Differences In Pain Sensitivity Research Articles

Sex differences in perceived pain are affected by an anxious brain

Decades of research confirm that women have greater pain sensitivity than men. Women also show greater overall anxiety sensitivity than men. Given these differences, we hypothesized that sex differences in anxiety would explain sex differences in experienced pain and physiological responses to pain (at both spinal and cortical levels). By measuring subjective pain, state/trait anxiety, nociceptive flexion reflexes, and somatosensory evoked potentials (SEPs), it was possible to test the effects of anxiety on the processing of painful drives at different levels of the neuraxis while also documenting the role played by anxiety on sex differences in experienced pain. Results confirm that women are indeed more sensitive to pain than men. Importantly, this difference was accompanied by a significant sex difference in cortical activity (SEP amplitude) but not spinal nociceptive activity, suggesting that much of the sex difference in experienced pain is attributable to variations in thalamocortical processing and to ensuing changes in the appraisal of and/or emotional response to noxious insult. In support of this claim, we found that sex differences in cortical activity and subjective pain disappeared when trait anxiety was controlled for. This means that stable predispositions to respond with heightened apprehension contribute to baseline pain sensitivity differences between the sexes. These results indicate that the modulatory effect of affect on pain-related brain processes may explain why men and women experience painful shocks so differently. In our study, the mediating role of anxiety on sex differences in pain was tested and confirmed using path analysis.

Differential startle magnitude in mice selected for high and low swim analgesia is not related to difference in nociception.

The acoustic startle response (ASR) elicited by 110 dB 10-ms pulses was studied in relation to pain sensitivity in mouse lines selectively bred for high (HA) and for low (LA) swim analgesia. The magnitudes of ASR, similarly as hot-plate latencies, differed between the lines in the rank order HA is greater than unselected controls (C) greater than LA. The animals' nociception did not change after the ASR session consisting of a sequence of 20 acoustic stimuli. Morphine hydrochloride (5 and 10 mg per kg i.p.) increased hot-plate latencies in the order of HA greater than C greater than LA, and was not effective on ASR magnitude in HA as well as in C mice. In the LA line, 10 mg per kg of morphine slightly attenuated ASR, but caused only a little analgesia. We conclude that (1) the difference in ASR between the selected lines is inversely correlated with the difference in pain sensitivity; (2) the magnitude of ASR is not altered by morphine analgesia; (3) the procedure of ASR using brief acoustic pulses is not stressful enough to elicit a form of stress analgesia. The lack of a direct relationship between the readiness to startle and pain sensation may be beneficial for an animal's survival in dangerous situations. It is beneficial when the startle to a warning signal precedes defensive behaviors and it often must be effectuated in a state of decreased nociception.

Individual Differences in the Subjective Experience of Pain: New Insights Into Mechanisms and Models

Individual differences in pain sensitivity have long remained a perplexing and challenging clinical problem. How can one individual have a sensory experience that is vastly different than that of another, even when they have received similar sensory input? Developing an understanding of such differences and the mechanisms that support them has progressed substantially as psychophysical findings are integrated with measures of brain activation provided by functional brain imaging techniques. Continued delineation of these mechanisms will contribute substantially to the development of combined psychophysical/psychological models that can be used to optimize pain treatment on an individual-by-individual basis.

Isolated and combined effects of electroacupuncture and meditation in reducing experimentally induced ischemic pain: a pilot study.

Acupuncture and meditation are promising treatment options for clinical pain. However, studies investigating the effects of these methods on experimental pain conditions are equivocal. Here, the effects of electroacupuncture (EA) and meditation on the submaximum effort tourniquet technique (SETT), a well-established, opiate-sensitive pain paradigm in experimental placebo research were studied. Ten experienced meditators (6 male subjects) and 13 nonmeditators (6 male subjects) were subjected to SETT (250 mmHG) on one baseline (SETT only) and two treatment days (additional EA contralaterally to the SETT, either at the leg on ST36 and LV3 or at the arm on LI4 and LI10 in randomized order). Numeric Rating Scale (NRS) ratings (scale 0–10) were recorded every 3 min. During baseline, meditation induced significantly greater pain tolerance in meditators when compared with the control group. Both the EA conditions significantly increased pain tolerance and reduced pain ratings in controls. Furthermore, EA diminished the group difference in pain sensitivity, indicating that meditators had no additional benefit from acupuncture. The data suggest that EA as a presumable bottom-up process may be as effective as meditation in controlling experimental SETT pain. However, no combined effect of both the techniques could be observed.

The major histocompatibility complex genes are associated with basal pain sensitivity differences between Dark-Agouti and novel congenic DA.1U rats

Aims To investigate whether MHC genes are associated with basal pain sensitivity differences in Dark-Agouti (DA) rats and a novel congenic inbred DA.1U rats, whose genetic background is the same as DA rats except for major histocompatibility complex (MHC) genes. Main methods Mechanical withdrawal threshold (MWT) and heat withdrawal latencies (HWL) were compared in the two rat strains to reflect basal pain sensitivity. Immunohistochemistry was used to observe the expression level of RT1B, representative of MHC class II DQ region, and the basal expression of phosphorylated cAMP response element-binding protein (pCREB) in the L4/L5 spinal cord in the two rat strains. Key findings The MWT and HWL of DA rats were significantly less than that of DA.1U rats. The expression level of pCREB in the L4/L5 spinal cord in DA rats was greater than that found in DA.1U rats. The expression level of RT1B in the spinal cord was greater in DA rats, which suggested MHC class II DQ region is likely involved in the differences in sensitivity to noxious mechanical and thermal stimulation between the two rat strains. Significance These results suggest MHC genes are associated with basal pain sensitivity, which may contribute to the identification of pain sensitivity and/or individually tailored pain treatment regimens.

Facing a threat in a 3D environment: Evaluation of the impact of depth perception on the emotional state by skin conductance and near infrared spectroscopy

Whether there are sex differences in pain sensitivity is a topic of enduring interest. This question has essentially been answered, with a clear consensus emerging in the direction of the difference in humans. More importantly, though, there is also much evidence for robust qualitative differences in pain mechanisms between the sexes, in both rodents and humans, predictive of the eventual sex-specific treatment of pain. This review details some of the known differences in pain circuitry between males and females, and asks whether pain is unique in featuring such divergence.

Introgression of Brown Norway Chromosome 1 onto the Fawn Hooded Hypertensive Background Rescues Long-Term Fear Memory Deficits

The isolation of genes influencing long-term memory is critical for an understanding of learning at the molecular level. Recently, chromosomal substitution rat strains, known as consomics, have been developed. Here we report the results of the first study on aversive learning and memory with these consomic rats. We compared the Fawn Hooded Hypertensive (FHH) and Brown Norway (BN) parent strains with a Brown Norway chromosome 1 substitution on the FHH background (FHH-1(BN)). Results indicated that while all strains had normal short-term memory, the FHH animals were impaired relative to BN in tests of long-term memory for a discrete auditory cue. This deficit was rescued by the introgression of the BN1 chromosome onto the FHH background. Furthermore, the FHH-1(BN) consomic showed an enhancement in long-term contextual fear memory relative to the FHH strain. These changes were not due to differences in pain sensitivity as both strains performed equally on two different pain tests. These results provide preliminary support that consomic rat strains can be a useful tool in identifying genes related to long-term fear memory formation.

Women experience greater heat pain adaptation and habituation than men

It is not clear how males and females cope with pain over time and how sensory and emotional qualities fluctuate from moment to moment, although studies of pain at discrete time points suggest that women are more pain sensitive than men. Therefore, we developed a new broader-based pain model that incorporates a temporally continuous assessment of multiple pain dimensions across sensory and affective dimensions, and normalized peak pain intensity to unmask sex differences that may otherwise be confounded by inter-individual variability in pain sensitivity. We obtained continuous ratings of pain, burning, sharp, stinging, cutting, and annoyance evoked by repeated prolonged noxious heat stimuli in 32 subjects. Strikingly, females reported more pain than males at the outset of the first exposure to pain, but then experienced less pain and annoyance than males as a painful stimulus was sustained and with repeated stimulation. Patterns of pain and annoyance attenuation in women resembled the attenuation of sharp, stinging and cutting sensations, whereas patterns of pain and annoyance in men resembled burning sensations. Taken together, these data demonstrate a prominent sex difference in the time course of pain. Notably only females demonstrate adaptation and habituation that allow them to experience less pain over time. These findings suggest a sexual dichotomy in mechanisms underlying pain intensity and annoyance that could involve specific quality-linked mechanisms. Importantly, temporal processing of pain differs between males and females when adjusted for sex differences in pain sensitivity. Our findings provide insight into sex differences in tonic and possibly chronic pains.

Menstrual cycle phase does not influence gender differences in experimental pain sensitivity

Influence of menstrual cycle phase on experimental pain sensitivity in women and on gender differences in pain sensitivity was examined in 48 men and 49 women in response to cold pressor, heat, and ischemic pain. Each woman was tested at three points in their menstrual cycle in randomized order, the early follicular, late follicular, and luteal phases, while men were also tested three times, controlling for number of days between test sessions. Cycle phase was confirmed via serum hormone levels. As expected, women were significantly more sensitive to cold pain ( p < .01), to heat pain ( p < .0001), and to ischemic pain ( p < .01) than men. However, pain perception during each task was not influenced by the menstrual cycle in women, nor did the menstrual cycle influence the magnitude of the gender differences in pain sensitivity. These results indicate that although women are more sensitive to a variety of noxious stimuli than men, menstrual cycle phase does not appear to moderate those differences in healthy men and women.

Individual Differences in Pain Sensitivity: Measurement, Causation, and Consequences

Not only are some clinical conditions experienced as more painful than others, but the variability in pain ratings of patients with the same disease or trauma is enormous. Available evidence indicates that to a large extent these differences reflect individual differences in pain sensitivity. Pain sensitivity can be estimated only through the use of well-controlled experimental pain stimuli. Such estimates show substantial heritability but equally important environmental effects. The genetic and environmental factors that influence pain sensitivity differ across pain modalities. For example, genetic factors that influence cold pressor pain have little impact on phasic heat pain and visa versa. Individual differences in pain sensitivity can complicate diagnosis, among other reasons because low sensitivity to pain may delay self-referral. Inclusion of patients with reduced pain sensitivity can attenuate treatment effects in clinical trials, unless controlled for. Measures of pain sensitivity are predictive of acute postoperative pain, and there is preliminary evidence that heightened pain sensitivity increases risk for future chronic pain conditions. At this time, however, it is unclear which experimental pain modalities should be used as predictors for future pain conditions. Careful assessment of each individual's pain sensitivity may become invaluable for the prevention, evaluation, and treatment of pain. Large individual differences in pain sensitivity can complicate diagnosis and pain treatment and can confound clinical trials. Pain sensitivity may also be of great importance for the development of clinical pain. Thus, assessment of pain sensitivity may be relevant for the prevention, evaluation, and treatment of acute and chronic pain.

Molecular genetic aspects of individual differences in pain sensitivity and thermoregulation

The molecular genetic aspects of individual differences in thermoregulation and pain sensitivity that may be used to evaluate and predict the physical state of humans under contrast climate conditions, as well as during high physical and psychic loads, are reviewed. In response to abrupt changes in both external and internal temperature, the body activates internal resources that support homeostasis and adapts to the environment. Active movements are often associated with traumas accompanied by a sense of pain whose intensity and suppression depend on individual body characteristics. Understanding the functioning of the systems of thermoregulation and pain sensitivity at the molecular level and study of the polymorphism of genes involved in these processes is important for creation of optimal conditions for both rapid adaptation to the loads of everyday life and high physical activity and for success in sports.

Amygdala Deactivation as a Neural Correlate of Pain Processing in Patients with Borderline Personality Disorder and Co-Occurrent Posttraumatic Stress Disorder

Previous studies have revealed altered affective pain processing in patients with borderline personality disorder (BPD) as well as in patients with posttraumatic stress disorder (PTSD). Reduced levels of activation in the amygdala might be related to antinociceptive mechanisms pertinent to both disorders. This study aimed at clarifying whether central antinoceptive mechanisms discriminate BPD patients with and without co-occurrent PTSD. We investigated 29 medication-free female outpatients with BPD, 12 with and 17 without co-occurrent PTSD. Psychophysical characteristics were assessed, and functional magnetic resonance imaging was performed during heat stimulation with stimuli adjusted for equal subjective painfulness. No difference in pain sensitivity was found between both groups of patients. Amygdala deactivation, however, was more pronounced in BPD patients with co-occurrent PTSD compared with those without PTSD. Amygdala deactivation was independent of BPD symptom severity and dissociation. Amygdala deactivation seems to differentiate patients who meet criteria for both BPD and PTSD from BPD patients without co-occurrent PTSD. On the basis of these preliminary findings it might be speculated that reduced pain sensitivity or at least the emotional component of it is associated with amygdala deactivation in patients with both disorders, whereas BPD patients without PTSD use different yet unknown antinociceptive mechanisms.

Characteristics of electronic visual analogue and numerical scales for ratings of experimental pain in healthy subjects and fibromyalgia patients

Comparisons of measurement characteristics were made for three types of electronic pain scales: (a) visual analogue scale (VAS), (b) VAS combined with an electronic number box (VAS-N; 0–100), and (c) electronic number box scale (NUM). The three scales were capable of discriminating pain sensations from very small (0.5 °C) temperature steps in 13 healthy males, 26 healthy females, and 16 female fibromyalgia (FM) patients. All scales provided monotonic functions when used by subjects to rate pain from 5 s nociceptive temperatures (45–49 °C), thereby demonstrating the generality of these results across different demographic groups. As expected, FM patients rated heat pain sensations higher on all scales in comparison to healthy females, demonstrating the capacity of these scales to detect well-established group differences in pain sensitivity that exist across these two groups. However, in comparison to male subjects, healthy females gave higher NUM but not VAS or VAS-N ratings to the range of nociceptive presented temperatures. We interpret this difference as a selective scaling bias of female subjects for NUM. Finally, all three groups (total of 55 subjects) found the scales easy to use after brief instructions, though subjects strongly preferred the use of VAS-N or VAS in comparison to NUM scale.

The relation between catastrophizing and facial responsiveness to pain

Pain catastrophizing has recently been suggested to have a social function based on a positive association observed with facial responsiveness to noxious stimulation. However, this assumption is based on studies applying nociceptive stimuli of fixed intensity, such that high catastrophizers not only displayed increased pain behavior but also rated the stimulation as being more painful. The aim of this study was to investigate the relation between catastrophizing and facial responsiveness while controlling for individual differences in pain sensitivity. The facial expression of pain was investigated in 44 young and pain-free individuals in response to painful and non-painful phasic heat stimuli. Painful temperatures were tailored to the individual sensitivity to produce moderate pain. Facial responses were videotaped and objectively examined using the Facial Action Coding System. We also assessed skin conductance activity as an autonomic indicator of pain-related responses. Catastrophizing was assessed using the Pain Catastrophizing Scale (PCS). In accordance with previous findings, subjects scoring higher on pain catastrophizing required lower thermal intensities to induce a moderately painful sensation ( r = −0.40, p = 0.007). However, catastrophizing did not correlate with facial responsiveness to perceptually controlled painful stimulation ( r = −0.02, p = 0.88). Moreover, correlation analyses revealed no significant associations between catastrophizing and skin conductance responses. The present findings provide further support for the impact of pain catastophizing on pain sensitivity. However, our finding of no relation between catastrophizing and facial responsiveness when participants are experiencing comparable psychophysical pain intensities, challenges previous assumptions that high catastrophizers display amplified pain behavior; at least in young and pain-free individuals.

Age-related differences in pain sensitivity and regional brain activity evoked by noxious pressure

Compared with young adults, older people report more chronic pain complaints, and show reduced tolerance to experimental pain. Atrophy of brain parenchyma in normal ageing is well documented, with grey matter reduction occurring across many regions known to be involved in pain processing. However, the functional consequences of these changes, in particular their contribution toward age-related differences in pain perception and report, are yet to be elucidated. The present study investigated the effects of ageing on supraspinal pain processing by comparing regional brain responses to noxious pressure stimulation in 15 young (aged 26 ± 3 years) and 15 older (aged 79 ± 4 years) adults. Both groups showed significant pain-related activity in a common network of areas including the insula, cingulate, posterior parietal and somatosensory cortices. However, compared with older adults, young subjects showed significantly greater activity in the contralateral putamen and caudate, which could not be accounted for by increased age-associated shrinkage in these regions. The age-related difference in pain-evoked activity seen in the present study may reflect reduced functioning of striatal pain modulatory mechanisms with advancing age.

Sex Differences in Thermal Pain Sensitivity and Sympathetic Reactivity for Two Strains of Rat

Human females are more sensitive than males to brief nociceptive stimuli such as heat and cold. However, a more pronounced peripheral vasoconstriction by females than by males during prolonged nociceptive stimulation predicts that females would be more sensitive to prolonged cold but not heat stimulation. We tested this possibility with reflex (lick/guard) and operant escape and preference tests of sensitivity to prolonged stimulation of Long-Evans and Sprague-Dawley rats. Escape responses to cold stimulation revealed a greater sensitivity of females. In contrast, males were more sensitive to nociceptive heat stimulation. An operant preference test of relative sensitivity to cold or heat stimulation confirmed these results. Cold was more aversive than heat for females, but heat was more aversive than cold for males. Recordings of skin temperature during nociceptive heat stimulation were consistent with the results of operant testing. A reduction in skin temperature (peripheral vasoconstriction) during nociceptive stimulation should increase cold sensitivity as observed for females relative to males. Lick/guard testing did not confirm the results of operant testing. Lick/guard (L/G) responding to nociceptive heat stimulation was greater for females than for males. Female escape responses to heat were more variable than males, but L/G responding of males to the same stimulus was more variable than for females. A variety of chronic pain conditions are more prevalent for females, and psychological stress (with attendant sympathetic activation) is implicated in development and maintenance of these conditions. Therefore, understanding relationships between gender differences in pain sensitivity and sympathetic activation could shed light on mechanisms for some varieties of chronic pain.

Sex-specific pain modulation: The growth factor, neuregulin-1, as a pro-nociceptive cytokine

An increasing amount of evidence indicates that there are significant sex differences in clinical and experimental pain sensitivity in men and women. While it is now clear that the endogenous sex steroids are involved in mediating these sex differences, the cellular and molecular mechanisms that underlie their effects on nociceptive sensitivity remain elusive. Recent studies have shown that sex steroids are potent regulators of gene expression in glial cells, particularly astrocytes. This review specifically highlights some of the evidence of sex steroid regulation of growth factor expression. Growth factors have been shown to be potent pro-nociceptive mediators in rodents. Thus, regulation of their expression by sex steroids may be a general mechanism by which sex steroids exert their effect on pain sensitivity. One such mechanism, the progesterone specific regulation of the growth factor, neuregulin-1, following nerve root injury in the rat, is described in detail. Neuregulin-1 expression is increased in spinal cord astrocytes only in female rats with circulating progesterone. Neuregulin-1 has also been shown to produce transient tactile allodynia when delivered intrathecally in rats. Our understanding of growth factor regulation by sex steroids promises to open up new avenues of investigation into the mechanisms that drive sex differences in pain sensitivity.

Genetic Variation in theCatechol-O-Methyltransferase (COMT)Gene and Morphine Requirements in Cancer Patients with Pain

BackgroundGenetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the COMT gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the COMT gene also contributes to interindividual variability in morphine efficacy.ResultsWe genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype.ConclusionThis study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.

Gender differences in brain activity evoked by muscle and cutaneous pain: A retrospective study of single-trial fMRI data

Gender greatly influences pain processing. Not only do females display greater pain sensitivity, many chronic pain conditions affect females more than males. Although gender-based differences in pain sensitivity may be related to cultural and social factors, animal studies also reveal gender differences in pain sensitivity, suggesting that physiological factors may contribute to differences in the processing of pain in males and females. It has been recently reported that noxious cutaneous heat stimuli evoke gender-based differences in activity in some brain regions. Given that most chronic pain conditions, including those with gender bias are of “deep” origin (e.g. arising in muscle, joints or viscera), we investigated whether gender differences also exist in the central processing of muscle pain. In 24 healthy adults we used functional magnetic resonance imaging (fMRI) to measure signal intensity changes during muscle and cutaneous pain induced by intramuscular and subcutaneous injections of hypertonic saline, respectively. In addition to activating the “pain neuromatrix”, i.e. cingulate, insular, somatosensory and cerebellar cortices, both muscle pain and cutaneous pain evoked gender-based differences in the mid-cingulate cortex, dorsolateral prefrontal cortex, hippocampus and cerebellar cortex. These differences may reflect differences in emotional processing of noxious information in men and women and may underlie the gender bias that exists in many chronic pain conditions.

Influence of pain and gender on impact loading during walking: A randomised trial

Background Knee joint osteoarthritis is painful and with an overweight of female incidence. The cardinal symptom is pain, which causes compensatory gait changes, and gender differences in pain sensitivity exist. Impact loadings at heel strike during walking are suspected as a co-factor in development of knee osteoarthritis. Thus the purpose of this study was to investigate the influence of experimental muscle pain and gender on generation and attenuation of impact loading during walking. Methods Ten healthy males and 10 healthy females were recruited. Impact loadings during walking were measured using force platforms and accelerometers attached to the tibia and sacrum. Impact ground reaction force peaks and loading rates, and peak accelerations were used to quantify impact loadings. Attenuation was quantified by means of a transfer function between the tibial and sacral accelerometer signals, and the relative peak acceleration reduction. Knee joint kinematics were collected using a three-dimensional movement analysis system. The study was a cross-over study and data were collected before, during, and after experimental vastus medialis pain and a control situation. Findings Experimental muscle pain did not affect generation or attenuation of impact loading in either gender. While the impact loading magnitude was similar across genders, lower loading rates and more efficient attenuation were observed in females. Interpretation It is concluded that generation and attenuation of impact loadings during walking are independent of quadriceps pain in both genders. The present study does not provide any evidence of the tested variables to address the gender differences in loading rates and attenuation.