Study reveals first evidence of sex differences in pain production

A recent study from the University of Arizona Health Sciences has revealed critical differences in how males and females experience pain, potentially paving the way for more tailored and effective pain management strategies. Published in BRAIN, this groundbreaking research identifies functional disparities in nociceptors—the specialized nerve cells responsible for pain perception—between the sexes.

Key Discoveries in Nociceptor Functionality

The research team, led by Frank Porreca, PhD, from the Comprehensive Center for Pain & Addiction, focused on the excitability of nociceptor cells located near the spinal cord in the dorsal root ganglion. These cells, when activated by damage or injury, transmit pain signals through the spinal cord to the brain. The adaptability of nociceptors allows them to respond to various levels of stimuli, from severe burns to mild irritations, like a shirt collar rubbing against sunburned skin.

Hormonal Influences on Pain Perception

Intrigued by previous findings on the relationship between chronic pain and sleep, Porreca and his team investigated the roles of prolactin and orexin B in nociceptor activation. Prolactin, commonly associated with lactation and breast development, and orexin B, a neurotransmitter involved in wakefulness, were found to have sex-specific effects on pain thresholds.

Using tissue samples from male and female mice, nonhuman primates, and humans, the researchers discovered that prolactin lowered the activation thresholds of nociceptors in females but not in males. Conversely, orexin B had a similar effect on male nociceptors but not on female ones. This led to the remarkable conclusion that nociceptors function differently in males and females, a distinction that had not been previously recognized.

Blocking Pain Pathways

Building on these findings, the team experimented with blocking prolactin and orexin B signaling. In females, inhibiting prolactin signaling reduced nociceptor activation, while this method showed no effect in males. On the other hand, blocking orexin B signaling proved effective in males but not in females.

Implications for Pain Management

Porreca's research suggests that the fundamental mechanisms underlying pain perception differ between the sexes. This insight could revolutionize pain treatment, especially for conditions more prevalent in females, such as migraines and fibromyalgia. The study advocates for a precision medicine approach that considers a patient’s sex as a primary factor in treatment decisions.

Future Research and Potential Treatments

Looking ahead, Porreca and his team plan to investigate other sex-specific mechanisms of pain. They are particularly interested in developing ways to prevent nociceptor sensitization in both males and females. Preliminary findings, such as the potential use of a prolactin antibody for females and the existing FDA-approved orexin antagonists for males, show promise.

Collaboration and Contribution

This significant research involved numerous contributors from various departments. Key collaborators included Edita Navratilova, PhD; Laurent Martin, PhD; Grace Lee, PhD; Mahdi Dolatyari; Stefanie Mitchell; Xu Yue; Harrison Stratton, PhD; and Mohab Ibrahim, MD, PhD, from the University of Arizona. Additionally, experts from Saint Louis University and Anabios in San Diego also participated, highlighting the collaborative nature of this pioneering study.

Conclusion

The study's findings underscore the importance of considering sex differences in pain management and open new avenues for developing customized treatments. By incorporating the most basic genetic difference—male or female—into pain therapy considerations, medical practitioners can aim for more effective, tailored approaches to alleviating pain in their patients.

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