Review
Interactions between the cardiovascular and pain regulatory systems: an updated review of mechanisms and possible alterations in chronic pain

https://doi.org/10.1016/j.neubiorev.2004.06.004Get rights and content

Abstract

Endogenous pain regulatory system dysfunction appears to play a role in the maintenance of chronic pain. An important component of the pain regulatory process is the functional interaction between the cardiovascular and pain regulatory systems, which results in an association between elevated resting blood pressure (BP) and diminished acute pain sensitivity. This BP/pain sensitivity relationship is proposed to reflect a homeostatic feedback loop helping restore arousal levels in the presence of painful stimuli. Evidence is emerging that this normally adaptive BP/pain sensitivity relationship is significantly altered in chronic pain conditions, affecting responsiveness to both acute and chronic pain stimuli. Several mechanisms that may underlie this adaptive relationship in healthy individuals are overviewed, including endogenous opioid, noradrenergic, and baroreceptor-related mechanisms. Theoretical models are presented regarding how chronic pain-related alterations in the mechanisms above and increased pain facilatory system activity (central sensitization) may contribute to altered BP/pain sensitivity interactions in chronic pain. Clinical implications are discussed.

Introduction

The ability to adapt effectively to both acute and persistent pain stimuli is an important contributor to quality of life. Adaptation to pain is determined by a complex endogenous pain regulatory system composed of both descending inhibitory and descending facilatory pathways [1]. Activity within this system is dependent on duration of pain stimuli, and functions to maximize survival [1], [2]. The initial response to nociceptive stimuli engages descending inhibitory mechanisms that allow the organism to escape the injury-causing event (e.g. attack) without experiencing intense pain sensations that might interfere with immediate survival [1], [2]. After the acute danger has passed, the pain regulatory system shifts to a relative predominance of descending facilitation, making pain more salient as a signal to avoid additional injury and to allow healing [1], [2]. If pain persists beyond this initial healing period, descending inhibitory pathways display progressively increased activity to facilitate resumption of normal activities required for survival [1].

While the above process is adaptive, the development of chronically painful conditions is clearly maladaptive. Numerous authors have proposed that chronic pain develops when ongoing nociceptive stimulation results in failure of descending pain inhibitory mechanisms [1], [2], [3], [4], [5], [6]. In such circumstances, continued activation of descending pain facilatory mechanisms that sensitize the spinal nociceptive processing pathways may overwhelm the exhausted inhibitory system, leading to a chronic dysfunctional pain state [1], [7].

This review will focus on one important component of the pain regulatory process: the functional interaction between the cardiovascular and pain regulatory systems (see Ref. [8], for a general review). This functional interaction is reflected in the relationship between elevated resting blood pressure (BP) levels and diminished acute pain sensitivity that is reliably observed in normotensive humans (e.g. Refs. [9], [10], [11], [12], [13], [14], [15], [16]). It has been proposed that this adaptive cardiovascular/pain regulatory relationship reflects a homeostatic feedback loop that helps restore arousal levels in the presence of painful stimuli [4], [8], [17].

Nearly all published studies of the relationship between resting BP and acute pain sensitivity have used brief experimental pain stimuli in healthy or hypertensive subjects. However, until recently, the important question of whether these adaptive cardiovascular/pain regulatory interactions function normally in the context of chronically painful conditions had been largely neglected. As will be detailed below, recent work regarding this issue suggests that there may be substantial alterations in the BP/pain sensitivity relationship in chronic pain sufferers [18], [19], [20]. Identifying the source of these changes will provide important clues for understanding the processes contributing to pain regulatory dysfunction in chronic pain.

Section snippets

The relationship between blood pressure and acute pain sensitivity

Research initially focused on understanding the hypoalgesia associated with hypertension [21], [22], [23], [24] has highlighted the importance of interrelationships between the cardiovascular and pain regulatory systems. Even in the absence of clinical hypertension, familial risk for hypertension in healthy individuals appears to be associated with diminished responsiveness to acute pain apart from the influence of actual BP levels [25], [26], [27], [28], [29], [30], [31]. There is suggestive

Structural interactions

The relationship between resting BP and pain sensitivity arises from what has been described as a central autonomic network, reflecting integrated brain regions that coordinate responses to environmental stimuli [8]. The brain regions underlying control of the cardiovascular system are known to overlap substantially with those contributing to antinociception [17]. Fig. 1 summarizes the current literature with regard to brain pathways that may underlie the BP/pain sensitivity relationship. Given

Effects of prolonged acute pain

Nearly all studies of the BP/pain sensitivity relationship, animal and human, have used brief experimental acute pain stimuli (typically <5 min in duration). The importance of pain duration as a potential moderator of this relationship is suggested by three animal studies that have examined the BP/pain sensitivity relationship in the context of more prolonged acute pain stimuli. Injection of formalin into rat paws was used to produce prolonged (90 min) inflammatory pain [103], [106], [107]. While

Impaired descending inhibitory mechanisms

Descending pain inhibitory pathways appear to display progressively increased activity if nociceptive stimulation persists [1], [7]. It has been suggested that persistent and excessive antinociceptive demands may eventually exhaust these descending inhibitory systems, thereby contributing to development or maintenance of chronic pain [1], [3], [4]. Evidence supporting this antinociceptive dysfunction hypothesis comes from several sources. Studies in patients with diverse chronic pain conditions

Possible theoretical models

Several theoretical models (not mutually exclusive) could help explain the alterations in the BP/acute pain sensitivity relationship observed in chronic pain patients. Model 1 is based on the finding that nociceptive input triggers a direct somatosympathetic reflex elevation in BP [36], [158]. If persistent nociceptive input leads to failure of descending alpha-2 adrenergic inhibitory systems contributing to the inverse BP/pain sensitivity relationship, direct SNS-mediated BP increases may

Methodological and interpretive issues in use of alpha-2 adrenergic blockade methodology

The role of endogenous opioid mechanisms that may contribute to the BP/acute pain sensitivity relationship has been examined in several human studies using opioid blockade. Although comparable alpha-2 adrenergic blockade methodologies are available to examine this possible mediator of the BP/pain sensitivity relationship in humans (e.g. yohimbine is an FDA-approved selective alpha-2 antagonist), no studies to date have yet employed this methodology. Many of the animal data implicating alpha-2

Clinical implications

The review above has been generally focused on understanding the basic mechanisms underlying important aspects of the pain regulatory process, and how these may be altered in chronically painful conditions. However, the theoretical models presented may have clinical ramifications as well. As described above, we have previously reported a positive relationship not only between resting BP and acute pain sensitivity, but between resting BP and chronic pain intensity [10], [18]. This latter

Conclusions

Functional interactions between the cardiovascular and pain regulatory systems appear to be an important part of the pain regulatory process. In healthy normotensive humans, there is much evidence that baroreceptor-mediated mechanisms are an important determinant of the adaptive BP/pain sensitivity relationship. There is weak evidence for partial mediation by endogenous opioids, with opioid mechanisms possibly more important in clinically hypertensive populations. Animal work suggests that

Acknowledgements

This work was supported by grant No. R01-NS38145 from the National Institutes of Neurological Disorders and Stroke.

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