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

doi:10.1016/j.neuroimage.2007.10.045

NeuroImage

Volume 39, Issue 4, 15 February 2008, Pages 1867-1876

https://doi.org/10.1016/j.neuroimage.2007.10.045 Get rights and content

Abstract

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.

Introduction

The influence of gender on pain perception is well recognized. During experimentally-induced acute pain in humans, females display both greater pain sensitivity and greater pupillary dilation than males (Ellermeier and Westphal, 1995, Feine et al., 1991). Furthermore, females suffer more frequently from chronic pain conditions such as fibromyalgia and temporomandibular joint dysfunction (Wiesenfeld-Hallin, 2005). Although it has been suggested that gender-based differences in pain perception may be related to social and cultural factors (Walker and Carmody, 1998), animals studies have revealed not only gender differences in pain sensitivity (Tall and Crisp, 2004), but also gender differences in the electrical responses of nociceptive-specific and wide dynamic medullary dorsal horn neurons to certain opiate agonists (Flores et al., 2001). These studies suggest that neurophysiological differences may contribute to gender-based differences in pain perception and processing. For example, it is known that the density of mu-opioid receptors is reduced in post menopausal women compared to men (Zubieta et al., 1999).

Despite evidence of gender-based differences in perception of pain, little information is available about gender-based differences in the central processing of pain. To date, two positron emission tomography (PET) investigations have suggested that there are significant differences in the central processing of pain in males and females. Paulson and colleagues (1998) found that, in addition to a significant overlap of regional brain activation patterns, gender-based differences emerged in the prefrontal cortex, insula and thalamus during cutaneous heat pain. However, given that perceived pain intensities were significantly different between the male and female groups, the authors suggest that these differences may be due to the perceived pain intensity, gender, or both. More recently, Derbyshire and colleagues (2002) reported significant gender-based differences in prefrontal, somatosensory, parietal, cingulate and insula cortices during cutaneous heat pain in which the maximal pain intensity ratings were similar in male and female groups. This study suggests that gender differences in the perception of cutaneous heat pain may result from differences in central neural processing.

Although the processing of cutaneous noxious stimuli is of interest, chronic pain conditions with gender bias most often originate in deep structures such as muscle, joint or viscera. Furthermore, it has been suggested that gender-based differences in sensitivity to acute pain occur most consistently during pain of deep origin (Riley et al., 1998). The primary aim of this study was to examine the central processing of pain originating in muscle or skin in a larger cohort of subjects than we had previously examined (Henderson et al., 2006). Our study design was gender-balanced, but the intention to divide the data according to gender was made after the primary analyses were performed. Thus, we did not control for the stage of the menstrual cycle. Nevertheless, using fMRI we have uncovered significant gender differences in the central processing of muscle and cutaneous pain.

Section snippets

Subjects

Twenty-two healthy subjects (11 males, 11 females) aged 19–49 years were recruited. All procedures were performed with the understanding and written consent of the subjects and the study was approved by the Human Research Ethics Committee of the University of New South Wales. The raw data from 15 subjects was used in a previous investigation (Henderson et al., 2006).

Noxious stimuli

With each subject lying in a supine position, two fine stainless-steel needles (23 gauge), each connected via a 10 cm cannula to a

Pain perception

Hypertonic saline injections rapidly evoked pain which reached maximal intensity within 60 s and returned to baseline ∼ 8 min later (Fig. 1). The mean pain intensity rating during muscle pain in all (n = 11) female subjects was 6.4 ± 0.7 (mean [± S.E.M.]) and in all (n = 11) male subjects was 6.0 ± 0.7. The mean pain intensity rating during cutaneous pain in all female subjects was 4.6 ± 0.7 and in all male subjects was 3.5 ± 0.8. Following the removal of those subjects that reported a pain intensity below 3

Discussion

We have shown gender-based differences in the central processing of muscle pain and verified that gender-based differences also exist for cutaneous pain. In addition to activation of the broad set of structures within the “pain neuromatrix” i.e. the cingulate, insular, somatosensory and cerebellar cortices (Henderson et al., 2006, Melzack, 1999, Peyron et al., 2000), both muscle pain and cutaneous pain evoked gender-specific differences in the cingulate cortex, DLPFC, hippocampus and cerebellar

Acknowledgments

We thank Kathy M. Hughes for help in all imaging procedures and Dr Paul Macey (UCLA) for help with image analysis. Scans were performed at the Mayne Clinical Research Imaging Centre. This work was supported by NHMRC grant 350889.

References (62)

A.M. Aloisi et al.
Sex differences in the behavioural response to persistent pain in rats
Neurosci. Lett.
(1994)
A.M. Aloisi et al.
Sex-related effects on behaviour and beta-endorphin of different intensities of formalin pain in rats
Brain Res.
(1995)
A.M. Aloisi et al.
Formalin-induced changes in adrenocorticotropic hormone and corticosterone plasma levels and hippocampal choline acetyltransferase activity in male and female rats
Neuroscience
(1996)
A.M. Aloisi et al.
Sex-dependent effects of formalin and restraint on c-Fos expression in the septum and hippocampus of the rat
Neuroscience
(1997)
K.J. Berkley
From psychophysics to the clinic?
Pain Forum
(1995)
U. Bingel et al.
Subcortical structures involved in pain processing: evidence from single-trial fMRI
Pain
(2002)
S.W. Derbyshire et al.
Gender differences in patterns of cerebral activation during equal experience of painful laser stimulation
J. Pain
(2002)
G. Drossopoulou et al.
Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats
Neuroscience
(2004)
P. Dutar et al.
Activation of identified septo-hippocampal neurons by noxious peripheral stimulation
Brain Res.
(1985)
W. Ellermeier et al.
Gender differences in pain ratings and pupil reactions to painful pressure stimuli
Pain
(1995)

J.S. Feine et al.

Sex differences in the perception of noxious heat stimuli

Pain

(1991)

R.B. Fillingim et al.

Gender differences in the responses to noxious stimuli

Pain Forum

(1995)

C.A. Flores et al.

Orphanin FQ produces gender-specific modulation of trigeminal nociception: behavioral and electrophysiological observations

Neuroscience

(2001)

S. Funahashi

Neuronal mechanisms of executive control by the prefrontal cortex

Neurosci. Res.

(2001)

C. Helmchen et al.

Differential cerebellar activation related to perceived pain intensity during noxious thermal stimulation in humans: a functional magnetic resonance imaging study

Neurosci. Lett.

(2003)

L.A. Henderson et al.

Distinct forebrain activity patterns during deep versus superficial pain

Pain

(2006)

J.P. Herman et al.

Limbic system mechanisms of stress regulation: hypothalamo–pituitary–adrenocortical axis

Progr. Neuro-Psychopharmacol. Biol. Psychiatry

(2005)

D. Hoyer et al.

Molecular, pharmacological and functional diversity of 5-HT receptors

Pharmacol., Biochem. Behav.

(2002)

S. Khanna

Dorsal hippocampus field CA1 pyramidal cell responses to a persistent versus an acute nociceptive stimulus and their septal modulation

Neuroscience

(1997)

E.G. Lentjes et al.

Glucocorticoid receptors, fibromyalgia and low back pain

Psychoneuroendocrinology

(1997)

M. Liotti et al.

Differential limbic–cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders

Biol. Psychiatry

(2000)

B.D. Naliboff et al.

Sex-related differences in IBS patients: central processing of visceral stimuli [see comment]

Gastroenterology

(2003)

A.C. Nugent et al.

Cortical abnormalities in bipolar disorder investigated with MRI and voxel-based morphometry

NeuroImage

(2006)

P.E. Paulson et al.

Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans

Pain

(1998)

R. Peyron et al.

Functional imaging of brain responses to pain. A review and meta-analysis (2000)

Neurophysiol. Clin.

(2000)

W.A. Prado et al.

An assessment of the antinociceptive and aversive effects of stimulating identified sites in the rat brain

Brain Res.

(1985)

G.B. Rollman et al.

Does past pain influence current pain: biological and psychosocial models of sex differences

Eur. J. Pain

(2004)

J.M. Tall et al.

Effects of gender and gonadal hormones on nociceptive responses to intraplantar carrageenan in the rat

Neurosci. Lett.

(2004)

T.D. Wager et al.

Valence, gender, and lateralization of functional brain anatomy in emotion: a meta-analysis of findings from neuroimaging

NeuroImage

(2003)

K. Wiech et al.

Modulation of pain processing in hyperalgesia by cognitive demand

NeuroImage

(2005)

Z. Wiesenfeld-Hallin

Sex differences in pain perception

Gender Med.

(2005)

Cited by (90)

Gender Differences in Pain Threshold, Unpleasantness, and Descending Pain Modulatory Activation Across the Adult Life Span: A Cross Sectional Study
2024, Journal of Pain
The neurobiological underpinnings of gender differences in pain perception, and how these differences may be modified by age, are incompletely understood, placing patients at risk of suboptimal pain management. Using functional magnetic resonance imaging, we examined brain responses in the descending pain modulatory system (DPMS, specifically, dorsolateral prefrontal cortex, anterior cingulate cortex, insula, hypothalamus, amygdala, and periaqueductal gray, during an evoked pain task. We investigated the interaction of age and gender in our sample of healthy adults (27 females, 32 males, 30–86 years) on DPMS response. In a perceptually matched thermal pain paradigm, we investigated pain unpleasantness and neural responses for 3 heat pain percepts: just noticeable pain, weak pain, and moderate pain (MP). Females reported just noticeable pain at a lower temperature, but reported less unpleasantness at weak pain and MP percepts, compared to males. There was a significant age-by-gender interaction during moderate pain in the right anterior cingulate cortex and bilateral insula, such that, males had a stronger positive relationship between DPMS response and age compared to females in these regions. Our results indicate that differences in DPMS responses may explain some gender differences in pain perception and that this effect may change across the adult lifespan.
Gender differences in pain have been well-documented but the brain mechanisms for these differences are still unclear. This article describes potential differences in brain functioning during different levels of pain that could explain differences in pain responses between men and women across the adult lifespan.
Gene expression changes in the cerebellum are associated with persistent post-injury pain in adolescent rats exposed to early life stress
2023, Neurobiology of Pain
Chronic pain develops following injury in approximately 20% of adolescents, at twice the rate in females than males. Adverse childhood experiences also increase the risk for poor health outcomes, such as chronic pain. Emerging literature suggests the cerebellum to be involved in pain processing, however detailed explorations into how the cerebellum contributes to pain are lacking. Therefore, this study aimed to characterise chronic pain outcomes and cerebellar gene expression changes following early life stress and injury in both sexes. The adverse childhood experience of neglect was modelled using a maternal separation (MS) paradigm, which was combined with a subsequent injury (mild traumatic brain injury (mTBI) or plantar incision surgery) in adolescent male and female Sprague-Dawley rats. We measured behavioural nociceptive sensitivity, systemic modulators of pain such as calcitonin gene-related protein (CGRP) and Substance P, as well as gene expression of IL1β, GFAP, GR, MR, GABRA1, CNR1, MAOA, and DAT1 in the cerebellum to examine associations between pain and neuroinflammation, the stress response, inhibitory neurotransmission, and monoaminergic function. We found increases in mechanical nociceptive sensitivity following plantar incision surgery. Sex differences were observed in anxiety-like behaviour and neuroinflammation, whereas systemic pain modulators showed cumulative effects with the addition of stressors. Most interestingly however, the increases in nociceptive sensitivity were associated with the suppressed expression of cerebellar genes that regulate stress, inhibition, cannabinoid function, and dopaminergic function, alongside sex-dependent distinctions for genes involved in inflammation and injury. This study highlights a novel link between nociception and molecular function in the cerebellum. Further investigation into how the cerebellum contributes to pain in males and females will facilitate novel therapeutic insights and opportunities.
Regional hypothalamic, amygdala, and midbrain periaqueductal gray matter recruitment during acute pain in awake humans: A 7-Tesla functional magnetic resonance imaging study
2022, NeuroImage
Over the past two decades, magnetic resonance imaging (MRI) studies have explored brain activation patterns during acute noxious stimuli. Whilst these human investigations have detailed changes in primarily cortical regions, they have generally not explored discrete changes within small brain areas that are critical in driving behavioural, autonomic, and endocrine responses to pain, such as within subregions of the hypothalamus, amygdala, and midbrain periaqueductal gray matter (PAG). Ultra-high field (7-Tesla) MRI provides enough signal-to-noise at high spatial resolutions to investigate activation patterns within these small brain regions during acute noxious stimulation in awake humans. In this study we used 7T functional MRI to concentrate on hypothalamic, amygdala, and PAG signal changes during acute noxious orofacial stimuli. Noxious heat stimuli were applied in three separate fMRI scans to three adjacent sites on the face in 16 healthy control participants (7 females). Images were processed using SPM12 and custom software, and blood oxygen level dependent signal changes within the hypothalamus, amygdala, and PAG assessed. We identified altered activity within eight unique subregions of the hypothalamus, four unique subregions of the amygdala, and a single region in the lateral PAG. Specifically, within the hypothalamus and amygdala, signal intensity largely decreased during noxious stimulation, and increased in the lateral PAG. Furthermore, we found sex-related differences in discrete regions of the hypothalamus and amygdala. This study reveals that the activity of discrete nuclei during acute noxious thermal stimulation in awake humans.
Sex and gender differences in pain
2022, International Review of Neurobiology
Chronic pain affects 20% of adults and is one of the leading causes of disability worldwide. Women and girls are disproportionally affected by chronic pain. About half of chronic pain conditions are more common in women, with only 20% having a higher prevalence in men. There are also sex and gender differences in acute pain sensitivity. Pain is a subjective experience made up of sensory, cognitive, and emotional components. Consequently, there are multiple dimensions through which sex and gender can influence the pain experience. Historically, most preclinical pain research was conducted exclusively in male animals. However, recent studies that included females have revealed significant sex differences in the physiological mechanisms underlying pain, including sex specific involvement of different genes and proteins as well as distinct interactions between hormones and the immune system that influence the transmission of pain signals. Human neuroimaging has revealed sex and gender differences in the neural circuitry associated with pain, including sex specific brain alterations in chronic pain conditions. Clinical pain research suggests that gender can affect how an individual contextualizes and copes with pain. Gender may also influence the susceptibility to develop chronic pain. Sex and gender biases can impact how pain is perceived and treated clinically. Furthermore, the efficacy and side effects associated with different pain treatments can vary according to sex and gender. Therefore, preclinical and clinical research must include sex and gender analyses to understand basic mechanisms of pain and its relief, and to develop personalized pain treatment.
Thermal sensitivity mapping - warmth and cold detection thresholds of the human torso
2020, Journal of Thermal Biology
Skin as the largest organ of the human body accomplishes many important functions, including thermoregulation. In this context, investigating cold (CDT) and warmth detection thresholds (WDT) constitutes an important research branch, and investigating thermal thresholds has a significant impact on the clothing and fabric textile industry. In this regard, not only the extremities, but also torso regions are of high relevance. However, only few examinations have conducted detailed mapping studies of the human torso. Additionally, some of these studies show certain methodological limitations. Furthermore, the issue of whether cutaneous thermal sensitivity is gender-dependent is still controversial. Therefore, the present study investigated the cutaneous thermal sensitivity (CDT, WDT) of 42 male and female young and healthy subjects. Measurements were taken at 11 anatomical regions. We found that gender plays an important role when investigating thermal thresholds: Females tended to be more sensitive than males. We also found considerable differences between the tested regions, even within the anterior torso, for example. We identified locations which were constantly sensitive (lower back), while others were consistently insensitive (e.g. scapula). We also detected greater data variability for males compared to females, and for WDT compared to CDT. Furthermore, mainly for WDT, we found a proximal-to-distal increase of thermal torso and upper arm sensitivity. In line with previous investigations, our subjects were more sensitive to cold than to warmth. The findings of this study have important implications. First, our data may complement basic research, e.g. in terms of reference data of body regional maps. Second, our data provides important insights that could be leveraged in the textile industry, and also used to optimize current broadly applicable test methods and tools, like thermal manikins and thermophysiological models.
Sex differences and mechanisms of muscle pain
2019, Current Opinion in Physiology
Clinical conditions resulting in musculoskeletal pain show important sex differences in both prevalence and degree of functional disability. The underlying mechanisms for these distinctions in pain manifestation are not fully known. However, recent preclinical studies have shown at the primary afferent level that males and females present fundamental differences in their peripheral response properties and injury-related gene expression patterns that may underlie observed afferent sensitization. At the spinal cord level, studies in various models of pain suggest important roles for the immune system, glutamate signaling and hormones in modulating sex differences. While preclinical studies have been able to characterize some of the basic underlying molecular mechanisms of sex differences in muscle pain, human studies have relied mainly on functional brain imaging studies to explain differences. Further complicating our understanding of how sex influences muscle pain is the notion that the type of injury sustained, or clinical condition may differentially activate distinct mechanisms of muscle pain development in males versus females. More research is necessary to better understand how the sexes differ in their perception of muscle pain. This review highlights recent advances in both human and animal studies of sex differences in muscle pain.

View all citing articles on Scopus

View full text