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Published on: October 20, 2012
Developmental differences in spinal cyclooxygenase 1 expression after surgical incision
Douglas G Ririe1, Heather D Prout, David Barclay
1Department of Anesthesiology and Center for the Study of Pharmacological Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009, USA. dririe@wfubmc
Background:
Systemic administration of a cyclooxygenase 1 (COX-1) inhibitor reduces hypersensitivity to mechanical stimuli after incisional paw surgery in 4-week-old, but not 2-week-old, animals. The purpose of the current study was to test whether this developmental difference was reflected by differences in COX-1 expression in the spinal cord after surgery.
Methods:
Rats 2 and 4 weeks of age, paralleling infant and child human neurologic developmental stages, were used. A paw incision was made under general anesthesia and the withdrawal thresholds were measured before and after systemic and intrathecal administration of a COX-1 selective inhibitor (SC560). Immunohistochemistry was used to assess COX-1 protein in the spinal cord, and real-time polymerase chain reaction was used to quantify gene expression of COX-1 mRNA.
Results:
Systemic and intrathecal administration of SC560 produced an increase in withdrawal threshold in the 4-week-old, but not in the 2-week-old, animals. Intrathecal SC560 increased withdrawal thresholds in the 4-week-old animals at a dose 100-fold less than with systemic administration. Cyclooxygenase 1 protein in the spinal cord was increased ipsilateral to surgery in the 4-week-old, but not in the 2-week-old, animals. Cyclooxygenase 1 mRNA was increased in the 4-week-old animals in the spinal cord ipsilateral to surgery relative to the contralateral side of the spinal cord, but not in the 2-week-old animals.
Conclusions:
These results suggest that developmental differences in COX-1 expression in the spinal cord likely explain the lack of efficacy of COX-1 inhibitors in the 2-week-old rats. Whether this reflects a deficit in factors that stimulate COX-1 expression or a difference in response to these factors is not addressed, but should similar deficits occur in humans, COX-1 inhibitors may exhibit reduced efficacy in infants.
Insights
Cyclooxygenase 1 (COX-1) inhibitors effectively reduce pain sensitivity in 4-week-old rats but not in 2-week-old rats. This difference is linked to developmental variations in spinal cord COX-1 expression following surgery.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Systemic cyclooxygenase 1 (COX-1) inhibition alleviates mechanical hypersensitivity post-surgery in older, but not younger, rats.
- This age-dependent efficacy suggests underlying developmental differences in COX-1 expression within the central nervous system.
Purpose of the Study:
- To investigate age-related differences in spinal cord cyclooxygenase 1 (COX-1) expression following incisional paw surgery.
- To correlate these expression changes with the efficacy of COX-1 inhibitors in pain management.
Main Methods:
- Utilized rats aged 2 and 4 weeks, modeling human infant and child development.
- Administered a selective COX-1 inhibitor (SC560) systemically and intrathecally, measuring withdrawal thresholds.
- Assessed spinal cord COX-1 protein and mRNA levels via immunohistochemistry and real-time PCR.
Main Results:
- SC560 increased withdrawal thresholds in 4-week-old rats, but not 2-week-old rats, with intrathecal administration being significantly more potent.
- Spinal cord COX-1 protein and mRNA levels were elevated ipsilateral to the surgical site in 4-week-old rats, but not in 2-week-old rats.
Conclusions:
- Developmental variations in spinal cord COX-1 expression appear to account for the differential efficacy of COX-1 inhibitors in young rats.
- These findings suggest that reduced COX-1 inhibitor efficacy may occur in human infants due to similar developmental deficits.
