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The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting differences in mechanisms that promote pain in men and women. A major factor that influences the likelihood of pain perception is the threshold for activation of nociceptors. Peripheral nociceptor sensitization has been demonstrated to be clinically relevant in many pain conditions. Whether peripheral nociceptor sensitization can occur in a sexually dimorphic fashion, however, has not been extensively studied. To address this fundamental knowledge gap, we used patch clamp electrophysiology to evaluate the excitability of dorsal root ganglion neurons from male or female rodents, non-human primates, and humans following exposure to putative sensitizing agents. Previous studies from our laboratory, and others, have shown that prolactin promotes female-selective pain responses in rodents. Consistent with these observations, dorsal root ganglion neurons from female, but not male, mice were selectively sensitized by exposure to prolactin. The sensitizing action of prolactin was also confirmed in dorsal root ganglion neurons from a female macaque monkey. Critically, neurons recovered from female, but not male, human donors were also selectively sensitized by prolactin. In the course of studies of sleep and pain, we unexpectedly observed that an orexin antagonist could normalize pain responses in male animals. We found that orexin B produced sensitization of male, but not female, mouse, macaque, and human dorsal root ganglion neurons. Consistent with functional responses, increased prolactin receptor and orexin receptor 2 expression was observed in female and male mouse dorsal root ganglia, respectively. Immunohistochemical interrogation of cultured human sensory neurons and whole dorsal root ganglia also suggested increased prolactin receptor expression in females and orexin receptor 2 expression in males. These data reveal a functional double dissociation of nociceptor sensitization by sex, which is conserved across species and is likely directly relevant to human pain conditions. To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurons. Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men. Additional implications of these findings are that the design of clinical trials for pain therapies should consider the proportions of male or female patients enrolled. Lastly, re-examination of selected past failed clinical trials with subgroup analysis by sex may be warranted.
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http://dx.doi.org/10.1093/brain/awae179 | DOI Listing |
Interv Pain Med
December 2024
Department of Physical and Rehabilitation Medicine, University of Turku, Turku, Finland.
Background: Spinal Cord Stimulation (SCS) is a widely recognized treatment for Complex Regional Pain Syndrome (CRPS), particularly in cases where traditional methods are ineffective. This paper systematically reviews randomized controlled trials to analyze the efficacy of SCS, as well as Dorsal Root Ganglion (DRG) Stimulation in treating CRPS, focusing on its long-term effectiveness.
Methods: This systematic review focused exclusively on randomized controlled trials to assess a primary outcome of improvement in pain symptoms in patients diagnosed with CRPS.
Zhongguo Gu Shang
December 2024
Derpartment of Spine Surgery, Nuclear Industry 416 Hospital, Chengdu 610000, Sichuan, China.
Objective: To explore feasibility, clinical and imaging outcomes of percutaneous endoscopic interlaminar discectomy (PEID) for single level large lumbar disc herniation(LDH).
Methods: From October 2018 to March 2023, 31 patients with single level LDH treated with PEID were retrospectively analyzed. Among patients, including 18 males and 13 females, aged from 15 to 40 years old with an average of (28.
J Neurosurg Case Lessons
December 2024
Neurosurgery Artificial Intelligence Lab, Stanford University School of Medicine, Stanford, California.
Background: The inability to localize pain generators often results in failed back surgery syndrome (FBSS). Structural imaging can identify multiple and/or noncausative abnormalities. Molecular imaging of glucose transporters offers the opportunity to localize metabolically active sites.
View Article and Find Full Text PDFPLoS Genet
December 2024
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Background: The development and diversification of sensory proprioceptive neurons, which reside in the dorsal root ganglia (DRG) and express the tropomyosin receptor kinase C (TrkC), depend on the transcription factor (TF) Runx3. Runx3-deficient mice develop severe limb ataxia due to TrkC neuron cell death. Two additional TFs Pou4f1 (also called Brn3a) and Isl1 also play an important role in sensory neuron development.
View Article and Find Full Text PDFMol Neurobiol
December 2024
Department of Physical Therapy, School of Health and Social Services, Saitama Prefectural University, 820 San-Nomiya, Koshigaya-Shi, Saitama, 343-8540, Japan.
Accumulation of senescent neurons in the dorsal root ganglion (DRG) is an important tissue phenotype that causes age-related degeneration of peripheral sensory nerves. Senescent neurons are neurons with arrested cell cycle that have undergone cellular senescence but remain in the tissue and play various biological roles. To understand the accumulation of senescent neurons in the DRG during aging, we aimed to elucidate the mechanism that induces cellular senescence in DRG neurons and the role of senescent DRG neurons.
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