Male-Specific Conditioned Pain Hypersensitivity in Mice and Humans

• Published in: Current biology Vol. 29; no. 2; pp. 192 - 201.e4
• Main Authors: Martin, Loren J., Acland, Erinn L., Cho, Chulmin, Gandhi, Wiebke, Chen, Di, Corley, Elizabeth, Kadoura, Basil, Levy, Tess, Mirali, Sara, Tohyama, Sarasa, Khan, Sana, MacIntyre, Leigh C., Carlson, Erika N., Schweinhardt, Petra, Mogil, Jeffrey S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 21.01.2019
• Subjects: Animals; Female; Hypothalamo-Hypophyseal System - physiology; Lipopeptides - pharmacology; Male; Memory; Mice; pain; Pain - etiology; Pain Perception - physiology; Pituitary-Adrenal System - physiology; Protein Kinase C - antagonists & inhibitors; sex difference; Sex Factors; Stress, Physiological; translation; translation; pain; memory; sex difference
• ISSN: 0960-9822; 1879-0445; 1879-0445
• DOI: 10.1016/j.cub.2018.11.030

Pain memories are hypothesized to be critically involved in the transition of pain from an acute to a chronic state. To help elucidate the underlying neurobiological mechanisms of pain memory, we developed novel paradigms to study context-dependent pain hypersensitivity in mouse and human subjects, respectively. We find that both mice and people become hypersensitive to acute, thermal nociception when tested in an environment previously associated with an aversive tonic pain experience. This sensitization persisted for at least 24 hr and was only present in males of both species. In mice, context-dependent pain hypersensitivity was abolished by castrating male mice, pharmacological blockade of the hypothalamic-pituitary-adrenal axis, or intracerebral or intrathecal injections of zeta inhibitory peptide (ZIP) known to block atypical protein kinase C (including the protein kinase Mζ isoform). In humans, men, but not women, self-reported higher levels of stress when tested in a room previously associated with tonic pain. These models provide a new, completely translatable means for studying the relationship between memory, pain, and stress. •Re-exposure to a context associated with pain results in pain hypersensitivity•Conditioned pain sensitivity is only present in males via testosterone•The phenomenon can be demonstrated in both mice and humans•The phenomenon is dependent on stress and blocked by zeta inhibitory peptide (ZIP) Martin et al. develop a new model of pain memory—in both mice and humans—in which re-exposure to a context previously associated with tonic pain results in hypersensitivity to acute pain. Surprisingly, this phenomenon only occurs in males of both species and appears to be linked with testosterone, stress levels, and the atypical protein kinase C.