation. Annu Rev Pharmacol Toxicol1998;38:289-319.
5. Keith DE, Murray SR, Zaki PA, et al. Morphine activates opioidreceptors without causing their rapid internalization. J Biol Chem1996;271:19021-4.
6. Sternini C, Spann M, Anton B, et al. Agonist-selective endocytosis ofmu opioid receptor by neurons in vivo. Proc Natl Acad Sci USA1996;93:9241-6.
7. Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M. Functionaldissociation of mu opioid receptor signaling and endocytosis:implications for the biology of opiate tolerance and addiction. Neuron1999;23:737-46.
8. Whistler JL, von Zastrow M. Morphine-activated opioid receptorselude desensitization by beta-arrestin. Proc Natl Acad Sci USA1998;95:9914-9.
9. Mjanger E, Yaksh TL. Characteristics of dose-dependent antagonismby beta-funaltrexamine of the antinociceptive effects of intrathecal muagonists. J Pharmacol Exp Ther 1991;258:544-50.
10. Granados-Soto U, Kalcheuo I, Hua K-Y, Newton A, Yaksh TL.Spinal PKC activity and expression: Role in toleranceproduced by continuous spinal morphine infusion.Pain (In press)
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