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