ReviewInteractions between the cardiovascular and pain regulatory systems: an updated review of mechanisms and possible alterations in chronic pain
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.
References (226)
Descending control of pain
Prog Neurobiol
(2002)- et al.
Theoretical review: altered pain regulatory systems in chronic pain
Neurosci Biobehav Rev
(1999) - et al.
Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief
Pain
(2000) - et al.
Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation
Pain
(1999) - et al.
The relationship between pain sensitivity and blood pressure in normotensives
Pain
(1992) - et al.
The relationship between resting blood pressure and acute pain sensitivity in healthy normotensives and chronic back pain sufferers: the effects of opioid blockade
Pain
(2002) - et al.
Do endogenous opioids mediate the relationship between blood pressure and pain sensitivity in normotensives?
Pain
(1994) - et al.
Menstrual cycle, blood pressure and ischemic pain sensitivity in women: a preliminary investigation
Int J Psychophys
(1997) - et al.
Interactions between cardiovascular and pain regulatory systems
Neurosci Biobehav Rev
(1984) - et al.
Group differences in pain modulation: pain-free women compared to pain-free men and to women with TMD
Pain
(2002)
Genetic predisposition to hypertension, elevated blood pressure and pain sensitivity: a functional analysis
Behav Brain Res
Factors influencing the altered pain perception in the spontaneously hypertensive rat
Brain Res
Hypertension-induced analgesia: Changes in pain sensitivity in experimental hypertensive rats
Brain Res
Pain sensitivity and opioid activity in genetically and experimentally hypertensive rats
Brain Res
Blood pressure but not parental history for hypertension predicts pain perception in women
Pain
Adrenocortical and hemodynamic predictors of pain perception in men and women
Pain
Altered central nervous system processing of noxious stimuli contributes to decreased nociceptive responding in individuals at risk for hypertension
Pain
Objective evidence of decreased pain perception in normotensives at risk for hypertension
Pain
Resting systolic blood pressure, parental history of hypertension, and sensitivity to noxious stimuli
Pain
Antinociception and cardiovascular responses produced by electrical stimulation in the nucleus tractus solitarius, nucleus reticularis ventralis, and the caudal medulla
Pain
Periaqueductal gray area and cardiovascular function
Pharmacol Res
Antagonisms of stimulation-produced antinociception from ventrolateral pontine sites by intrathecal administration of alpha-adrenergic antagonists and naloxone
Brain Res
Characterization of descending modulation of nociception from the A5 cell group
Brain Res
Descending noradrenergic influences on pain
Prog Brain Res
possible interface between autonomic function and pain control: opioid analgesia and the nucleus tractus solitarius
Brain Res
Immunohistochemical profiles of spinal lamina I neurons retrogradely labeled from the nucleus tractus solitarii in rat suggest excitatory projections
Neuroscience
Suppressive effects of vagal afferents on theactivity of the trigeminal spinal neurons related to the jaw-opening reflex in rats: Involvement of the endogenous opioid system
Brain Res Bull
Effects of cardiac vagal afferent electrostimulation on the responses of trigeminal and trigeminothalamic neurons to noxious orofacial stimulation
Pain
Acute increases in arterial blood pressure produced by occlusion of the abdominal aorta induces antinociception: peripheral and central substrates
Brain Res
Association between hypoalgesia and hypertension in rats after short-term isolation
Neuropharmacology
Blood pressure but not cortisol mediates stress effects on subsequent pain perception in healthy men and women
Pain
Cardiopulmonary baroreflex stimulation and blood pressure-related hypoalgesia
Biol Psychiatry
Psychophysiology of arterial baroreceptors and the etiology of hypertension
Biol Psychiatry
Baroreceptor stimulation: pain perception and sensory thresholds
Biol Psychol
Baroreceptor cortical effects, emotions, and pain
Int J Psychophys
The influence of low blood pressure and baroreceptor activity on pain responses
Physiol Behav
Sensory and affective dimensions of phasic pain are indistinguishable in the self-report and psychophysiology of normal laboratory subjects
J Pain
Relationship between a genetic predisposition to hypertension, blood pressure levels and pain sensitivity
Pain
Naloxone reversible decrease in pain sensitivity in young and adult spontaneously hypertensive rats
Brain Res
Endogenous beta-endorphins in hypertension: correlation with 24-hour ambulatory blood pressure
JACC
Effects of naloxone on hemodynamic and sympathetic nerve responses to pain in normotensives vs. borderline hypertensive men
J Auton Nerv Syst
Differential effects of antisense oligodeoxynucleotides directed against g (z alpha) and g (alpha) on antinociception produced by spinal opioid and alpha-2 adrenergic receptor antagonists
Pain
Microinjection of carbachol in the lateral hypothalamus produces opposing actions on nociception mediated by alpha-1 and alpha-2 adrenoceptors
Brain Res
Release of neurotransmitters in the locus coeruleus
Prog Neurobiol
Involvement of supraspinal and spinal segmental alpha-2-adrenergic mechanisms in the medetomidine-induced antinociception
Neuroscience
Antinociception induced by amitriptyline and imipramine is mediated by alpha2A-adrenocpetors
Jpn J Pharmacol
Alpha2-adrenoceptor antagonists enhance responses of dorsal horn neurons to formalin induced inflammation
Eur J Pharmacol
Endogenous noradrenergic tone controls symptoms of allodynia in the spinal nerve ligation model of neuropathic pain
Eur J Pharmacol
Formalin-induced nociception activates a monoaminergic descending inhibitory system
Brain Res
Involvement of biogenic amines and amino acids in the central regulation of cardiovascular homeostasis
Trends Pharmacol Sci
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