A little over 10 years ago a series of clinical studies were published showing that untreated pain in the neonatal period (circumcision in male infants) enhanced subsequent pain responses in infancy and childhood. Basic science responded with a number of rodent studies but the majority of these studies used animals that are equivalent in age to a pre-term human infant and used inflammatory pain models. In contrast, the majority of under-treated pain in the hospital setting involves full-term infants and young children who are experiencing acute nociceptive pain. To this end, this proposal will use endothelin-1, an endogenous peptide released at sites of injury and disease, to model an acute nociceptive pain experience in a rat that is equivalent in development to a full-term human infant. We postulate that pain experience early in development decreases endothelin B receptor expression on keratinocytes in a testosterone-dependent manner. The end result of these changes is that early pain experiences sensitize males to subsequent pain. A combination of behavior, histological and pharmacological methods will be used to determine the mechanisms by which exposure to endothelin-1 early in life down-regulates the endothelin B receptor pathway. By determining the mechanism of endothelin-induced sensitization this work will lay the foundation for the development of therapeutic strategies to minimize pain and prevent pain-induced sensitization in infants and children.

Public Health Relevance

Understanding how a pain experience early in life changes pain sensations experienced later in life is important to adequately assess pain and treat pain in infants and children. This proposal will define the mechanism by which one pain experience can enhance a subsequent pain experience. The goal of this proposal is to identify novel therapeutic targets for the development of therapies to prevent pain sensitization.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023593-04
Application #
8019589
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Thomas, David A
Project Start
2008-04-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$248,922
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Smith, Terika P; Schlenz, Alyssa M; Schatz, Jeffrey C et al. (2015) Modulation of pain in pediatric sickle cell disease: understanding the balance between endothelin mediated vasoconstriction and apelin mediated vasodilation. Blood Cells Mol Dis 54:155-9
Smith, Terika; Beasley, Sarah; Smith, Sherika et al. (2014) Endothelin-1-induced priming to capsaicin in young animals. Neurosci Lett 567:15-8
Smith, Terika P; Smith, Sherika N; Sweitzer, Sarah M (2014) Endothelin-1 induced desensitization in primary afferent neurons. Neurosci Lett 582:59-64
Yang, F; Xu, Q; Cheong, Y-K et al. (2014) Comparison of intensity-dependent inhibition of spinal wide-dynamic range neurons by dorsal column and peripheral nerve stimulation in a rat model of neuropathic pain. Eur J Pain 18:978-88
He, Shao-Qiu; Yang, Fei; Perez, Federico M et al. (2013) Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats. Pain 154:2477-86
Schlenz, Alyssa M; Schatz, Jeffrey; McClellan, Catherine B et al. (2013) Information-seeking coping behaviors during painful procedures in African-American children with sickle cell disease. Pain Manag Nurs 14:e54-8
Schlenz, Alyssa M; McClellan, Catherine B; Mark, Teresa R M et al. (2012) Sensitization to acute procedural pain in pediatric sickle cell disease: modulation by painful vaso-occlusive episodes, age, and endothelin-1. J Pain 13:656-65
McClellan, Catherine B; Schatz, Jeffrey C; Mark, Teresa R M et al. (2009) Criterion and convergent validity for 4 measures of pain in a pediatric sickle cell disease population. Clin J Pain 25:146-52
McKelvy, Alvin D; Sweitzer, Sarah M (2009) Endothelin-1 exposure on postnatal day 7 alters expression of the endothelin B receptor and behavioral sensitivity to endothelin-1 on postnatal day 11. Neurosci Lett 451:89-93
McKelvy, Alvin D; Sweitzer, Sarah M (2009) Decreased opioid analgesia in weanling rats exposed to endothelin-1 during infancy. Neurosci Lett 466:144-8

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