Emotional control of nociceptive reactions (ECON): Do affective valence and arousal play a role?

Prior research suggests emotional picture-viewing modulates motoric (nociceptive flexion reflex), autonomic (skin conductance response, heart rate acceleration), and subjective (pain rating) reactions to noxious electrodermal stimulation. The present study sought to determine whether emotional valence and arousal contribute to nociception modulation. To do so, pictures varying in emotional content (erotica, food, neutral, loss, attack) were chosen to manipulate emotional valence (pleasant=erotic and food; unpleasant=loss and attack) and arousal (low=food and loss; moderate=erotica and attack). Pictures were presented in pseudorandom order to elicit emotional processing while noxious electric stimulations were delivered to the sural nerve. Nociceptive flexion reflex (NFR) magnitude, skin conductance response (SCR), heart rate (HR) acceleration, and subjective pain ratings to each stimulation were measured, standardized, averaged by picture content, and analyzed. Results suggested that picture-viewing explained 52% of the variance in the multivariate combination of the nociceptive reactions and modulated them in parallel. Pleasant pictures inhibited reactions, whereas unpleasant pictures enhanced them. However, only erotica and attack pictures elicited significant modulation relative to neutral pictures, suggesting arousal also contributed. An exploratory multilevel analysis also supported this conclusion. Together, these data suggest emotional control of nociceptive reactions (ECON) is associated with a valence-by-arousal interaction. Implications of these findings for how emotional picture-viewing can be used to study supraspinal modulation are discussed.     

Emotional modulation of spinal nociception and pain: the impact of predictable noxious stimulation

Recent evidence suggests that emotional picture-viewing is a reliable method of engaging descending modulation of spinal nociception. The present study attempted to replicate these findings and determine the effect of noxious stimulus predictability. Participants viewed pictures from the International Affective Picture System (IAPS), during which pain and nociceptive flexion reflexes (NFR) were elicited by electric shocks delivered to the sural nerve. For half of the participants (n=25) shocks were preceded by a cue (predictable), whereas the other half received no cue (unpredictable). Results suggested emotion was successfully induced by pictures, but the effect of picture-viewing on the NFR was moderated by the predictability of the shocks. When shock was unpredictable, spinal nociception (NFR) and pain ratings were modulated in parallel. Specifically, pain and NFR magnitudes were lower during pleasant emotions and higher during unpleasant emotions. However, when shocks were predictable, only pain was modulated in this way. NFRs from predictable shocks were not altered by pictures. Further, exploratory analyses found that pain ratings, but not NFRs, were lower during predictable shocks. These data suggest emotional picture-viewing is a reliable method of engaging descending modulation of spinal nociception. However, descending modulation could not be detected in NFRs resulting from predictable noxious stimuli. Although preliminary, this study implies that separate mechanisms are responsible for emotional modulation of nociception at spinal vs. supraspinal levels, and that predictable noxious events may disengage modulation at the spinal level. The current paradigm could serve as a useful tool for studying descending modulation.     

Habituation,sensitization, and emotional valence modulation of pain responses

The Emotional Controls of Nociception (ECON) paradigm involves the presentation of emotionally-charged pictures during which painful stimuli are delivered. Across several ECON studies, unpleasant pictures enhanced pain and nociception, whereas pleasant pictures inhibited pain and nociception. However, at this time it is unknown whether emotional valence (unpleasant, neutral, pleasant) influences the habituation or sensitization of pain responses that occurs within a testing session. Indeed, ECON assumes that emotional valence modulation of pain is consistent throughout testing; otherwise the interpretation of valence modulation (unpleasant > neutral > pleasant) could be threatened. To address this issue, the present study (N = 120) presented 108 pictures that varied in emotional valence. During and in between pictures, 52 suprathreshold electrocutaneous stimuli were delivered to evoke pain, the nociceptive flexion reflex [NFR], and pain-evoked skin conductance response [SCR]. Mixed effects ANOVAs verified that within-subject changes in pain responses were influenced by stimulus repetition (NFR and SCR habituated, pain ratings sensitized) and emotional valence (responses were highest during unpleasant pictures, intermediate during neutral pictures, and lowest during pleasant pictures). However, habituation/sensitization slopes were unaffected by emotional valence, thus indicating emotional valence modulation was consistently observed throughout the testing session. These results provide additional validation for the ECON paradigm and suggest that the circuit responsible for emotional modulation of pain and nociception is less susceptible to habituation or sensitization than the circuits responsible for responses to suprathreshold shocks.     

A comparison of diffuse noxious inhibitory controls in men and women.

Results from clinical and experimental pain studies provide consistent evidence of sex differences in pain perception, with women reporting more clinical pain and demonstrating lower pain threshold and tolerance levels than men. The present study was designed to assess the notion that sex differences in pain perception may be related to differential activation of supraspinal pain modulation systems. Specifically, the phenomenon of diffuse noxious inhibitory controls (DNIC) was examined in healthy young adult men (n = 39) and women (n = 44) using repeated assessment of nociceptive flexion reflex activity before, during and after exposure to forearm ischemia. Consistent with previous research, women exhibited significantly lower nociceptive flexion reflex thresholds than men, and reported significantly greater pain in response to both forearm ischemia and repeated electrocutaneous stimulation required to elicit the nociceptive flexion reflex. Application of forearm ischemia was associated with a significant decrease in nociceptive flexion reflex activity in both men and women, however, the degree of attenuation of nociceptive flexion reflex activity was not significantly different between the sexes. These findings suggest that men and women exhibit similar activation of diffuse noxious inhibitory controls, but they do not exclude the possibility of sex differences in other forms of central pain modulation.     

Modulation of the human nociceptive flexion reflex by pleasant and unpleasant odors

The nociceptive withdrawal reflex (NWR), a defensive response that allows withdrawal from a noxious stimulus, is a reliable index of spinal nociception in humans. It has been shown that various kinds of stimuli (emotional, visual, auditory) can modulate the transmission and perception of pain. The aim of the present study was to evaluate, by means of the NWR, the modulatory effect on the spinal circuitry of olfactory stimuli with different emotional valence. The magnitude of the NWR elicited by electrical stimulation of the sural nerve was measured while 18 subjects (9 women, 9 men) smelled pleasant, unpleasant, or neutral odors. The NWR was conditioned by odor probe with interstimulus intervals (ISIs) of 500 ms and 1,500 ms. The magnitude of NWR was significantly greater after the unpleasant odor probe (P <.001) and reduced following the pleasant odor probe (P < .001) at both ISIs. A significant effect of olfactory stimuli on subjective pain ratings were found at both ISIs for pleasant vs unpleasant odors (P < .000), and for both pleasant and unpleasant odors vs neutral and basal conditions (P < .000). No statistical differences in subjective pain ratings at different ISIs were found. Consistent with the notion that NWR magnitude and pain perception can be modulated by stimuli with different emotional valence, these results show that olfactory stimuli, too, can modulate spinal nociception in humans.     

Transcranial Direct Current Stimulation of the Dorsolateral Prefrontal Cortex Alters Emotional Modulation of Spinal Nociception

Emotion has a strong modulatory effect on pain perception and spinal nociception. Pleasure inhibits pain and nociception, whereas displeasure facilitates pain and nociception. Dysregulation of this system has been implicated in development and maintenance of chronic pain. The current study sought to examine whether emotional modulation of pain could be altered through the use of transcranial direct current stimulation (tDCS) to enhance (via anodal stimulation) or depress (via cathodal stimulation) cortical excitability in the dorsolateral prefrontal cortex. Thirty-two participants (15 female, 17 male) received anodal, cathodal, and sham tDCS on three separate occasions, followed immediately by testing to examine the impact of pleasant and unpleasant images on pain and nociceptive flexion reflex (NFR) responses to electrocutaneous stimulation. Results indicated that tDCS modulated the effect of image content on NFR, F(2, 2175.06) = 3.20, P= .04, with the expected linear slope following anodal stimulation (ie, pleasant < neutral < unpleasant) but not cathodal stimulation. These findings provide novel evidence that the dorsolateral prefrontal cortex is critical to emotional modulation of spinal nociception. Moreover, the results suggest a physiological basis for a previously identified phenotype associated with risk for chronic pain and thus a potentially new target for chronic pain prevention efforts.PerspectiveThis study demonstrated that reduction of dorsolateral prefrontal cortical excitability by transcranial direct current stimulation attenuates the impact of emotional image viewing on nociceptive reflex activity during painful electrocutaneous stimulation. This result confirms there is cortical involvement in emotional modulation of spinal nociception and opens avenues for future clinical research.     

Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures

Trigeminal and somatic nociceptive systems were studied in controls (n=15), episodic migraine (n=16), analgesics (n=14) and triptan-induced medication overuse headache (MOH) (n=15) before and after withdrawal. Patients with MOH and comorbid depressive symptoms and depression without headache were studied to investigate the influence of depression. Trigeminal nociception was studied by simultaneous registration of pain-related cortical potentials (PREP) and nociceptive blink reflex (nBR) following nociceptive-specific electrical stimulation of the forehead. Somatic nociception was evaluated using PREP of upper limbs. We found facilitation of both trigeminal and somatic PREP but not of nBR in MOH, which normalized after withdrawal. No differences were found comparing analgesics vs. triptan MOH. No differences were observed between controls and patients with episodic migraine and depression without headache. A transient facilitation was found of trigeminal and somatic nociceptive systems in MOH, which was more pronounced on a supraspinal level.     

Tonic and phasic descending dopaminergic controls of nociceptive transmission in the medullary dorsal horn

The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2-like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited. We show that D2 receptors are mostly located within superficial medullary dorsal horn where trigeminal nociceptive fibers abut. Activating these D2-like receptors inhibits, whereas blocking them enhances, both formalin- and capsaicin-evoked pain behavior and C-fiber-evoked action potential firing of trigeminal wide dynamic range (WDR) neurons. Moreover, windup and diffuse noxious inhibitory controls (DNIC), 2 dynamic properties of C-fiber-evoked firing of WDR neurons, are inhibited by activating and blocking, respectively, these D2-like receptors. Altogether, our results are consistent with a tonic inhibition of the trigeminal nociceptive input by descending dopaminergic controls via activation of D2-like receptors at the level of superficial medullary dorsal horn. Such dopamine-dependent tonic inhibition of nociceptive information can be dynamically modulated by pain. This suggests that dysregulation of descending dopaminergic controls should translate in patients into diffuse, cephalic, and extracephalic pain symptoms—spontaneous pain, decreased pain thresholds, deficient DNIC, or some combination of these.     

Emotional modulation of pain and spinal nociception in fibromyalgia

Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (eg, depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in 4 blocks; 2 blocks assessed only physiological-emotional reactions (ie, pleasure/arousal ratings, corrugator electromyography, startle modulation, skin conductance) in the absence of pain, and 2 blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (eg, reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all 3 groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes.     

Emotional modulation of pain and spinal nociception in persons with major depressive disorder (MDD)

Major depressive disorder (MDD) is associated with risk for chronic pain, but the mechanisms contributing to the MDD and pain relationship are unclear. To examine whether disrupted emotional modulation of pain might contribute, this study assessed emotional processing and emotional modulation of pain in healthy controls and unmedicated persons with MDD (14 MDD, 14 controls). Emotionally charged pictures (erotica, neutral, mutilation) were presented in 4 blocks. Two blocks assessed physiological-emotional reactions (pleasure/arousal ratings, corrugator electromyography (EMG), startle modulation, skin conductance) in the absence of pain and 2 blocks assessed emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations. Results indicated pictures generally evoked the intended emotional responses; erotic pictures elicited pleasure, subjective arousal, and smaller startle magnitudes, whereas mutilation pictures elicited displeasure, corrugator EMG activation, and subjective/physiological arousal. However, emotional processing was partially disrupted in MDD, as evidenced by a blunted pleasure response to erotica and a failure to modulate startle according to a valence linear trend. Furthermore, emotional modulation of pain was observed in controls but not MDD, even though there were no group differences in NFR threshold or emotional modulation of NFR. Together, these results suggest supraspinal processes associated with emotion processing and emotional modulation of pain may be disrupted in MDD, but brain to spinal cord processes that modulate spinal nociception are intact. Thus, emotional modulation of pain deficits may be a phenotypic marker for future pain risk in MDD.     

Abnormal modulatory influence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients

The aim of this study was to evaluate the function of pain modulating systems subserving diffuse noxious inhibitory controls (DNICs) in primary headaches. DNICs were examined in 24 migraineurs, 17 patients with chronic tension-type headache (CTTH) and 20 healthy subjects by means of nociceptive flexion RIII reflex and the cold pressor test (CPT) as heterotopic noxious conditioning stimulation (HNCS). The subjective pain thresholds (Tp) and the RIII reflex threshold (Tr) were significantly lower in CTTH vs. controls. In controls a significant inhibition of the RIII reflex was observed during the CPT (-30%, P < 0.05). Conversely, migraine and CTTH patients showed facilitation (+31%, P < 0.05 and +40%, P < 0.01, respectively) of the RIII reflex during the HNCS. This study demonstrates a dysfunction in systems subserving DNICs in both migraine and CTTH. Impairment of endogenous supraspinal pain modulation systems may contribute to the development and/or maintenance of central sensitization in primary headaches.     

The influence of pain catastrophizing on experimentally induced emotion and emotional modulation of nociception.

Pain catastrophizing is associated with enhanced pain and pain-related outcomes. Unfortunately, the mechanisms underlying the catastrophizing-pain relationship are poorly understood. Given evidence suggesting significant relationships among catastrophizing, emotion, and pain, it is possible that catastrophizing may alter nociception and pain through affective processes. Research has shown that emotionally charged pictures (erotica, neutral, threat/attack scenes) manipulate emotional valence (positive affect vs negative affect) and modulate physiological and subjective nociceptive reactions (pleasure-induced inhibition, displeasure-induced facilitation). Using this methodology, the present study addressed 2 questions: (1) Does pain catastrophizing moderate affective reactions to standard emotional stimuli (eg, augmented negative affect)? and (2) Does pain catastrophizing moderate the relationship between emotion and nociception (eg, augmented displeasure-induced facilitation)? Erotic, neutral, and attack pictures were presented to 53 participants who rated their emotional responses. During pictures, noxious electric stimulations were delivered to evoke nociceptive reactions (nociceptive flexion reflex, skin conductance response, heart rate acceleration, subjective pain). Results suggest that pain catastrophizing did not moderate emotional reactions to standardized picture stimuli, nor did catastrophizing moderate the influence of emotion on nociceptive reactions. This suggests that catastrophizing does not influence pain indirectly through emotional processes.PerspectivePain catastrophizing is commonly associated with negative emotions and maladaptive responses to pain. The current study provides evidence indicating catastrophizing does not alter pain and nociception indirectly via emotional processes.     

Serotonin Depletion Increases Nociception‐Evoked Trigeminal NMDA Receptor Phosphorylation

Objective.— To investigate the effect of serotonin depletion on phosphorylation and expression of NR1 subunit of N‐methyl‐D‐aspartate (NMDA) receptor in trigeminal nucleus caudalis (TNC), and on trigeminal nociception evoked by dural inflammation. Background.— Migraine is associated with low serotonin condition and an increased neuronal excitability. NMDA receptor is implicated in central plasticity change that leads to neural sensitization. Alteration in NMDA receptor phosphorylation or expression in TNC may be responsible for increased trigeminal nociception in serotonin‐depleted state. Methods.— Adult male Wistar rats were separated into normal and low serotonin groups. Serotonin was depleted by intraperitoneal injection with para‐chlorophenylalanine 3 days before the experiment. Trigeminal nociception was induced by applying inflammatory soup on exposed dura. Two hours after induction, phosphorylated NR1, NR1, and Fos expressions were studied in TNC by immunohistochemistry. Results.— Dural application of inflammatory soup led to the activation of trigeminal nociceptive system as well as the phosphorylation of NR1, which were further enhanced in the low serotonin condition. There was a strong relationship between NR1 phosphorylation and trigeminal nociception. However, neither meningeal inflammation nor serotonin depletion altered NR1 expression. Conclusions.— Low serotonin condition facilitates dural inflammation‐induced NR1 phosphorylation and trigeminal nociception. It is suggested that the mechanism of nociceptive facilitation in serotonin‐depleted state may involve the increase in NR1 phosphorylation rather than the upregulation of NR1 subunit of NMDA receptor.     

The effect of trigeminal nociceptive stimulation on blink reflexes and pain evoked by stimulation of the supraorbital nerve

The aim of this study was to investigate the effect of painful conditioning stimuli on pain and blink reflexes to supraorbital nerve stimulation. Electromyograph activity was recorded bilaterally from the orbicularis oculi muscles in 13 normal participants in response to low (2.3 mA) and high-intensity (18.6 mA) electrical stimulation of the left supraorbital nerve before, during and after the application of ice to the left or right temple or immersion of the left hand in ice-water for 60 s. The pain evoked by the high-intensity electrical stimulus was greater during painful conditioning stimulation of the ipsilateral temple than during the recovery period afterwards, and was greater than during painful conditioning stimulation of the contralateral temple. These findings imply that spatial summation of nociceptive signals across different divisions of the trigeminal nerve can heighten pain. However, painful conditioning stimulation, particularly to the right temple, strongly suppressed the R2 component of the blink reflex to the low-intensity stimulus, and also suppressed R2 to the high-intensity stimulus. Thus, an inhibitory influence (e.g. diffuse noxious inhibitory controls) appeared to mask ipsilateral segmental facilitation of R2 during ice-induced headache. This finding contrasts with recent electrophysiological evidence of trigeminal sensitization in migraine.     

The effect of the menstrual cycle on affective modulation of pain and nociception in healthy women

Research indicates pain may be influenced by the menstrual cycle. While the mechanisms underlying these effects are unclear, it is possible that menstrual phase-related changes in endogenous pain modulation contribute. The present study used well-validated methods to study affective modulation of pain and the nociceptive flexion reflex (NFR) in healthy women during two menstrual phases (mid-follicular vs. late-luteal). Women (N = 41) tracked their menstrual phases for three complete cycles and were asked to attend two laboratory testing sessions in the second and third cycles to assess affective modulation of pain and nociception (testing order counterbalanced). Menstrual phase was assessed from daily diaries, luteinizing hormone tests, and basal body temperature. At each session, emotionally charged pictures were presented and suprathreshold electrocutaneous stimulations were delivered during and in between pictures. Subjective and physiological emotional reactions were recorded in response to each picture and pain ratings and NFRs were recorded in response to each suprathreshold stimulus. Results suggested pictures effectively manipulated emotion in both menstrual phases. Moreover, arousing unpleasant pictures enhanced pain and NFR, whereas arousing pleasant pictures inhibited pain and NFR. These modulatory effects were similar in both menstrual phases. Together, these findings suggest that affective engagement of corticospinal mechanisms does not differ across these phases of the menstrual cycle. However, future research is needed to directly assess the relationship between affective modulation of pain/nociception and inter- and intra-individual differences in ovarian hormones and to extend these findings to women who suffer from menstrual cycle-related pain (e.g., premenstrual dysphoric disorder, fibromyalgia).     

Pathophysiology of Medication Overuse Headache—An Update

The pathogenesis of medication overuse headache is unclear. Clinical and preclinical studies have consistently demonstrated increased excitability of neurons in the cerebral cortex and trigeminal system after medication overuse. Cortical hyperexcitability may facilitate the development of cortical spreading depression, while increased excitability of trigeminal neurons may facilitate the process of peripheral and central sensitization. These changes may be secondary to the derangement of central, probably serotonin (5‐HT)‐, and perhaps endocannabinoid‐dependent or other, modulating systems. Increased expression of excitatory cortical 5‐HT_2A receptors may increase the susceptibility to developing cortical spreading depression, an analog of migraine aura. A reduction of diffuse noxious inhibitory controls may facilitate the process of central sensitization, activate the nociceptive facilitating system, or promote similar molecular mechanisms to those involved in kindling. Low 5‐HT levels also increase the expression and release of calcitonin gene‐related peptide from the trigeminal ganglion and sensitize trigeminal nociceptors. Thus, derangement of central modulation of the trigeminal system as a result of chronic medication use may increase sensitivity to pain perception and foster or reinforce medication overuse headache.     

Does Pain Catastrophizing Moderate the Relationship Between Spinal Nociceptive Processes and Pain Sensitivity?

Existing evidence indicates that pain catastrophizing is associated with enhanced pain reports and lower pain threshold/tolerance levels, but is not significantly related to nociceptive flexion reflex (NFR) threshold in healthy and clinical pain samples. This suggests pain catastrophizing may modulate pain threshold at a supraspinal level without influencing descending modulation of spinal nociceptive inputs. To examine this issue further, the present study assessed NFR threshold, electrocutaneous pain threshold, and electrocutaneous pain tolerance, as well as subjective ratings of noxious stimuli in a sample of 105 healthy adults. Pain catastrophizing was assessed prior to testing using traditional instructions and after pain testing with instructions to report on cognitions during testing (situation-specific catastrophizing). As expected, NFR threshold was correlated with pain sensitivity measures, but uncorrelated with both measures of catastrophizing. Although situation-specific catastrophizing was correlated with some pain outcomes, neither catastrophizing measure (traditional or situation specific) moderated the relationship between NFR and pain sensitivity. These findings confirm and extend existing evidence that catastrophizing influences pain reports through supraspinal mechanisms (eg, memory, report bias, attention) without altering transmission of spinal nociceptive signals.PerspectiveAssessing catastrophic thoughts related to a specific painful event (situation-specific catastrophizing) provides important additional information regarding the negative cognitions that influence pain-related processes. However, neither situation-specific nor traditionally measured pain catastrophizing appear to enhance pain by engaging descending controls to influence spinal nociceptive processes.     

Inhibitory effects do not depend on the subjective experience of pain during heterotopic noxious conditioning stimulation (HNCS): a contribution to the psychophysics of pain inhibition.

Heterotopic noxious conditioning stimulation (HNCS) has been thought to give access to the diffuse noxious inhibitory controls (DNIC) in man, which can be activated in wide-dynamic-range neurons by noxious stimulation from remote areas of the body and form the neurophysiological basis of the phenomenon 'pain inhibits pain'. The latter phenomenon suggests that the subjective experience of pain is a prerequisite for an inhibitory action. The necessity of using painful stimuli as conditioning and as test stimuli to produce inhibitory effects was investigated in the present study, using a HNCS paradigm. Twenty young men received conditioning stimuli created by tonic heat at painful and non-painful levels, using either hot water (hand) or thermode (forearm). The test stimuli were phasic heat stimuli (thermode) at painful and non-painful levels applied to the cheek. Only painful but not non-painful heat as conditioning stimulus increased the heat pain threshold and decreased the ability to discriminate between painful heat of different intensities. These two findings are in accord with an inhibitory effect depending on a painful conditioning stimulus. However, the intensity ratings of the test stimuli indicated inhibitory effects of the conditioning stimuli also upon non-painful levels. Furthermore, non-painful heat as conditioning stimulus also appeared to be capable of decreasing the ratings of the test stimuli at painful levels. The latter two findings suggest: (i) that very strong but subjectively still non-painful stimulation can trigger pain inhibitory effects and (ii) that also subjectively non-painful stimuli are affected by inhibitory influences during HNCS.     

Effects of odors on pain perception: deciphering the roles of emotion and attention

Emotions have been shown to alter pain perception, but the underlying mechanism is unclear since emotions also affect attention, which itself changes nociceptive transmission. We manipulated independently direction of attention and emotional state, using tasks involving heat pain and pleasant and unpleasant odors. Shifts in attention between the thermal and olfactory modalities did not alter mood or anxiety. Yet, when subjects focused attention on the pain, they perceived it as clearly more intense and somewhat more unpleasant than when they attended to the odor. In contrast, odor valence altered mood, anxiety level, and pain unpleasantness, but did not change the perception of pain intensity. Pain unpleasantness ratings correlated with mood, but not with odor valence, suggesting that emotional changes underlie the selective modulation of pain affect. These results show that emotion and attention differentially alter pain perception and thus invoke at least partially separable neural modulatory circuits.     

Central mechanisms in pain.

Nociceptive input into the central nervous system is not simply passively received but rather is subject to modulation through spinal cord neuroplasticity and descending influences from supraspinal sites activated by a variety of environmental signals, including the acute or persistent nociceptive input itself and behavioral and emotional stimuli. The significant role of NMDA receptors and production of NO. in central sensitization, hyperalgesia, and chronic pain has been demonstrated in numerous models of peripheral injury. It has been shown that persistent nociceptive input is also subject to centrifugal descending modulation through activation of both prominent facilitatory and masked inhibitory influences from supraspinal sites (e.g., RVM) likely involving a spino-bulbar-spinal loop. These descending modulatory influences from the RVM appear to contribute selectively to hyperalgesia observed in uninjured tissue, distant from the site of insult (secondary hyperalgesia), and involve mechanisms similar to those found in the spinal cord (i.e., NMDA receptors and production of NO.). The significant role that modulatory influences in the central nervous system have in the development and maintenance of chronic pain and hyperalgesia clearly supports continued investigation into the physiologic mechanisms contributing to these events.