THE CONTRIBUTION OF FUNCTIONAL IMAGING TECHNIQUES TO OUR UNDERSTANDING OF RHEUMATIC PAIN

PAIN MANAGEMENT IN THE RHEUMATlC DISEASES

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THE CONTRIBUTION OF FUNCTIONAL IMAGING TECHNIQUES TO OUR UNDERSTANDING OF RHEUMATIC PAIN Anthony K.P. Jones, MB, BS, FRCP

In this article, some of the recent advances in functional brain imaging that allow us to view molecular events within the brain are reviewed. The focus is on positron emission tomography (PET), but some of the important results using other techniques such as single photon emission tomography (SPET), functional magnetic resonance imaging (fMRI), surface electrophysiology (EEG and pain-evoked potentials) and magnetoencephalography (MEG) are mentioned where appropriate. The aim is to describe how these techniques have contributed to a much more detailed understanding of how the brain processes information about actual or potential noxious stimuli. Some of these observations have provided new insights into how different aspects of pain and behavioral responses to pain might be regulated and how new approaches to pain therapy might be developed. Each of these techniques has a contribution to make to the understanding of different aspects of the elaboration of the experience of pain. It is not within the scope of this article to review all these techniques, but a brief outline of what they measure is included.

From the Human Physiology and Pain Research Laboratory, The University of Manchester Rheumatic Diseases Centre, Hope Hospital, Salford, United Kingdom

RHEUMATIC DISEASE CLINICS OF NORTH AMERICA

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VOLUME 25 NUMBER 1 * FEBRUARY 1999

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Problems with The Integration of Anatomy, Physiology and Psychology

During episodes of inflammatory arthritic pain, the brain has the task of integrating new information from receptors of muscle, tendon, and skin afferents with nociceptive information from the joint capsule and possibly periarticular bone. This integration or parallel processing incorporates motivational, affective, discriminative, attentional and motor responses that may result in changes of behavior and modification of CNS pain processing. It is as yet unclear what the nature of this CNS modification may be, and suggested influences on pain-related affectivemotor responses or the inflammatory process itself remain largely speculative. Nevertheless, the result of any behavioral changes will be viewed by both the physician and patient as one of the important outcomes in terms of lifestyle changes and adaptations. Whatever the more objective measures in terms of eventual joint damage may be, it is the behavioral changes that will determine a patient’s quality of life for a given level of disease activity and determine the pathway from the development of disease or symptoms to possible disability or handicap (Fig. 1). Level of function

Process

No impairment

Neural modulation of pathology Joint damage

Rheumatoid Arthritis

responses Nociception

“Stiff, painfid knee”

I

t l “Can’t walk”

‘Can’t do shopping”

I

T l

I \ Disability

Motivation Affect Coping strategies Adaptive motor behavior

I Social and financial support

Figure 1. Components of processes leading to handicap and the different components of disease-related behavior that may contribute to it (From Jones AKP, Derbyshire SWG. Reduced cortical responses to noxious heat in patients with rheumatoid arthritis Ann Rheum Dis 56 601-607, 1997, with permission )

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Understanding the brain’s responses to nociception offers an opportunity to advance behavioral and pharmacological pain therapy and interfere with this process. It is likely to be some time before we begin to have a proper understanding of the complex integrated processes which operate during arthritic pain and other chronic pains; however, we are now able to measure aspects of such changes in terms of measurement of behavioral and cerebral responses to pain. These measurements are providing early clues to the possible underlying CNS mechanisms and their relation to changes in affective-motivational behavior. In this article, the normal brain mechanisms of the conscious appreciation of pain are reviewed together with working hypotheses for how these mechanisms are altered during inflammatory and other types of clinical pain syndromes. The identification of areas of the brain involved in human nociceptive processing requires the following factors to be taken into account. Pain is an experience involving sensory, cognitive-evaluative, and affective-motivational componentss4 and is not a primary sensation. In addition, the pain response involves an evaluative response that may include learning associated with the prediction and avoidance of future noxious stimuli and preparation for appropriate motor responses. Attention and anticipation are also likely to be of crucial importance in determining higher responses. Experimental neuroscience has been slow to incorporate the theoretical understanding of pain processing. As a consequence, ideas are maintained because of their simplicity rather than their ability to explain observable phenomena. For example, it is still widely suggested that pain is a specific sensory modality in its own right, with its own specific peripheral receptors and central pathways.1h Whatever areas of the brain are involved in pain processing, the integration of the different components of pain experience and actual or potential response to that experience needs to be accommodated. This implies that there is unlikely to be any final common area of the brain which processes pain. The search for a single dominant ”pain center” has probably been a substantial diversion in the understanding of the functional anatomy of pain. Parallel processing of the conscious appreciation of primary sensations such as vision and touch” are now well documented and it would be surprising if such parallel processing did not also exist for nonprimary sensations such as pain. There is now growing evidence that pain is processed by a network or “matrix” of structures in the brain, as proposed by Melzack.82Some components of the “pain matrix” could be considered to comprise parallel but integrated processing. Much of the specific information regarding the ”pain matrix” in humans is a consequence of recent studies using functional imaging techniques such as PET and fMRI. These techniques enable the imaging of events in the grey matter of the brain, providing a snapshot of the function of the brain. Before going on to review the exciting possibilities for theoretical advancement that functional imaging presents, the pain inputs to the brain and their terminations will be considered.

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Subcortical Neuroanatomy of Nociception in Animals

Studying pain in animals presents an insoluble problem. Human beings can call out and express their pain in ways that are commonly understandable to other members of their species; unfortunately, there is no equivalent frame of reference when dealing with animals. Raised blood pressure, movements of withdrawal, dilation of the pupil, increased respiratory depth, attacking the source of noxious stimulation, and cries may be common to all mammals in the face of seemingly painful stimulation, but all such responses can be elicited after the cerebral cortex has been destroyed in the probable absence of any subjective experience. Furthermore, the subjective experiences of an animal may be totally different from humans. For these reasons, the human interpretation of what is observed in another species cannot be based on extrapolation from human experience. It is also a fair assumption, however, that some of the underlying biological processes involved in human pain experience are likely to be shared with other animals. A distinction is drawn therefore between "nociception" and pain, the term nociception being used to refer to the biological response of receptors in tissue to potentially damaging stimuli such as intense heat or cold, chemical irritation, or intense pressure. The terms "nociceptive" and "painful" should not be used interchangeably. The study of nociceptive pain avoids the fact that pain in humans can occur without any evidence of nociceptor activation, as in peripheral and central deafferentation pain, and may also occur without any evidence of spinothalamic tract activation, as in psychogenic pain. The spinothalamic tract has been demonstrated to be "both necessary and sufficient" for nociception in most species studied.xyIt provides the major direct nociceptive input from the spinal cord to the thalamus. As a consequence, the spinothalamic tract ascending in the anterolateral cord is widely considered as the pain pathway. This does not diminish the possible role of other ascending and descending pathways in either modifying the responses in the spinothalamic tract or in transmitting nociceptive information; however, we know most about the spinothalamic tract and discussion will be focused on this. The anatomy of nociception may be studied by observing the effects of discrete lesions on pain behavior, retrograde and anterograde uptake of markers of projections, and recording cerebral responses to nociceptive or electrical stimulation at distant sites of the nervous system. Combinations of these dpproaches underpin our knowledge of the anatomy of nociception. The Spinothalamic Tracts

In the early nineteenth century, Brown-Sequard performed experiments where the \rentrolateral quadrants of the spinal cord were sectioned in anim& and the results were compared to humans with sensory deficits owing to similar lesions.'" Sherrington and Laslett"'" obsewed "that the lateral column furnishes the headward path in the

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spinal cord for nociceptive (algesic) arcs" and "that this is true for these arcs, whether they are traced from skin, muscle, or viscera." Lesions of the ventral quadrant in monkeys result in a consistent elevation in response thresholds to nociceptive stimuli on the contralateral side, below the level of the lesion.x1,l I 7 This analgesic response usually recovers 1 to 6 months after lesioning.x' The most long-lasting analgesic effects were produced by the most extensive lesions, including dorsal and ventral quadrants, indicating that other pathways may also transmit nociceptive information or that the spinothalamic tract may have important dorsal components. More recently, quantitative studies have demonstrated an important contribution of the dorsolateral fasciculus to the spinothalamic tract.5 The terminations of the spinothalamic tracts in different thalamic nuclei have been studied using anterograde transport of HRP injected into the lumbar segments in monkeys.'j Extensive termination of both components of the spinothalamic tracts was demonstrated in the lateral and medial thalamic nuclei. The lateral terminations were predominantly to the suprageniculate nucleus, pulvinar oralis, the caudal and oral divisions of the ventral posterior lateral (VPL) nucleus, the ventral posterior inferior (VPI) nucleus, and the zona incerta. In the medial thalamus, the main terminations were in the medial dorsal, intralaminar nuclei of the central lateral, central median, and parafascicular nuclei. There was extensive overlap between the regions innervated by the ventral and dorsal quadrants of the spinothalamic tracts; however, there were more extensive projections of the ventral spinothalamic tract to the medial thalamic nuclei. Other studies have also shown substantial spinothalamic projections to the midline thalamic nuclei.I5 The cortical projections of the thalamic nuclear terminations of the dorsal and ventral spinothalamic tracts are not clearly defined in any species. Although the cortical connections of some of the more important nuclei have been described in different species, it cannot be assumed that all these connections are necessarily relevant to the spinothalamic terminations. The following descriptions of cortical projections therefore can be only a pointer to some of the possible functional connections in relation to the spinothalamic tracts. Both components of the spinothalamic tracts have a heavy projection to the caudal portion of the ventral posterior lateral (VPL) nucleus of the thalamus. This nucleus, in addition to the VPI and the centrolateral nuclei of the thalamus, has important projections to neurons in the primary somatosensory cortex (SI) that are probably nociceptive."" There are also nociceptive projections from thalamic nuclei (VPL, posterior nucleus, and the centrolateral nucleus) to secondary somatosensory cortex SII."" Although it has been shown that SI contains units that respond to noxious s t i m ~ l i ,Apkarian ~' et al" have argued that "nociception does not seem to be a sensory modality that is prominently represented in either the first or the second somatic sensory area of the parietal cortex. Since the terminals of the DSTT and the VSTT (ventral and lateral spinothalamic tracts) are scattered in small patches, since the cortical

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projections from the VPL, (caudal section of the ventral posterior lateral nucleus) are restricted to small areas,'08 since VPL, cells in a given somatotopic area project to multiple cortical zones and not all VPL, cells project to the cortex. . . ."77 The pulvinar oralis and the suprageniculate nucleus are termed the posterior region of the thalamus and this region receives overlapping terminations from both spinothalamic components. This area in turn projects to the insular cortex in primates,2I which, because of its connections with the amygdala, has been implicated in the autonomic responses to nociceptive stimuli. A subdivision of the ventral medial nucleus of the thalamus (VM,,) in the ventroposterior part of the lateral thalamus has recently been identified as being a relay nucleus for nociceptivespecific information from lamina I of the dorsal horn in primates.31This nucleus also projects to the anterior insula cortex and may be a source of nociceptive inputs to the insula parallel to those from the medial thalamic nuclei. The cortical projections of the medial thalamic nuclei are described subsequently. Spino-reticulothalamictracts

Studies in the macaque monkey72,73 have demonstrated that fibers in the anterior part of the anterolateral spinothalamic tract that originate

in the contralateral posterior horns end in the gigantocellular part of the medulla and pons and in the lateral reticular nucleus. Fibers or collaterals from these areas terminate in the medial geniculate body, the posterior group, and the intralaminar nuclei of the thalamus. The fibers of the spinoreticulothalamic tract may be divided into a caudal and ventral group of fibers. The caudal fibers terminate in the central median, parafascicular, centrolateral, and dorsomedial nuclei of the thalamus. The ventral group synapses in the subthalamus and the hypothalamus. There is also a connection with the Edinger-Westphal nucleus that may be the pathway mediating pupillary dilation in response to noxious stimuli. Fibers from the ventrolateral spinothalamic tract have a crossed and double-crossed projection to a reticular nucleus in the medulla called the subnucleus reticularis dorsalis. This nucleus appears to have nociceptive-specific inputs that are totally convergent on units with hemi- or whole-body receptive fields. Efferent projections are to the parafascicular and ventromedian nuclei of the thalamus.'?, Projections by way of the dorsal accessory olive to motor areas such as motor and premotor cortices and striatum suggest possible involvement in arousal and motor reactions. Cortical Projections: Medial and Lateral Pain Systems

The intralaminar group of nuclei are an important group of medial thalamic nuclei that were originally described as those nuclei that lay within the internal medullary lamina of the thalamus. They are now

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considered to comprise the central medial nucleus (CeM) located in the midline and the more lateral paracentral (Pc) and central lateral nuclei (CL) and a third, more posterior, group that includes the posterior intralaminar, centromedian (CM), and parafascicular nuclei. These structures have been considered for many years to be a cranial extension of the brain stem reticular formation, on anatomical These nuclei, in addition to the mediodorsal nucleus, have been found to have important connections with both the cingulate120and prefrontal in the monkey. Cells within these medial thalamic nuclei respond to nociceptive stimuli and often have large and often bilateral receptive fields with a nonsomatotopic organization.2 For these reasons, these structures are considered to subserve the so-called ”medial pain system” as distinct from the somatotopically arranged projections of the ventral posterior lateral nucleus, which are thought to subserve the ”lateral pain system.” Vogt et a1 extended considerably the concept of the medial pain system by demonstrating projections of the medial thalamic group of nuclei to area 24 of the anterior cingulate cortex.lo6,121 The anterior cingulate cortex is an extensive area of the limbic cortex overlying the corpus callosum and is involved in the integration of cognition, affect, and response selection.38 There is also evidence for medial thalamic nociceptive projections to the prefrontal cortex.l13 The descending connections of the anterior cingulate cortex to the medial thalamic nuclei and to the periaqueductal grey in the brain stem suggest that this system may also be involved in the modulation of reflex responses to noxious stimuli.121 The lateral pain system is subserved by monosynaptic projections from the dorsal horn and therefore is rapid, compared with the polysynaptic medial pain system. This makes it a more likely candidate for processing information about acute pain. Certainly first pain, which is that first well-defined pricking or stabbing sensation, would require such a relatively rapid system; however, acute pain incorporates both first pain and second pain. First pain is important for avoidance of potentially damaging stimuli; second pain, which is the more enduring, \low, and often burning and unpleasant component of pain, is likely to bc of greater relevance to the experience of most acute clinical pain. Groups of neurons have been identified in the contralateral primary c l n d secondary sensory cortex of unanaesthetized primates capable of 1-cspondingto noxious stimuli.2xThe receptive fields of the nociceptive wurons in SI are small and somatotopically arranged.7hThey also appear to encode stimulus intensity, and therefore are adequate for localization. somatic pain localization in humans, contrary to popular belief, is highly developed and independent of tactile input with a mean error of 14 mm, which is only 2 mm more than tactile ensa at ion.^' Pain is therefore, in this sense, a self-contained sensory modality and any nociceptive schema 11~15to account for this. STI also receives spinothalamic input. SII and the neighboring areas of 7b and the retroinsular cortex contain neurons with ldrge nociceptive receptive fields.I2’ Nociceptive intensity coding also

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occurs in SII but is generally poor.41 For these reasons it has been suggested that SII and neighboring areas of the parietal association cortex may be more involved in integration with other sensory modalities such as visual inputs and subconscious attention to new events, as is discussed in subsequent sections. The thalamic inputs to SI and SII have been considered traditionally to derive mainly from the VPL nucleus in addition to VPM and VPI, and their presence has reinforced the classic idea that the lateral pain system is the main system for processing acute pain, whereas the medial pain system is the main system processing chronic pain. An alternative hypothesis is that the lateral pain system is dealing primarily with the sensory-discriminative aspects of pain, whereas the medial pain system is concerned mainly with the motivational-affective components of pain response.x3 Neuroanatomy of Nociception in Humans

The human neuroanatomy of nociception is discussed in relation to such postmortem studies that have been done to establish the projections of the ascending anterolateral spinothalamic tract. The results of electrical stimulation of different parts of the brain and spinal cord is discussed below. Of the more recent studies using silver staining techniques to stain axon terminal degeneration, the most extensive postmortem study has been on the effects of anterolateral tractotomy, performed on four patients with intractable cancer pain." After careful exclusion of possible artifact, a number of sites of degeneration were identified. Within the thalamus, extensive degeneration was seen in the VPL nucleus on the side of the lesion, with a little staining in the contralateral VPL nucleus. Degeneration was also seen in the intralaminar nuclei and the reticular nucleus ipsilateral to the side of the lesion; however, the terminations in the thalamus were relatively sparse compared to those in the brain stem, where there was evidence of connections with a number of structures: terminal degeneration was found in the superior and inferior colliculi and ipsilaterally in the lateral reticular nucleus of the medulla, which relays to the cerebellum. Extensive degenerations were seen bilaterally in the medial reticular formation, the periaqueductal grey, and the central pontine nuclei. The greatest amount of degeneration was found in the medulla in the nucleus medulla oblongatae centralis and the caudal part of the nucleus gigantocellularis. All these brain stem connections appeared to be bilateral. The sparse direct termination of anterolateral spinothalamic tract fibers to the thalamus in this study prompted the speculation that pain may be predominantly processed and possibly experienced at a subcortical level. This hypothesis has had some support from early cerebral stimulation studies that reported the difficulties in eliciting pain when stimulating the lateral system in awake patients prior to undergoing neurosurgical procedures."' It has further support from careful studies of patients with cortical and subcortical lesions by Head and Holmes'"; however, this hypothesis has little support from

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more recent functional imaging and electrophysiological studies that have established a matrix of cortical and subcortical structures responsible for nociceptive processing in humans. PRINCIPLES OF PAIN IMAGING AND ELECTROPHYSIOLOGY PET is a technique for scanning chemical events in living tissues. Very small amounts of introduced, radioactively labelled molecules can be measured at nanomolar to picomolar concentrations in a defined volume of tissue over time (seconds-minutes). Its strength therefore is high chemical resolution with moderate temporal resolution. The characteristics of positron emission (dual photon emission) enable more accurate quantitation than techniques that use single photon emission such as SPET.27Different aspects of brain function can be measured, including events at specific receptor and neurotransmitter reuptake sites, regional cerebral blood flow (rCBF), blood volume, oxygen, and glucose m e t a b o l i ~ m .Measurements ~~ of altered neuronal activity using PET or SPET are made indirectly by measuring changes in rCBF (PET and SPET) or glucose metabolism (PET), which are closely correlated with changes in neuronal activity.% fMRI also measures changes in neuronal activity indirectly by measuring changes in blood deoxyhemoglobin concentration and blood volume in the brain. Potential advantages over PET are increased temporal resolution (seconds) and spatial resolution.3o Ongoing EEG is generated when "current flows into (current 'sink') or out of (a 'current source') a cell across charged neuronal memb r a n e ~ . ' The ' ~ ~ EEG at the scalp is mostly attributable to graded postsynaptic potentials of the cell body and large dendrites of vertically orientated pyramidal cells in cortical layers 3 through 5. It is therefore a more direct but selective measure of neural activity. Surface electrophysiological techniques mostly have used time-locked evoked responses (event related potentials [ERPs]) to noxious stimuli such as laser stimuli (laser evoked responses [LEPs])as a means of analyzing nociceptive processing in the brain. The advantages of being a direct measure of neuronal response and the high temporal resolution (msec) have to be offset cilgainst the much greater uncertainty about the location of the source of measured activity. MEG measures changes in magnetic field at right <1nglesto the change in electrical field with increased certainty about the source, but is less sensitive to deep cortical sources.'.' The Human Pain Matrix

The cerebral neural substrate mediating painful response to noxious stimuli in humans has been understood poorly until recently. Studies in humans to identify the principal areas of the brain involved in the response

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to pain have relied predominantly either on stimulating specific areas of the brain in order to relieve57or elicit pain7haor on observing the effects of brain lesions resulting from an infarct or surgery.'x,42, 53, l I 2 These different approaches have provided some very important insights into human pain physiology, but have not identified those areas of the brain germane to the integrated response to painful stimuli in normal individuals. Penfield observed that only 11 of 800 cortical stimulus locations in the primary motor-sensory cortex elicited pain when stimulated'.' and none of these sites produced severe pain, but mostly a sharp, burning pain. More recent studies in patients undergoing craniotomies for severe intractable pain have been described, in which pain was elicited by stimulating the primary and secondary sensory cortex. In some cases, this has reproduced the type of chronic pain experienced by the subject.Iw,11", Iz3 It is difficult to know whether these experiences in response to this type of stimulation result from local neuronal excitation or as a result of activation of corticothalamic pathways. Because these studies are difficult to reproduce, it is hard to assess how relevant these findings are to normal pain physiology or to the majority of patients suffering from different types of chronic pain. Whereas experiments in primates suggest that the cingulate cortex plays an important part in conditioning responses to painful stimuli,48it has been observed that removal of the frontal or cingulate cortex in patients with intractable pain may ameliorate its unpleasant emotional component without necessarily abolishing the pain itselP2 or the perception of acute nociceptive stimuli.'*, Io9 Foltz and White4*also observed that after frontal cingulumotomy, no patients who had been addicted to opiates prior to surgery required opiates after the operation. Of the 14 patients who had been addicted, 9 had no withdrawal symptoms and only 5 had mild withdrawal symptoms, suggesting that this operation may attenuate opiate withdrawal symptoms. The significance of these structures to the integrated normal human pain response has been unknown until recently because of absence of noninvasive techniques for observing such responses in specific brain regions. Electrophysiologic techniques recently have been reviewed extensively." Noninvasive neuroimaging techniques such as PET and fh4RI provide the exciting possibility of defining functional neuroanatomical substrates of different internally or externally generated physiological stimuli. The benefit of these techniques is that the integrated function of the whole brain can be studied at the same time. PET experiments have been designed to determine which areas of the brain respond specifically to acutely painful thermal stimuli, usually applied to the hand. These experiments depend on comparing brain activity in two or more different states. The significant differences between the two states are the basis of cognitive subtraction to identify areas of the brain that show increased rCBF in relation t o specific aspects of the pain experienced. A different approach to the analysis uses correlation analysis, in which a particular aspect of behavior such as visual analogue pain rating (VAS rating) is correlated across subjects with changes in rCBF. As an example

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of the cognitive subtraction approach, in the case of the author’s early experiments, a thermal stimulus was applied to the back of the right hand in comparison with nonpainful thermal stimuli applied to the same spot. The experiment was specifically designed to exclude the temporal and spatial localization components of this response. The hypothesis being tested was that pain is a predominantly emotional experience and therefore, substantial specific responses to pain are more likely to be seen in the cortical and subcortical structures relating to the medial pain system. The principle of the author’s first group of experiments was to exclude the sensory-discriminative components of an acute painful stimulus, such as localization and surface features, but to include intensity coding and affective-cognitive components. A series of painful or nonpainful phasic stimuli were given for 2 minutes while rCBF was measured. The subjects did not move during the delivery of the stimuli and therefore possibly suppressed the desire to withdraw the hand. The results of these early experiments showed significant increases in rCBF in response to these components of pain in the thalamus, lentiform nucleus, insula, and anterior cingulate cortex contralateral to the side of stimulation, with subsignificant increases in the prefrontal cortexhs ipsilateral to the site of stimulation. There were no increases in either somatosensory cortex. A contemporary study from the Montreal group”’ with a similar design, but in which the heat source was moved, provided very similar results except that primary somatosensory cortex was also activated, which may have been because, it was argued, the design of the experiment was to include the localization components of the nociceptive stimuli.

Since those early experiments, more sensitive PET techniques and improved analytic methods have been developed. The results in a number of groups of pain-free volunteers have shown that there is a unique network of structures activated by the sensory-discriminatory, affectivemotivational, and cognitive components of pain not coactivated during other cognitive, motor, or sensory tasks. This matrix consists of the periaqueductal grey, thalamus, lentiform [1ucleus, amygdala, hippocampus, insula, inferior parietal, primary and xwndary somatosensory, prefrontal (Brodmann areas 9 and lo), premolor, and anterior cingulate cortices (Brodmann area 24). These findings 1 ~ summarized ’ in Table 1 and diagrammatically represented in Figure 2. These results are collated from published results from a number of p ~ i nimaging groups in Ann Arbor,”, ?” Montreal,”’ Bethesda (NIH),”’,”’ ~tockholm,”’~ ”” Ly011s,(’’ London,”” Mc1nc]1ester,7’, C. hS. ‘1‘’ and Rome (sl’ECT)?‘’and have been extensively re\,iewed.’ I” Some of the Inciin components o f the pain matrix and their principal connections arc ~~Immcirized in Figure 2. The components o f the m a t r i u ‘ire> h,iscd 011 ~ l ~ l n i r functional in imaging studies, L3ut thc connections ‘ir~‘cbased < ) t i ‘1 \.ombination o f human and animal (mostly primate) studies. Current e\idence suggests that the same pain m a t r i x is ,icti\,atecl by ill.

Study

-

Methods

Rosen et al, 1994"" Di Piero et al, 1991'"

Hsieh et a1, 1995"

Adler et al, 1997' Craig et al, 1996 I ' Case\ t s t al, 1996 ' Hs1ch et '1, 1995 ' D c r h 4 i i r e ct al, 1998 l ' ~ L ~ ~ ~ i et o l '11, ' l 1998 ' Clinical Hsieh et al, 1996 \\killer et al, 1995""

8 patients, mononeuropathy pain 12 patients, angina pain 5 patients, cancer pam

9 controls, cold pressor 4 controls, ethanol injection 12 controls, tonic heat 1 3 controls, capsaicin pain tonic pain 7 patients, cluster headache 9 patients, migraine

9 controls, tonic heat 11 controls, tonic heat

Experimental tonic pain Rain\ illt et '11, 1997'"' 8 controls, tonic heat A 7 l / C't '11, 1')97' 8 controls, esophageal stimulation Sil\erinaii et al, 19Y7" 6 controls, \ isceral pain

--_

NA

-

BT

Cl

Bt

Cl

BT

-

-

-

BT

Ct

CT

-

BT

IT

ct ct

IT

-

tCT

CT BT

NA

-

-

Bt -

Bf

ct

BT -

Bt

Bl -

BT

B t It

-

CT tBf

-

7

7

-

-

-

IT

-

-

BT -

-

RT

-

IT IT

-

IT

-

B?

-

44/46

T

BT NA

RT

BT

RT

NA

LS

Br BT

LS

Bt

LT

Bt BT C/B

-

-

-

-

-

ct CT ct ct

-

-

-

-

Lt

CT

SI

-

-

-

39/40

CT BT

Lt

I T

BT

BT

ACC

Reported Regions

9/10

-

-

LN

CT RT

Ins

tBT

-

Tha

Table 1. RESULTS OF PREVIOUS STUDIES USING PET AND EXPERIMENTAL TONIC PAIN, CLINICAL TONIC PAIN, AND EXPERIMENTAL PHASIC PAIN

-

-

-

-

-

BT

-

CT NA

-

-

ct -

Sll

111

w

U

57 17* 86

Tonic studies with a n rCBF increase (%) Clinical studies with ‘in rCBF increase (%) Phasic studies with a n rCBF increase (%)

71 50 71

-

-

ct

ct

40

14

33

57

29 40*

ci

100 100 100

ct

ct ct ct

Bt Ct

14 50* 29*

71 57

00

33 00 43

The numbers tinder ’Reported regions’ refer to Brodmann’s areas; Tha = thalamus; Ins = insula; LN = lentiform nucleus; ACC = anterior cingulate cortex; SI = primary somatosensory cortex; SII = secondary somatosensory cortex; C = contralateral; B = bilateral; I = ipsilateral; R = right; L = left; N A = not assessed; t = increased rCBT; 1 = decreased rCBF, ’ = uncertainty regarding the activation (assumed inactive for the summary calculation). *Some 3tudies reported decreases (decreases treated as inactive for the summary calculation). tPcrsonal communication from the author (included as active for the summary calculation) Ailopfnl fiwi Derbyshire SWG, Jones AKP: Cerebral responses to a continual tonic pain stimulus measured using positron emission tomography. Pain 76:127-135, 1998; with permision.

ct Bf ct ct

-

E x p ~ n n i t w t cp~ll i ~ s i pi i n Derbyshire et al, 1997”‘ 12 controls, laser heat Vogt et al, 1996”“ 7 controls, phasic heat p a i n Derbyshire et al, 1994’’ 6 controls, phasic heat p a i n Coghill et al, 1994’“ 9 controls, phasic heat p a i n Casey et al, 1994” 18 controls, phasic heat pain Talbot et al, 1991LL1 8 controls, phasic heat p a i n Jones et nl, 1991”’ 6 controls, phasic heat p a i n

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Prefrontal Cortex

v Cingulate Cortex

T

Hypothalamus Brain Stem Sympathetic Output

Brain Stem

a-delta c-fibres

Contralateral Spinothalamic Tract

Figure 2. The pain matrix The motor components of the matrix have been left out for clarity See text for specialized function of each area PAG = periaqueductal grey

pliasic ,ind tonic'" experimen t d pain, somatic and \risceralH pain, and chronic and acutc n e u r o p t h i c pciiiif" "';liowcver, the pattern and level ot acti\.it!r I\.ithin the matrix ma)' be significantly different in different psychological and chronic p i n conditions."', I" There are some problems, h o w c ~ \ ~ lvitli r, the interpretation of rCBF studies within and between

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groups of patients with ongoing pain. These problems relate to the general assumption that increased flow equals increased neuronal firing, and the converse. Whereas there appears to be a close relationship between rCBF and synaptic activity, it is possible that increased neuronal firing may be associated with synaptic activation of long inhibitory efferents. If activation of inhibitory efferents is the dominant activity on a background of less-pronounced increased activity of local inhibitory interneurons, then there could still be an increase in rCBF as a result of mainly local and distant inhibition. The converse could also apply. This may be relevant to understanding some interesting findings in patients with chronic pain. For instance, decreased thalamic rCBF has been found in patients during neuropathic pain,sycancer pain,’” and fibromyalgia,XH when compared with either a control group or the same group in a pain-free state. This could be related to increased tonic inhibitory tone in the thalamus, as has been suggested, or it could be because of a reduction in local and distant inhibition. The combination of electrophysiological studies using pain-evoked potentials in combination with PET may provide an interesting way of probing the effect of such changes in thalamic rCBF on some of the cortical nociceptive projections.

The Sensory-Discriminatory Components of Pain The sensory-discriminative components of pain include three elements: stimulus localization, intensity discrimination, and quality discrimination. The human capacity to localize pain is part of the “currency” of medical diagnosis. It is precise for the skin, less so for the joints and muscle, and poor for the viscera. The commonly held belief that precise localization of skin nociception is dependent on the touch information transmitted by means of the lemniscal pathways of the dorsal columns is erroneous. On the human hand, laser radiant heat, which only excites nociceptors, can be localized with an error of 14 ? 3 mm,x7compared to touch, which has a mean localization error of 12 L 2 mm. Pain localization is therefore not dependent on tactile input. The nociceptive system provides the brain with sufficient information for us to know where it hurts. The somatotopic organization of the lateral pain system from the spinal cord to the primary somatosensory cortex (SI) provides the potential for any or all of these structures, including the thalamus, to be involved in localization. Which of these structures is necessary for localization is still unresolved, but from primate studies it seems likely that the SI is involved.” Functional imaging studies have demonstrated surprising variability of responses in the somatosensory cortex. The Manchester group has been unable to elicit consistent responses in SI, finding increases and decreases in flow in response to pain with a nonmoving heat stimulus, b u t with possible increases in SI with
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and five studies in SII in response to phasic and tonic pain (see Table 1). The reason for these inconsistencies is likely because of the differences in experimental design and quite small changes in rCBF, the nociceptive inputs to SI being relatively sparse. Most of the groups (except the Manchester group) moved a heat probe at a given temperature from one location to another on the forearm in order to minimize the effect of habituation. This is likely to increase attention to the discriminatory components of the stimulus, which is unlikely to be matched in the control condition. There was also a variable tactile component to all studies using a contact probe; however, two studies using tonic' chemically induced pain (capsaicinb' and ethanolh")also demonstrated SI responses. The latter two studies compared the effect of pain on rCBF with a baseline pain-free rest condition rather than with a nonpainful stimulation, which is likely to increase considerably the signal noise of the SI signal. There is little doubt that SI is involved in the sensory discriminatory components of nociceptive processing3 and it has been shown to have some somatotopic properties in humans. The presence or absence of pain is unlikely to be the main determinant of whether there is an increase in flow in this area, however. Affective-Motivational and Cognitive-Evaluative Components of Pain

The affective and cognitive components of pain will determine most of the highly variable pain behavior of patients suffering from different types of acute and chronic pain syndromes. It is difficult to truly dissociate some of the sensory-discriminative components such as intensity discrimination (magnitude estimation: how intense is it?) from affective response (how unpleasant is it?); however, partial dissociation can be achieved. The motivational component includes some preparation for action or vocalization or suppression of these (executive control). AS these components of pain are highly variable, any component of the pain matrix involved in these processes would be expected to show evidence of plasticity of responses in relation to these different aspects of higher integrative processing. It seems likely that most of the structures of the matrix above the brainstem, apart from SI and SII, are i n v o l \ d in some way with these affective and cognitive components of nocicepti\re processing. Consistent with this is the growing evidence for bilateral nociceptive responses in thalamus, insula, anterior cingulate c ~ n dprefrontal cortices (see Table l), although the contralateral component may well be quantitatively more important. Nociceptive processing units in area 24 of anterior cingulate often exhibit whole-body receptive fields.'"'' Some bilaterality of response might therefore be expected in this region. This may explain lvhy, iii two PET studies of chronic neuropathic pain, nocicepti\re processing appeared to occur ipsilaterally.'" "I If bilateral processing is common, within small studies the chances of ipsilateral processing being obser\Ted in a group analysis are quite high.

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It should also be remembered that the effective spatial resolution of activation studies is about 16 mm and therefore there always remains some uncertainty about the distinction between structures either side of the midline. Functional magnetic resonance studies suggest, however, that there is bilateral anterior cingulate activation in response to pain."' Activity in most of the main components of the pain matrix (and mostly bilateral) apart from SI was found to correlate with pain experience,'" with poor correlation with the energy of stimulation. This confirms that these areas of the brain are likely to be less involved in the sensorydiscriminative components of pain and more likely to be involved in some aspects of higher nociceptive processing. The cingulate cortex is involved in a number of integrated tasks including cognition, affect, and response selection.38In addition to the midcingulate area previously described, a recent study has shown an additional highly significant area at the perigenual cingulate."y It has been suggested that the perigenual cingulate may be more concerned with affective, autonomic, and vocalization components of nociception, whereas the midcingulate responses may be more concerned with the attentional and executive components.3xAlthough local anesthetic injection into the cingulum bundle induces analgesia in animals,'lS removal or deafferentation of the anterior cingulate cortex in patients with severe intractable pain did not abolish the pain, instead the patients reported that the pain was no longer bothersome.42This suggests that the cingulate cortex is not necessary for the registration of pain, but may be responsible for the attentional and affective responses to pain. Recent PET studies, where the unpleasantness of a thermal stimulus was varied under hypnotic suggestion, confirm that the anterior cingulate cortex is involved in the encoding of perceived unpleasantness. This area, however, was well rostra1 to the perigenual area. "'" In the conscious appreciation of any sensory experience, the brain has to prioritize the components of a stream of sensory information with subsequent selection of appropriateness and timing of response. This 'ibility is generally called attention. Based on the study of patients with neglect syndromes, it has been proposed that there is a network of three main structures concerned with directing attention: a motivational map within the anterior cingulate cortex which includes response and target wlection; a schema for exploratory movements and supervision of attenlion in the frontal cortex""; and a sensory representation in the posterior pirictal cortex.S" In addition, a subsystem responsible for alerting or \.igilance that is located in the right anterior hemisphere has been proposed by Posner and colleagues."' Cognitive tasks that make severe attentional demands, such as the Stroop conflict task, commonly activate the right anterior cingulate cortex. The Stroop task consists of asking subjects to call out the ink color ot color words which are incongruent with their ink color (such 'is the \vord 'red' written i n green ink). PET studies suggest that attention to sensory stimuli is also processed in the right anterior cingulate cortex, regardless of side of stimulus"'; however, the precise conditions of the

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attentional task are critical in determining which aspects of the attention network are activated.’? To what extent the anterior cingulate responses to pain involve the attentional network is not established. A series of experiments to determine whether similar areas of cingulate cortex are activated by an ,ittentionally demanding task (Stroop) and pain in the same individuals has been performed. This suggests that both pain and attention activate structures within midcingulate cortex but that only pain activates the more anterior perigenual cingulate cortex.I2,i’,” Nonspecific attention and pain both appear to activat.? parallel but discrete structures within the cingulate cortex, suggesting that the nociceptive responses in the cingulate cortex cannot be described under the general rubric of attention. It is possible that the anterior cingulate responses comprise a linked attentional and affective network concerned with response selection mainly within the midcingulate and the more affective components of the response are processed more anteriorly. In support of this suggestion, there are important connections between midcingulate cortex and dorsolateral prefrontal cortex (DLPF) area 46, which has been associated with the generation of willed actions and response inhibition.s” This is also consistent with PET studies that have not demonstrated a midcingulate response where the pain is inescapable, such as laser-induced pain,36 whereby the stimulus is too brief to be avoided, and visceral pain.x The inferior parietal cortical involvement in the pain response may be concerned with the posterior attentional system, which Posner has suggested is involved in directed spatial attenti~n.~’ With its connections to the posterior cingulate cortex, where substantial reductions in flow in responses to pain have been recorded, it is more likely that this represents a nociceptive visual orientation response, however, as has been demonstrated in animals. The amygdala, which lies within the temporal lobe at the tail-end of the caudate nucleus, is likely to be involved in pain perception for a number of reasons. Animal studies have implicated the amygdala in avoidance conditioning.’” Papez originally suggested that the hypothalamus, anterior tlialamic nuclei, cingulate cortex, and hippocampus and their connections are concerned with emotional expression and perception.”’Gabriel and coworkers’ work over the last ten years4’have defined dctailed circuitry involved in acquisition of avoidance conditioning and execution of conditioned r e s p i s e s involving tlie amygdala, hippocampis, medial m d anterior tlialamic nuclei, and posterior (primacy) and anterior (recency) cingulate cortices. The motor outputs for these res”()I1ses are b y way of premotor components of the cingulate cortex and the striatum. The amygdala, thalamus, and cingulate cortices are in\vl\xxI in tlie acquisition of conditioned responses. This forms the template, nThich is compared with new sensory inputs. If there is a match, the ;1ppropriate motor respoiist’ is initiated by w a y o f the cingulate motor cortex and the primed striatum. If there is ‘1 mismatch, the hippocampus is activated to hlock any motor response. The evidence in humans that the amygdala is involved in nocicep-

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to determine the level at which these cortical responses are modified by ascending inputs. The anterior insula receives projections from nociceptive-specific components of the ventromedial nucleus (VM,,,) of the thalamus.” The anterior cingulate and the frontal cortex are innervated by the parafascicular and medial thalamic group of nuclei. The cingulate cortex is also implicated in avoidance conditioning,.lhattention,?’ mood,” and willed actions. The design and spatial resolution of this study do not allow the various components of the anterior cingulate response to be discriminated; however, it is likely that the reduced responses to phasic pain may be related to enhanced coping and attentional strategies’” related to altered response selection. Support for this concept comes from the observations in patients with atypical facial pain who have no identifiable source of nociceptive input but poor coping strategies with frequent depression. They have enhanced anterior cingulate responses to standardized experimental heat pain”; however, patients with acute pain caused by a definite nociceptive input from the face 4 hours after molar extraction have reduced anterior cingulate and prefrontal cortical responses with intact thalamic and lentiform nucleus responses to a standardized thermal pain These different patterns of cortical response suggest that adaptation may be mainly at the level of the thalamo-cortical projections of the medial thalamic nuclear group. There are extensive projections from dorsolateral prefrontal (DLPF) cortex including areas 9, 46, and lo1” to anterior cingulate cortex in primates. Reduced responses in the DLPF cortex area 10 have also been found in atypical facial pain”’ and dental pain.” The DLPF cortex has been implicated in normal supervision of attentional processes,” depressed mood” (areas 9 and 46), and willed actions (areas 46 and 10). The reduced DLPF response was found during the ongoing molar extraction pain and during psychogenic and inflammatory pain and is likely to be related to the presence of persistent pain. The reduced DLPF responses may be related to the attempted recruitment of coping strategies (even if unsuccessful), response inhibition, or possibly reduced alerting or vigilance responses. Hsieh et a1 have shown that prefrontal responses to pain are critically dependent on the psychological state of the subject.+ If subjects are preconditioned by a painful stimulus and know when to expect the painful stimulus, prefrontal (ventromedial) responses are reduced rather than increased.’s Further sequential studies are underway to resolve these issues. Recently developed surface electrophysiological mapping techniques allow frontal responses to pain to be studicd in detail. The late vertex pain-evoked potential, which probably corresponds to cingulate response, has been shown to be dependent on the pain intensity.”. Using these techniques, sequential studies in patients with inflammatory pain may well be the most sensitive and cost-effective way o f correlating behavior with physiological events in the forebrain. This stud!, clt.arly demonstrates ‘1 striking reduction in frontal and anterior cingulate cortical responses during inflammatory pain that is distinct from previously reported increased cingulate responses in pa-

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tients with psychogenically maintained pain, suggesting different cortical substrates of these two types of pain experience. At present, it is difficult to explain these observations in terms of any mechanisms that have been described in animal studies because no equivalent experiment has been done. Experiments in rodents with induced hindpaw inflammatory arthritis have demonstrated neurons with expanded receptive fields and prolonged after-discharges to touch in SI but not in the ventrobasal complex of the thalamus (VB complex).’1xThis increase in a unit’s receptive field was correlated with its increased spontaneous activity. They also found larger numbers of units with prolonged afterdischarges in the ventrobasal complex of the thalamus and SI up to one day after induced inflammation in response to movement or light pressure of the inflamed joint.52These effects are substantially blocked by both morphine and nonsteroidal analgesics. This group also made a further observation that the total proportion of units excited by nonjoint inputs (brushing and pinching) was considerably decreased after induction of arthritis5] and this effect was most marked for the cortex. On the current evidence, however, it is not clear that these responses are nociceptive-specific, as control nonnociceptive stimulation was not performed. It is possible that joint movement may comprise considerable non-nociceptive proprioceptive stimulation and that pinch will also contain considerable touch stimulation. It is also a concern that noxious pressure on the joint may not elicit frequently any thalamic or primary somatosensory cortical response (personal communication, 1995). The possibility therefore exists that, whereas these observations are undoubtedly related to the presence of inflammatory pain, they may not be related to the pain processing but instead to altered proprioceptive processing. It seems likely that the primary somatosensory cortex is primarily involved in the localization of pain in both time and space, such as the sensory discriminative components of pain. Adaptive motor responses during inflammatory arthritis will certainly require more precise proprioceptive processing. An expansion of receptive fields to non-nociceptive stimuli such as touch within the cortex would be consistent with this process. Human experiments are necessary to validate this hypothesis. The involvement of the anterior cingulate, frontal cortices, and medial thalamic nuclei in ongoing inflammatory pain in animals has been established recently in freely moving rodents using 2-deoxyglucose autoradiography. This was performed at different stages of acute inflammation in response to formalin injection into a single paw of rats. As a result, the sequence of metabolic changes caused by increased neuronal activity in the spinal cord, brain stem,5” and telencephalic structures (Porro et al, personal communication, 1995) was studied. In addition to significant activation of bilateral medullary, pontine reticular formation, and superior colliculi, several higher structures are activated bilaterally including medial and lateral posterior thalamic nuclei, parietal, anterior cingulate anterior insula, and SI and SII cortex. The medial thalamic nuclei are activated throughout the period o f study (2, 30, and 60 min). Frontal, orbitofrontal, SI, SII, anterior cingulate cortex, and

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portions of the basal ganglia are activated during the second phase of the response. These patterns may be influenced by motor response but they are very different from the pattern of activation during repetitive motor response (Porro et al, personal communication, 1997). Coactivation of SI and SII within the context of these experiments, which do not discriminate between any components of the pain response, is consistent with the functional imaging results in humans. SII is probably implicated in the nondiscriminatory components of the acute phasic and persistent-pain responses. When the sensory-discriminative components of an acute pain stimulus are included in the analysis of human PET studies of acute pain, a very robust response in S1 can be detected.? The designs of experiments on acute inflammatory pain are now amenable to precise correlations of behavior with altered cortical and subcortical responses. Is it possible to create a unifying hypothesis for the experimental results obtained in different species? In the opinion of the author, it seems likely that SI is involved in the processing of the sensory-discriminatory components of pain and that during episodes of joint inflammation there are increases in the receptive fields of units in SI to nonnociceptive inputs. The increased spontaneous activity and prolonged after-discharges to both noxious and non-noxious stimulation in SI and the VB complex suggest some kind of cortical and subcortical sensitization to joint stimulation that is not nociceptor-specific. It seems most likely that these cortical and subcortical adaptive responses are related to adaptation of the sensory-discriminative components of pain related to joint proprioception rather than the affective-motivational components. The major responses to ongoing inflammatory pain in animals have been localized in the forebrain structures of the anterior cingulate, anterior insula, frontal cortices, SI, and SII. The substantial reduction in responses to pain in the forebrain areas of patients with arthritis suggests that there are also adaptive mechanisms operating to change the cerebral responses to the motivational-affective and evaluative components of nociceptive processing. Pharmacology

The neulopliarmacologic basis for the differences of cortical respoi1st.s to pain are not known, but indirect evidence implicates the cI1dogenous opioid system. Substantial changes in opioid receptor binding during inflammatory pain have been demonstrated in patients," consistent with increased cortical opioid peptide release demonstrated in animals'"' \Tit11 arthritis. So far, thc principal cerebral neurophari7iacolo~i~ studies on inflammator!~pain in humans Iia\.e been performed using PET. PET scanning was used to quantitate accurately the regional cerebral kinetics of tracer quantities of [ " C ] labtlled diprenorpl?ine for 90 minutes after

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intravenous injection. This tracer binds to available p, 6, and K opioid binding sites. The radioactivity retained is directly proportional to the concentration of available opioid binding Binding is quantitated by fitting the regional kinetic data obtained with the PET camera to the continuously sampled arterial plasma radioactivity after correcting for metabolism of the tracer. The error on the fitted values for regional ["C] diprenorphine binding has been minimized in these studies by injecting a saturating dose of the opiate antagonist naloxone 30 minutes after the injection of tracer. At that point in the fitting routine, the assumption can be made that there is no further binding of ["C] diprenorphine to specific binding sites, reducing the number of variables by one. The kinetics of each of a number of brain regions is fitted to derive quantitative values of in vivo ["C] diprenorphine binding. These measurements are made in each subject on one occasion while in considerable pain and on a second after substantial pain relief. The changes in ["C] diprenorphine binding are assumed to be caused by changes in occupancy of opioid receptors by endogenous opioid peptides, reducing the chances of trace quantities of ["C] diprenorphine associating with those receptors. These changes in binding are expressed as a volume of distribution of specific binding (VD,,). A group of patients with active RA was studied during a period of active inflammation and were subsequently substantially pain-free as a result of either natural remission of their disease or intra-articular, locally injected and retained steroid. Pain-free patients and patients in pain were also compared with non-age-matched controls. All patients who were studied twice showed a substantial reduction in the Ritchie index, ESR, CRP, or all three parameters at the time of the second study, suggesting a considerable reduction in inflammation. VAS pain scores (both affective and sensory components) for the 24 hours prior to the scan were reduced by 100% in three patients and by 62% in one patient at the time of the second scan. There was very little change in pain threshold, although there was an increase in pain tolerance consistent with the reduction in arthritic pain. Within-group analysis of the four patients scanned in two pain states showed substantial changes in ["C] diprenorphine binding in most brain regions analyzed except for inferior temporal, inferior and mid-occipital cortices, the primary visual cortex (cuneus), and posterior putamen."" Significant decreases in binding were observed in the superior and inferior frontal cortex, straight gyrus, anterior and posterior cingulate, and superior and midtemporal cortices. None of the changes seen in the subcortical structures achieved significance. In this particular study, no distinction can be made between the effects of inflammation and pain. It is therefore possible that all the changes observed may be mused by the inflammation alone; however, a similar pattern of changes in opiate-receptor binding has been observed in noninflammatory neurogenic pain, suggt'stiy that persistent pain is probably a n important component of the stimulus necessary to elicit such responses. Another possibility is that this may be a nonspecific response t o chronic stress.

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Severe physiological stress induced in rodents by swimming in ice-cold water caused a substantial displacement of in vivo ]H"[ diprenorphine binding in a number of subcortical structures including medial thalamus, amygdala, and periaqueductal grey.Io2Although no cortical changes in in vivo opioid receptor binding were induced by this type of severe stress in rodents, extrapolation to humans should be made with caution. It has been suggested that descending cinguloperiaqueductal efferents modulate activity of the descending 5HT mediated inhibitory system by way of the midline raphe nuclei in the brain stem.1ohIf uncontrolled, this system may deplete serotonin reserves and so disrupt descending analgesia,xsor directly interfere with opiate organization in the cingulate cortex itself. While it is unlikely that the observations on patients with inflammatory pain can be explained purely on the basis of a stress response, many have suggested that the pain of arthritis is mediated by the effects of stress in certain personalities.55,y3 Others have commented that psychological characteristics and attitudes to illness are more important predictors of disability and pain than the severity and activity of the arthritis.'", Neurons in anterior cingulate cortex show a plasticity that is not evident within the highly somatotopic structure of SI.4-',45, 47 It is possible that some of this plasticity of function may be modulated by endogenous opioid peptides. This may also explain why cognitive coping strategies for dealing with cold, pressor-induced pain have been shown to be less effective after administration of naloxone.y Strategies for dealing with the pain may become less accessible. Clinical studies of patients with chronic pain do not suggest any significant cognitive deficits of chronic morphine analgesia on a routine test battery'Ih; however, studies of the analgesic effect of morphine variously suggest either an effect on both the affective and the sensory components of the McGill score or an effect on the affective components alone." The general clinical experience is that morphine does not affect pain localization but makes the pain much less bothersome, suggesting the modification of a central affective, attentional, or even stress response. There is now evidence that the later P-endorphinergic components of the endogenous opiate response during inflammation may be mainly modifying behavior at a supraspinal level. The intraventricular injection of antibody to P-endorphin in rats seems to cause reduced pain response correlated with reduced brain activity at a supraspinal level only (Porro et al, personal communication, 1997)."'?The authors suggest that there may be a sequence of opioid-mediated events in the brain as follows. The early release of endogenous opiates may be associated with reinforcement of suppression of motor responses, facilitating the neuronal plasticity within the frontal and cingulate cortices, allowing greater de\relopment of psychological coping strategies. Prolonged opioid acti\.ation may, by way of descending afferents from these cortical areas to medial th,ilaniic and periciquductal gre). in the brainstem, result in a resetting of thresliolds for ascending nocicepti\,e inputs to these higher centers. We are now at an exciting stage of being able to test these and other hypotheses.

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SUMMARY

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