Chronic pain and disability after physical trauma, including surgery, is a major public health problem. Surprisingly, recovery from pain after cesarean delivery is more rapid than after similar injuries outside the postpartum period. In animals, recovery from hypersensitivity after surgery is more rapid if surgery occurs in the early postpartum period, and this is blocked by spinal injection of an oxytocin receptor antagonist. This grant was funded to probe in animals and humans the mechanisms and clinical translation of this effect. We are on track to complete the originally proposed studies and have published or submitted 15 manuscripts in the past 3 years. We have also generated novel ideas and methods to increase the impact of this research, including growth curve modeling to more powerfully describe the time course of recovery, novel methods to repeatedly assess motivated, high-intensity movement and pain-related fear of movement in animals, and novel viral vectors to knockdown receptors of interest and to control spinally projecting oxytocinergic neurons and high threshold mechanosensitive nociceptor peripheral neurons. We will apply these novel methods to 2aims in the proposed extension period to determine in animals and in humans: 1. Efficacy and mechanisms of oxytocin against injury-induced pain on movement: We will use novel outcome measures of high-intensity motivated behavior and kinesiophobia in animals to examine the role of oxytocin systems in recovery after surgery, the receptors involved, and methods to augment this recovery-hastening effect. In humans we will test the role of spinal and systemic oxytocin on pain with movement and kinesiophobia with painful physical therapy following surgery. 2. Actions and mechanisms of spinal oxytocin on mechanosensitive input: We will examine the detailed effects of oxytocin on tuning of mechanosensitive inputs, the receptors involved, and the subtype selectivity of these actions in normal animals and those recovering from injury. In healthy humans and those recovering from surgery, we will test the action of spinal and peripheral oxytocin on modality selective input from afferent fiber classes.

Public Health Relevance

Chronic pain and disability frequently follow physical injury, including surgery, and our studies in animals and humans show that this is reduced when injury occurs to mothers at the time of childbirth. In the past 3 years we have shown that oxytocin in the brain and spinal cord produces this protective effect. We will test whether there is a sex difference in this effect and where and how oxytocin works.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM048085-26
Application #
9475090
Study Section
Special Emphasis Panel (NSS)
Program Officer
Cole, Alison E
Project Start
1992-08-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
26
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Severino, Amie L; Chen, Rong; Hayashida, Kenichiro et al. (2018) Plasticity and Function of Spinal Oxytocin and Vasopressin Signaling during Recovery from Surgery with Nerve Injury. Anesthesiology 129:544-556
Gutierrez, Silvia; Boada, M Danilo (2018) Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+). Cancer Cell Int 18:216
Boada, M Danilo; Ririe, Douglas G; Eisenach, James C (2017) Post-discharge hyperpolarization is an endogenous modulatory factor limiting input from fast-conducting nociceptors (AHTMRs). Mol Pain 13:1744806917726255
Eisenach, James C; Warner, David S; Houle, Timothy T (2016) Reporting of Preclinical Research in Anesthesiology: Transparency and Enforcement. Anesthesiology 124:763-5
Booth, Jessica L; Harris, Lynnette C; Eisenach, James C et al. (2016) A Randomized Controlled Trial Comparing Two Multimodal Analgesic Techniques in Patients Predicted to Have Severe Pain After Cesarean Delivery. Anesth Analg 122:1114-9
Arora, Vipin; Morado-Urbina, Carlos Eduardo; Aschenbrenner, Carol A et al. (2016) Disruption of Spinal Noradrenergic Activation Delays Recovery of Acute Incision-Induced Hypersensitivity and Increases Spinal Glial Activation in the Rat. J Pain 17:190-202
Kharasch, Evan D; Eisenach, James C (2016) Wherefore Gabapentinoids?: Was There Rush Too Soon to Judgment? Anesthesiology 124:10-2
Boada, M Danilo; Eisenach, James C; Ririe, Douglas G (2016) Mechanical sensibility of nociceptive and non-nociceptive fast-conducting afferents is modulated by skin temperature. J Neurophysiol 115:546-53
Eisenach, James C (2015) Can a Blood Test of Immune Responsiveness Predict Speed of Recovery from Pain and Dysfunction after Surgery? Anesthesiology 123:1221-3
Peters, Christopher M; Hayashida, Ken-Ichiro; Suto, Takashi et al. (2015) Individual differences in acute pain-induced endogenous analgesia predict time to resolution of postoperative pain in the rat. Anesthesiology 122:895-907

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