Discovery and characterization of prolactin neutralizing monoclonal antibodies for the treatment of female-prevalent pain disorders

Maciuba, Stephanie; Bowden, Gregory D.; Stratton, Harrison J.; Wisniewski, Kazimierz; Schteingart, Claudio D.; Almagro, Juan C.; Valadon, Philippe; Lowitz, Joshua; Glaser, Scott M.; Lee, Grace; Dolatyari, Mahdi; Navratilova, Edita; Porreca, Frank; Rivière, Pierre J.M.

doi:10.1080/19420862.2023.2254676

Cited by 4 publications

(2 citation statements)

References 81 publications

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“…Individuals with prolactin-secreting pituitary adenomas were found to have a higher incidence of headaches and migraine attacks [108]. With monoclonal antibodies targeting prolactin receptors, a recent report opens new possibilities to better understand the complex interaction between prolactin and CGRP, but blocking prolactin receptors in humans poses risks of interfering with the other functions of this hormone [109].…”

Section: Prolactinmentioning

confidence: 99%

How Sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel Review

Godley,

Meitzen,

Nahman-Averbuch

et al. 2024

JPM

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Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal.

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Section: Prolactinmentioning

confidence: 99%

How Sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel Review

Godley,

Meitzen,

Nahman-Averbuch

et al. 2024

JPM

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“…Consequently, addressing the unmet medical need for satisfactory migraine therapy in men calls for approaches that extend beyond CGRP-based mechanisms. The female selective role of prolactin in sensitization of trigeminal nociceptors suggest a therapeutic opportunity for development of novel prolactin targeting therapies including anti-prolactin antibodies [ 83 ].…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Female-selective mechanisms promoting migraine

Singh,

Kopruszinski,

Watanabe

et al. 2024

J Headache Pain

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Sexual dimorphism has been revealed for many neurological disorders including chronic pain. Prelicinal studies and post-mortem analyses from male and female human donors reveal sexual dimorphism of nociceptors at transcript, protein and functional levels suggesting different mechanisms that may promote pain in men and women. Migraine is a common female-prevalent neurological disorder that is characterized by painful and debilitating headache. Prolactin is a neurohormone that circulates at higher levels in females and that has been implicated clinically in migraine. Prolactin sensitizes sensory neurons from female mice, non-human primates and humans revealing a female-selective pain mechanism that is conserved evolutionarily and likely translationally relevant. Prolactin produces female-selective migraine-like pain behaviors in rodents and enhances the release of calcitonin gene-related peptide (CGRP), a neurotransmitter that is causal in promoting migraine in many patients. CGRP, like prolactin, produces female-selective migraine-like pain behaviors. Consistent with these observations, publicly available clinical data indicate that small molecule CGRP-receptor antagonists are preferentially effective in treatment of acute migraine therapy in women. Collectively, these observations support the conclusion of qualitative sex differences promoting migraine pain providing the opportunity to tailor therapies based on patient sex for improved outcomes. Additionally, patient sex should be considered in design of clinical trials for migraine as well as for pain and reassessment of past trials may be warranted.

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Nociceptors are functionally male or female: from mouse to monkey to man

Stratton,

Lee,

Dolatyari

et al. 2024

Brain

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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 neurones 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 neurones 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 neurones from a female macaque monkey. Critically, neurones 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 neurones. 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 neurones 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 neurones. 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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Discovery and characterization of prolactin neutralizing monoclonal antibodies for the treatment of female-prevalent pain disorders

Cited by 4 publications

References 81 publications

How Sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel Review

How Sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel Review

Female-selective mechanisms promoting migraine

Nociceptors are functionally male or female: from mouse to monkey to man

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