Age-related differences in functional connectivity associated with pain modulation.

Growing evidence suggests that aging is associated with impaired endogenous pain modulation, and that this likely underlies the increased transition from acute to chronic pain in older individuals. Resting-state functional connectivity (rsFC) offers a valuable tool to examine the neural mechanisms behind these age-related changes in pain modulation. RsFC studies generally observe decreased within-network connectivity due to aging, but its relevance for pain modulation remains unknown. We compared rsFC within a set of brain regions involved in pain modulation between young and older adults and explored the relationship with the efficacy of distraction from pain. This revealed several age-related increases and decreases in connectivity strength. Importantly, we found a significant association between lower pain relief and decreased strength of three connections in older adults, namely between the periaqueductal gray and right insula, between the anterior cingulate cortex (ACC) and right insula, and between the ACC and left amygdala. These findings suggest that the functional integrity of the pain control system is critical for effective pain modulation, and that its function is compromised by aging.

Baseline heart rate variability predicts placebo hypoalgesia in men, but not women.

Introduction: Placebo hypoalgesic effects vary greatly across individuals, making them challenging to control for in clinical trials and difficult to use in treatment. We investigated the potential of resting vagally-mediated heart rate variability (vmHRV) to help predict the magnitude of placebo responsiveness. Methods: In two independent studies (total N = 77), we administered a placebo paradigm after measuring baseline HRV. In Study I, we delivered heat pain to the forearm, on skin patches treated with "real" and "control" cream (identical inactive creams). In Study II, electrical pulses to the forearm were modulated by sham transcutaneous electrical nerve stimulation. We combined data from both studies to evaluate the relationship between vagally-mediated HRV (vmHRV) parameters and the placebo response size, while also assessing sex differences in this relationship. Results and Discussion: This revealed a positive association between vmHRV and the degree of pain relief, and this effect was driven by men. These results not only reveal new insights into the (sex-specific) mechanisms of placebo hypoalgesia, but also suggest that measuring vmHRV may be helpful in predicting placebo responsiveness. Given that placebo hypoalgesic effects contribute substantially to treatment outcomes, such a non-invasive and easily obtained predictor would be valuable in the context of personalized medicine.

Pain and related suffering reduce attention toward others.

BACKGROUND: It has been proposed that the expression of pain-related suffering may lead to an enhanced focus on oneself and reduced attention toward the external world. This study aimed at investigating whether experimentally induced painrelated suffering may lead persons to withdraw into themselves, causing a reduced focus on external stimuli as reflected by impaired performance in a facial recognition task and heightened perception of internal stimuli measured by interoceptive awareness. METHODS: Thirty-two participants had to recognize different emotional facial expressions (neutral, sad, angry, happy), or neutral geometrical figures under conditions of no pain, low, and high prolonged pain intensities. Interoceptive accuracy was measured using a heartbeat-detection task prior to and following the pain protocol. RESULTS: Males but not females were slower to recognize facial expressions under the condition of high painful stimulation compared to the condition of no pain. In both, male and female participants, the difficulty in recognizing another person's emotions from a facial expression was directly related to the level of suffering and unpleasantness experienced during pain. Interoceptive accuracy was higher after the pain experiment. However, neither the initial interoceptive accuracy nor the change were significantly related to the pain ratings. CONCLUSIONS: Our results suggest that long-lasting and intense painful stimuli, which induce suffering, lead to attentional shifts leading to withdrawal from others. These findings contribute to a better understanding of the social dynamics of pain and pain-related suffering.

Better Executive Functions Are Associated With More Efficient Cognitive Pain Modulation in Older Adults: An fMRI Study.

Growing evidence suggests that aging is associated with less efficient endogenous pain modulation as demonstrated by reduced conditioned pain modulation, and that these changes may be mediated by differences in frontal functioning. Yet, little is known about potential age-related changes in cognitive pain modulation, such as distraction from pain. In a first session, 30 healthy young (19-35 years) and 30 healthy older (59-82 years) adults completed a battery of neuropsychological tests. In a second session, we acquired functional brain images while participants completed a working memory task with two levels of cognitive load (high vs. low) and concurrently received individually adjusted heat stimuli (warm vs. painful). In both age groups, completing the high load task was associated with a significant reduction in the perceived intensity and unpleasantness of painful stimuli and a reduction in activation of brain regions involved in pain processing. Group comparisons revealed that young adults showed a stronger de-activation of brain regions involved in pain processing during the high load vs. the low load task, such as the right insula, right mid cingulate cortex and left supramarginal gyrus, compared to older adults. Older adults, on the other hand, showed an increased activation in the anterior cingulate cortex during the high load vs. low load task, when compared to young adults. Covariate analyses indicated that executive functions significantly predicted neural pain modulation in older adults: Better executive functions were associated with a more pronounced de-activation of the insula, thalamus and primary somatosensory cortex and increased activation of prefrontal regions during the high vs. low load task. These findings suggest that cognitive pain modulation is altered in older age and that the preservation of executive functions may have beneficial effects on the efficacy of distraction from pain.

Anterior Cingulate Cortex Activity During Rest Is Related to Alterations in Pain Perception in Aging.

Alterations in the affective component of pain perception are related to the development of chronic pain and may contribute to the increased vulnerability to pain observed in aging. The present study analyzed age-related changes in resting-state brain activity and their possible relation to an increased pain perception in older adults. For this purpose, we compared EEG current source density and fMRI functional-connectivity at rest in older (n = 20, 66.21 ± 3.08 years) and younger adults (n = 21, 20.71 ± 2.30 years) and correlated those brain activity parameters with pain intensity and unpleasantness ratings elicited by painful stimulation. We found an age-related increase in beta2 and beta3 activity in temporal, frontal, and limbic areas, and a decrease in alpha activity in frontal areas. Moreover, older participants displayed increased functional connectivity in the anterior cingulate cortex (ACC) and the insula with precentral and postcentral gyrus. Finally, ACC beta3 activity was positively correlated with pain intensity and unpleasantness ratings in older, and ACC-precentral/postcentral gyrus connectivity was positively correlated with unpleasantness ratings in older and younger participants. These results reveal that ACC resting-state hyperactivity is a stable trait of brain aging and may underlie their characteristic altered pain perception.

Intact pain modulation through manipulation of controllability and expectations in aging.

BACKGROUND: Pain expectation and controllability can modulate pain processing. However, little is known about age-related effects on these cognitive factors involved in pain control. This study assessed age-related brain changes associated with pain expectation and controllability. METHODS: 17 healthy older adults (9 men; 65.65 ± 4.34 years) and 18 healthy younger adults (8 men; 20.56 ± 5.56 years) participated in the study. Pain evoked potentials and pain ratings were recorded while participants received painful electrical stimuli under two different conditions of pain controllability over the intensity of the stimulation (self-controlled vs. computer controlled) and two conditions of pain expectations (high vs. low pain). RESULTS: Although the intensity of the painful stimulation was kept constant, all participants showed reduced pain perception in the controllable and low pain expectancy conditions. However, older participants showed reduced amplitudes of pain evoked potentials in the time window between 150 and 500 ms after stimulus onset as compared to younger participants. Moreover, younger participants showed greater negative amplitudes from 80 to 150 ms after stimulus onset for uncontrollable versus controllable pain. CONCLUSIONS: These results suggest that although cognitive pain modulation is preserved during ageing, neural processing of pain is reduced in older adults. SIGNIFICANCE: This research describes the impact of age on cognitive pain modulation evoked by the manipulation of pain controllability and pain expectations. Our findings constitute a first step in the understanding of the greater vulnerability of older individuals to chronic pain. Moreover, we show that older adults can benefit from cognitive pain control mechanisms to increase the efficacy of pain treatments.

Alterations in Neural Responses and Pain Perception in Older Adults During Distraction.

OBJECTIVE: Although it is acknowledged that pain may be modulated by cognitive factors, little is known about the effect of aging on these control processes. The present study investigated electroencephalographical correlates of pain processing and its cognitive modulation in healthy older individuals. METHODS: For this purpose, the impact of distraction on pain was evaluated in 21 young (9 men; 20.71 [2.30]) and 20 older (10 men; 66.80 [4.14]) adults. Participants received individually adjusted electrical pain stimuli in a high-distraction condition (one-back task) and in a low-distraction condition (simple letter response task). Pain-related evoked potentials and pain ratings were analyzed. RESULTS: Both groups rated pain as less intense (F(1,39) = 13.954, p < .001) and less unpleasant (F(1,39) = 10.111, p = .003) when it was experienced during the high- rather than the low-distraction condition. However, in comparison to younger participants, older adults gave higher unpleasantness ratings to painful stimulation (F(1,39) = 4.233, p = .046), accompanied by attenuated neural responses (N1-P1 and P3 amplitudes), regardless of the distraction condition (F(1,38) = 6.028 [p = .019] and F(1,38) = 6.669 [p = .014], respectively). CONCLUSIONS: Older participants felt pain relief through distraction, like younger participants. However, we also found that aging may enhance affective aspects of pain perception. Finally, our results show that aging is characterized by reduced neural processing of painful stimuli. This phenomenon could be related to the increased vulnerability of older participants to develop chronic pain.

Distraction from pain: The role of selective attention and pain catastrophizing.

BACKGROUND: Previous research has demonstrated the efficacy of cognitive engagement in reducing concurrent pain. However, little is known about the role of individual differences in inhibitory control abilities and negative pain-related cognitions in modulating the magnitude of this type of distraction from pain. METHODS: In a pain distraction paradigm, 41 participants completed a working memory task with both a demanding high load condition (2-back) and an easy low load condition (0-back), while receiving warm or painful thermal stimuli to their left forearm. To control for individual differences in sensitivity to pain and perceived task difficulty, nociceptive stimulus intensity and task speed were individually calibrated. Additionally, participants completed a set of cognitive inhibition tasks (flanker, go/nogo, Stroop) and questionnaires about negative pain-related cognitions (fear of pain, pain catastrophizing) prior to the distraction paradigm. RESULTS: As expected, engaging in the high load condition significantly reduced perceived intensity and unpleasantness of nociceptive stimuli, compared to the low load condition. The size of the distraction effect correlated significantly with better cognitive inhibition and selective attention abilities, as measured by the flanker task. A moderation analysis revealed a significant interaction between pain catastrophizing and performance in the flanker task in predicting the distraction effect size: Participants who performed well on the flanker task showed more pain reduction, but only when they were average to high pain catastrophizers. CONCLUSIONS: Selective attention abilities and pain catastrophizing seem to be important factors in explaining individual differences in the size of the analgesic response to a distractive task. SIGNIFICANCE: Understanding which factors influence the effectiveness of cognitive engagement in distracting from pain could help to optimize its therapeutic application in patient care. This study shows that a complex interplay of cognitive inhibition abilities, specifically selective attention, and negative pain-related cognitions, such as pain catastrophizing, modulate the magnitude of the distraction effect.

Age-Related Changes in Pain Perception Are Associated With Altered Functional Connectivity During Resting State.

Aging affects pain experience and brain functioning. However, how aging leads to changes in pain perception and brain functional connectivity has not yet been completely understood. To investigate resting-state and pain perception changes in old and young participants, this study employed region of interest (ROI) to ROI resting-state functional connectivity (rsFC) analysis of imaging data by using regions implicated in sensory and affective dimensions of pain, descending pain modulation, and the default-mode networks (DMNs). Thirty-seven older (66.86 ± 4.04 years; 16 males) and 38 younger healthy participants (20.74 ± 4.15 years; 19 males) underwent 10 min' eyes-closed resting-state scanning. We examined the relationship between rsFC parameters with pressure pain thresholds. Older participants showed higher pain thresholds than younger. Regarding rsFC, older adults displayed increased connectivity of pain-related sensory brain regions in comparison to younger participants: increased rsFC between bilateral primary somatosensory area (SI) and anterior cingulate cortex (ACC), and between SI(L) and secondary somatosensory area (SII)-(R) and dorsolateral prefrontal cortex (PFC). Moreover, decreased connectivity in the older compared to the younger group was found among descending pain modulatory regions: between the amygdala(R) and bilateral insula(R), thalamus(R), ACC, and amygdala(L); between the amygdala(L) and insula(R) and bilateral thalamus; between ACC and bilateral insula, and between periaqueductal gray (PAG) and bilateral thalamus. Regarding the DMN, the posterior parietal cortex and lateral parietal (LP; R) were more strongly connected in the older group than in the younger group. Correlational analyses also showed that SI(L)-SII(R) rsFC was positively associated with pressure pain thresholds in older participants. In conclusion, these findings suggest a compensatory mechanism for the sensory changes that typically accompanies aging. Furthermore, older participants showed reduced functional connectivity between key nodes of the descending pain inhibitory pathway.

Psychological, cognitive factors and contextual influences in pain and pain-related suffering as revealed by a combined qualitative and quantitative assessment approach.

Previous psychophysiological research suggests that pain measurement needs to go beyond the assessment of Pain Intensity and Unpleasantness by adding the evaluation of Pain-Related Suffering. Based on this three-dimensional approach, we attempted to elucidate who is more likely to suffer by identifying reasons that may lead individuals to report Pain and Pain-Related Suffering more than others. A sample of 24 healthy participants (age range 18-33) underwent four different sessions involving the evaluation of experimentally induced phasic and tonic pain. We applied two decision tree models to identify variables (selected from psychological questionnaires regarding pain and descriptors from post-session interviews) that provided a qualitative characterization of the degrees of Pain Intensity, Unpleasantness and Suffering and assessed the respective impact of contextual influences. The overall classification accuracy of the decision trees was 75% for Intensity, 77% for Unpleasantness and 78% for Pain-Related Suffering. The reporting of suffering was predominantly associated with fear of pain and active cognitive coping strategies, pain intensity with bodily competence conveying strength and resistance and unpleasantness with the degree of fear of pain and catastrophizing. These results indicate that the appraisal of the three pain dimensions was largely determined by stable psychological constructs. They also suggest that individuals manifesting higher active coping strategies may suffer less despite enhanced pain and those who fear pain may suffer even under low pain. The second decision tree model revealed that suffering did not depend on pain alone, but that the complex rating-related decision making can be shifted by situational factors (context, emotional and cognitive). The impact of coping and fear of pain on individual Pain-Related Suffering may highlight the importance of improving cognitive coping strategies in clinical settings.

The combination of postnatal maternal separation and social stress in young adulthood does not lead to enhanced inflammatory pain sensitivity and depression-related behavior in rats.

The cumulative and match/mismatch hypotheses of stress are still under discussion regarding the effects of early life stress (ELS) on the vulnerability or resilience to psychopathology. In this context, an additional stress in later life (second hit) often leads to stress-related disorders that frequently include comorbid pain states. We previously observed that maternal separation (MS), a model of ELS, reduces vulnerability to neuropathic and inflammatory pain in rats. In the present study, we investigated the effects of an additional later stressor on the vulnerability to inflammatory pain. Sprague Dawley pups were divided into 4 groups: controls (CON, no stress), MS, social stress (SS) and MS+SS. At young adult age (from 7 to 15 weeks), stress- as well as pain-related parameters were evaluated prior and during 21 days following the induction of paw inflammation with complete Freund's adjuvant (CFA). Finally spinal glutamatergic transmission, immunocompetent cells, pro-inflammatory cytokines and growth factors were examined using qPCR. None of the stress conditions had a significant impact on corticosterone levels and anhedonia. In the forced swim test, MS and SS displayed increased passive coping whereas the combination of both stressors revoked this effect. The different stress conditions had no influence on basal mechanical thresholds and heat sensitivity. At 4 days post-inflammation all stress groups displayed lower mechanical thresholds than CON but the respective values were comparable at 7, 10, and 14 days. Only on day 21, MS rats were more sensitive to mechanical stimulation compared to the other groups. Regarding noxious heat sensitivity, MS+SS animals were significantly less sensitive than CON at 10 and 21 days after CFA-injection. qPCR results were mitigated. Despite the finding that stress conditions differentially affected different players of glutamatergic transmission, astrocyte activity and NGF expression, our biochemical results could not readily be related to the behavioral observations, precluding a congruent conclusion. The present results do neither confirm the cumulative nor corroborate or disprove the match/mismatch hypothesis.

Neonatal maternal separation leads to a dampening of inflammation-related mechanical and thermal hypersensitivity in juvenile rats.

Early life stress (ELS) constitutes a risk factor for the later development of psychopathological disorders partly displaying pain comorbidity. Since ELS may hence be expected to have an impact on pain processing the present study investigates whether ELS could be a factor of vulnerability or resilience against an enhancement of noxious sensitivity in the framework of inflammatory pain in later life. Rats were exposed to the maternal separation (MS) paradigm, an established ELS model. At adulthood, corticosterone levels and anxiety-related behaviors were evaluated. Subsequently, paw edema, noxious mechanical and thermal sensitivity were measured prior and during an inflammation induced by intraplantar injection of Complete Freunds Adjuvant (CFA). The open field test and the corticosterone measures showed no effect of MS. MS did not change mechanical thresholds prior to inflammation but reduced mechanical hyperalgesia after CFA-injection. MS animals did however present shorter latencies to display nocifensive behaviors compared to controls (CON). Furthermore, in CON but not MS, the repetitive noxious heat testing induced a decrease in reaction latencies. Moreover, MS dampened CFA-induced heat hyperalgesia. Altogether, our results suggest that ELS may have a protective impact on inflammatory pain.

Impact of controllability on pain and suffering.

INTRODUCTION: Chronic pain and pain-related suffering are major health problems. The lack of controllability of experienced pain seems to greatly contribute to the extent of suffering. This study examined how controllability affects the perception of pain and pain-related suffering, and the modulation of this effect by beliefs and emotions such as locus of control of reinforcement, pain catastrophizing, and fear of pain. METHODS: Twenty-six healthy subjects received painful electric stimulation in both controllable and uncontrollable conditions. Visual analogue scales and the "Pictorial Representation of Illness and Self Measure" were used to assess pain intensity, unpleasantness, pain-related suffering, and the level of perceived control. We also investigated nonverbal indicators of pain and suffering such as heart rate, skin conductance, and corrugator electromyogram. RESULTS: Controllability selectively reduced the experience of pain-related suffering, but did not affect pain intensity or pain unpleasantness. This effect was modulated by chance locus of control but was unrelated to fear of pain or catastrophizing. Physiological responses were not affected by controllability. In a second sample of 25 participants, we varied the instruction. The effect of controllability on pain-related suffering was only present when instructions focused on the person being able to stop the pain. DISCUSSION: Our data suggest that the additional measure of pain-related suffering may be important in the assessment of pain and may be more susceptible to the effects of perceived control than pain intensity and unpleasantness. We also show that this effect depends on personal involvement.

Maternal separation stress leads to resilience against neuropathic pain in adulthood.

Early life stress (ELS) leads to a permanent reprogramming of biochemical stress response cascades that may also be relevant for the processing of chronic pain states such as neuropathy. Despite clinical evidence, little is known about ELS-related vulnerability for neuropathic pain and the possibly underlying etiology. In the framework of experimental studies aimed at investigating the respective relationships we used the established ELS model of maternal separation (MS). Rat dams and neonates were separated for 3 h/day from post-natal day 2-12. At adulthood, noxious mechanical and thermal thresholds were assessed before and during induction of neuropathic pain by chronic constriction injury (CCI). The potential involvement of spinal glutamatergic transmission, glial cells, pro-inflammatory cytokines and growth factors was studied by using qPCR. MS per se did not modify pain thresholds. But, when exposed to neuropathic pain, MS rats exhibited a marked reduction of thermal sensitivity and a delayed development of mechanical allodynia/hyperalgesia when compared to control animals. Also, MS did not alter glucocorticoid receptor mRNA levels, but prevented the CCI-induced down-regulation of NR1 and NR2 sub-units of the NMDA receptor and of the glutamate transporter EAAT3 as observed at 21 days post-surgery. Additionally, CCI-provoked up-regulation of glial cell markers was either prevented (GFAP for astrocytes) or dampened (Iba1 for microglia) by MS. Pro-inflammatory cytokine mRNA expression was either not affected (IL-6) or reduced (IL-1ß) by MS shortly after CCI. The growth factors GDNF and NGF were only slightly downregulated 4 days after CCI in the MS-treated animals. The changes in glutamatergic signaling, astroglial and cytokine activation as well as neurotrophin expression could, to some extent, explain these changes in pain behavior. Taken together, the results obtained in the described experimental conditions support the mismatch theory of chronic stress where an early life stress, rather than predisposing individuals to certain pathologies, renders them resilient.

Chronic Social Stress Time-Dependently Affects Neuropathic Pain-Related Cold Allodynia and Leads to Altered Expression of Spinal Biochemical Mediators.

Clinical data have shown that chronic exposure to stress may be accompanied by an enhancement of inflammation-related pain sensitivity. In this context, little is however known on the impact of stress on neuropathic pain. In the present study we addressed this issue by combining the chronic constriction injury (CCI) model with an ongoing social stress (OSS) paradigm. Cold plate and von Frey tests were performed in 48 rats divided into four groups: OSS exposed to OSS, CCI subjected to chronic nerve constriction, OSS+CCI with a combination of neuropathy and stress and CON, a control group lacking any manipulation. While we did not observe any stress-related differences in mechanical sensitivity throughout the observation period, CCI rats were more sensitive to cold stimulation than OSS+CCI in the initial phase of neuropathy. A switch was observed at a later stage, leading to a hypersensitivity of the OSS+CCI compared to the CCI rats. At this time point we investigated the spinal mRNA expression of neuron and glia related molecules potentially involved in neuropathic pain and stress. The combination of psychosocial stress and neuropathic pain seemed to enhance glial cell activation, pro-inflammatory cytokine and neurotrophic factor mRNA levels, rather than glutamatergic transmission. Our data show that long lasting social stress may lead to time-dependent alteration of neuropathy-related cold pain sensitivity while mechanically-induced pain remains unchanged.

The role of cognitive reappraisal in placebo analgesia: an fMRI study.

Placebo analgesia (PA) depends crucially on the prefrontal cortex (PFC), which is assumed to be responsible for initiating the analgesic response. Surprisingly little research has focused on the psychological mechanisms mediated by the PFC and underlying PA. One increasingly accepted theory is that cognitive reappraisal-the reinterpretation of the meaning of adverse events-plays an important role, but no study has yet addressed the possible functional relationship with PA. We studied the influence of individual differences in reappraisal ability on PA and its prefrontal mediation. Participants completed a cognitive reappraisal ability task, which compared negative affect evoked by pictures in a reappraise versus a control condition. In a subsequent fMRI session, PA was induced using thermal noxious stimuli and an inert skin cream. We found a region in the left dorsolateral PFC, which showed a positive correlation between placebo-induced activation and (i) the reduction in participants' pain intensity ratings; and (ii) cognitive reappraisal ability scores. Moreover, this region showed increased placebo-induced functional connectivity with the periaqueductal grey, indicating its involvement in descending nociceptive control. These initial findings thus suggest that cognitive reappraisal mechanisms mediated by the dorsolateral PFC may play a role in initiating pain inhibition in PA.

Peripheral and central alterations affecting spinal nociceptive processing and pain at adulthood in rats exposed to neonatal maternal deprivation.

The nociceptive system of rodents is not fully developed and functional at birth. Specifically, C fibers transmitting peripheral nociceptive information establish synaptic connections in the spinal cord already during the embryonic period that only become fully functional after birth. Here, we studied the consequences of neonatal maternal deprivation (NMD, 3 h/day, P2-P12) on the functional establishment of C fiber-mediated neurotransmission in spinal cord and of pain-related behavior. In vivo recording revealed that C fiber-mediated excitation of spinal cord neurons could be observed at P14 only in control but not in NMD rats. NMD was associated with a strong alteration in the expression of growth factors controlling C nociceptor maturation as well as two-pore domain K+ channels known to set nociceptive thresholds. In good agreement, C-type sensory neurons from NMD animals appeared to be hypoexcitable but functionally connected to spinal neurons, especially those expressing TRPV1 receptors. In vivo and in vitro recordings of lamina II spinal neurons at P14 revealed that the NMD-related lack of C fiber-evoked responses resulted from an inhibitory barrage in the spinal cord dorsal horn. Eventually, C-type sensory-spinal processing could be recovered after a delay of about 10 days in NMD animals. However, animals remained hypersensitive to noxious stimulus up to P100 and this might be due to an excessive expression of Nav1.8 transcripts in DRG neurons. Together, our data provide evidence for a deleterious impact of perinatal stress exposure on the maturation of the sensory-spinal nociceptive system that may contribute to the nociceptive hypersensitivity in early adulthood.

Blood pressure and the perception of illusive pain.

Numerous studies have documented an inverse relationship between blood pressure and sensitivity to experimental nociceptive stimulation. The present study aimed to investigate possible associations between blood pressure and the occurrence and intensity of paradoxical pain induced by the thermal grill paradigm. Thirty-one healthy subjects were stimulated three times for 1 min with the nonnoxious temperatures of 15°C and 41°C set at the interlaced cold and warm bars of a water bath-driven thermal grill. Blood pressure and heart rate were recorded concomitantly. On account of previous observations of an association between the sensitivity of the cardiac baroreflex and pain perception, this parameter was additionally obtained. Numerical rating scales were used to quantify subjective pain intensity and pain unpleasantness; subjects were classified as responders and nonresponders to thermal grill stimulation based on pain intensity ratings. Responders exhibited lower systolic and diastolic blood pressure than nonresponders, and inverse linear associations arose between blood pressure and pain intensity and unpleasantness. Baroreflex sensitivity was unrelated to pain ratings. The findings confirmed the hypothesis of a blood pressure dependence of paradoxical pain and support the notion that the cardiovascular and pain regulatory systems interact not only in the processing of pain elicited by noxious input, but also in nonnoxiously generated illusive pain. While this finding is not consistent with the assumption of an involvement of the baroreflex system in mediating the observed interaction, psychological traits and neurochemical factors are alternatively considered.

Corticosterone analgesia is mediated by the spinal production of neuroactive metabolites that enhance GABAergic inhibitory transmission on dorsal horn rat neurons.

Corticosterone (CORT) is a glucocorticoid produced by adrenal glands under the control of the hypothalamic-pituitary-adrenal axis. Circulating CORT can enter the central nervous system and be reduced to neuroactive 3α5α-reduced steroids, which modulate GABAA receptors. In the dorsal spinal cord, GABAergic transmission modulates integration of nociceptive information. It has been shown that enhancing spinal inhibitory transmission alleviates hyperalgesia and allodynia. Therefore, the spinal neuronal network is a pivotal target to counteract pain symptoms. Thus, any increase in spinal 3α5α-reduced steroid production enhancing GABAergic inhibition should reduce nociceptive message integration and the pain response. Previously, it has been shown that high levels of plasma glucocorticoids give rise to analgesia. However, to our knowledge, nothing has been reported regarding direct non-genomic modulation of neuronal spinal activity by peripheral CORT. In the present study, we used combined in vivo and in vitro electrophysiology approaches, associated with measurement of nociceptive mechanical sensitivity and plasma CORT level measurement, to assess the impact of circulating CORT on rat nociception. We showed that CORT plasma level elevation produced analgesia via a reduction in C-fiber-mediated spinal responses. In the spine, CORT is reduced to the neuroactive metabolite allotetrahydrodeoxycorticosterone, which specifically enhances lamina II GABAergic synaptic transmission. The main consequence is a reduction in lamina II network excitability, reflecting a selective decrease in the processing of nociceptive inputs. The depressed neuronal activity at the spinal level then, in turn, leads to weaker nociceptive message transmission to supraspinal structures and hence to alleviation of pain.

Plasma glucocorticoids differentially modulate phasic and tonic GABA inhibition during early postnatal development in rat spinal lamina II.

Nociceptive processing is tuned by GABAA receptor-mediated inhibition in the spinal cord dorsal horn that undergoes postnatal maturation in rodents. These GABAergic inhibitory postsynaptic currents (IPSCs) are modulated by 3α5α-reduced steroids during early postnatal development in spinal cord lamina II. Thus an enhanced phasic inhibition is present in neonates and decreases over time. GABA can also activate extrasynaptic receptors, giving rise to tonic inhibition. In this study, we characterized the contribution of plasma corticosterone (CORT) to postnatal maturation of spinal phasic and, for the first time, tonic GABAergic inhibitions. We used Fisher and Lewis rat strains displaying respectively high and low hypothalamic-pituitary-adrenal axis reactivity, compared to control Sprague-Dawley rats. Measured plasma CORT levels were significantly higher in Fisher rats, which also displayed significantly higher mechanical nociceptive thresholds, supporting the hypothesis of an antinociceptive action of CORT. Recorded GABAA IPSCs shortened during maturation in all strains while remaining larger in Fisher rats. Blocking the 5α-reduction of steroids in Fisher rats produced a further decrease of IPSC deactivation time constant. In contrast, GABAA tonic inhibition progressively increased during maturation, without any difference among strains. In conclusion, we show that both phasic and tonic GABAergic inhibitions undergo postnatal maturation in lamina II. Moreover spinal production of 3α5α-reduced steroids that presumably derive from plasma CORT is correlated to spinal GABAA phasic (but not tonic) inhibition and to mechanical nociceptive thresholds.