Abstract
Chronic neuropathic pain is a major unmet clinical need affecting 10% of the world population, the majority of whom suffer from co-morbid mood disorders. Sex differences have been reported in pain prevalence, perception and response to analgesics. However, sexual dimorphism in chronic neuropathic pain and the associated neurobiology, are still poorly understood. The lack of efficacy and the adverse effects associated with current pharmacological treatments, further underline the need for new therapeutic targets. The endocannabinoid system (ECS) is a lipid signalling system which regulates a large number of physiological processes, including pain. The aim of this study was to investigate sexual dimorphism in pain-, anxiety- and depression-related behaviours, and concomitant alterations in supraspinal and spinal endocannabinoid levels in the spared nerve injury (SNI) animal model of peripheral neuropathic pain. Sham or SNI surgery was performed in adult male and female Sprague-Dawley rats. Mechanical and cold allodynia was tested weekly using von Frey and acetone drop tests, respectively. Development of depression-related behaviours was analysed using sucrose splash and sucrose preference tests. Locomotor activity and anxiety-related behaviours were assessed with open field and elevated plus maze tests. Levels of endocannabinoid ligands and related N-acylethanolamines in supraspinal regions of the descending inhibitory pain pathway, and spinal cord, were analysed 42 days post-surgery. SNI surgery induced allodynia in rats of both sexes. Female-SNI rats exhibited earlier onset and greater sensitivity to cold and mechanical allodynia than their male counterparts. In male rats, SNI induced a significant reduction of rearing, compared to sham controls. Trends for depressive-like behaviours in females and for anxiety-like behaviours in males were observed after SNI surgery but did not reach statistical significance. No concomitant alterations in levels of endogenous cannabinoid ligands and related N-acylethanolamines were observed in the regions analysed. Our results demonstrate differential development of SNI-induced nociceptive behaviour between male and female rats suggesting important sexually dimorphic modifications in pain pathways. SNI had no effect on depression- or anxiety-related behaviours in animals of either sex, or on levels of endocannabinoid ligands and related N-acylethanolamines across the regions involved in the descending modulation of nociception at the time points investigated.
Highlights
Pain, as defined by the International Association for the Study of Pain (IASP) is considered “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [1]
Significant differences between experimental groups were observed for mechanical allodynia, measured as paw withdrawal thresholds (PWT), of the ipsilateral hind paw (Figure 1A), at all the time-points tested [Kruskal-Wallis: PSD7: H(3) = 8.161, p < 0.01; PSD14: H(3)=11.019, p < 0.05; PSD21: H(3) = 12.110, p
This sex-dependent effect on mechanical hypersensitivity was observed in the contralateral PWT of spared nerve injury (SNI) rats (Figure 1B), no significant reduction of the contralateral PWT was observed in SNI groups compared to their Sham counterparts (Figure 1B)
Summary
As defined by the International Association for the Study of Pain (IASP) is considered “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [1]. Pain can be classified as acute or chronic, dependent on its duration. Pain persisting over 3 months, can be classified as inflammatory, idiopathic or neuropathic [2]. Neuropathic pain, caused by a lesion or disease affecting the somatosensory system, has a prevalence of 10% in the total world population [3], and is one of the major unmet clinical needs. Despite its higher prevalence in women, females are still underrepresented in pre-clinical studies relevant to chronic neuropathic pain, with
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