Insights into the mechanisms and the emergence of sex-differences in pain

Highlights

• Sex and gender influence the occurrence of pain and the response to treatments.

• Women are overrepresented in most clinical pain conditions.

• Biological and psychological factors are acting on sex and gender pain modulation.

• Sex and gender are essential factors in personalized pain medicine.

Abstract

Recent studies describe sex and gender as critical factors conditioning the experience of pain and the strategies to respond to it. It is now clear that men and women have different physiological and behavioral responses to pain. Some pathological pain states are also highly sex-specific. This clinical observation has been often verified with animal studies which helped to decipher the mechanisms underlying the observed female hyper-reactivity and hyper-sensitivity to pain states. The role of gonadal hormones in the modulation of pain responses has been a straightforward hypothesis but, if pertinent in many cases, cannot fully account for this complex sensation, which includes an important cognitive component. Clinical and fundamental data are reviewed here with a special emphasis on possible developmental processes giving rise to sex-differences in pain processing.

Introduction

Women and men do not experience pain equally. Women perceive painful stimuli as more intense than men and are overrepresented in the majority of clinical pain conditions (Mogil, 2012). Interestingly, the same is true in animals, females having a lower pain threshold than males, supporting the implication of biological differences (Craft et al., 2004).

A great interest in the problematic of sex-differences in pain responses and pain processing has emerged in recent years. The number of dedicated clinical and animal studies has widely increased and supports the idea that pain seems to be processed differentially in men and women. Animal studies have been a huge help in deciphering potential mechanisms linked to the differences observed, raising the question of inherent anatomical differences between the two populations, and of the role of gonadal hormones in the modulation of pain responses.

Pain is a complex phenomenon relying on intricate excitatory and inhibitory psychophysiological mechanisms. Chronic pain frequently results in an excessive recruitment of excitatory mechanisms often referred to as peripheral and central sensitization. Excitation is often further amplified by a reduced efficacy of inhibitory controls exerted by local interneuronal networks or by supraspinal axonal projections (e.g. Conditioned Pain Modulation – CPM) (Yarnitsky et al., 2014, Todd, 2015). Recent studies have highlighted that patients exhibiting an increased sensitization by temporal summation versus a deficit of CPM are expected to respond positively to different classes of drugs (Yarnitsky et al., 2012, Olesen et al., 2013) .

Beside the physiological responses after recruitment of somatic and autonomic systems, the role of cognitive and emotional processes is of utmost importance. In classical views, the term sex refers to a person’s biological status as defined by sex chromosomes, gonads, internal reproductive organs and external genitalia. Gender refers to the attitudes, feelings, and behaviors that a given culture associate with a person’s biological sex (American Psychological Association, 2012). In this review, we will use the term sex-specificities as a generic term, also covering any gender-specific differences in pain processing and expression. We will put some emphasis on the developmental origins of sex-differences in pain and provide some clinical and experimental observations supporting the differential pain responses during the development from childhood to adulthood in both animal models and human. The implication of the environment linked to early life events which could differentially imprint and alter pain processing in a long-term manner in a sex-specific manner will also be discussed.