Reversal of peripheral nerve injury-induced hypersensitivity in the postpartum period: role of spinal oxytocin

Abstract

Background: Physical injury, including surgery, can result in chronic pain; yet chronic pain following childbirth, including cesarean delivery in women, is rare. The mechanisms involved in this protection by pregnancy or delivery have not been explored.

Methods: We examined the effect of pregnancy and delivery on hypersensitivity to mechanical stimuli of the rat hindpaw induced by peripheral nerve injury (spinal nerve ligation) and after intrathecal oxytocin, atosiban, and naloxone. Additionally, oxytocin concentration in lumbar spinal cerebrospinal fluid was determined.

Results: Spinal nerve ligation performed at mid-pregnancy resulted in similar hypersensitivity to nonpregnant controls, but hypersensitivity partially resolved beginning after delivery. Removal of pups after delivery prevented this partial resolution. Cerebrospinal fluid concentrations of oxytocin were greater in normal postpartum rats prior to weaning. To examine the effect of injury at the time of delivery rather than during pregnancy, spinal nerve ligation was performed within 24 h of delivery. This resulted in acute hypersensitivity that partially resolved over the next 2-3 weeks. Weaning of pups resulted only in a temporary return of hypersensitivity. Intrathecal oxytocin effectively reversed the hypersensitivity following separation of the pups. Postpartum resolution of hypersensitivity was transiently abolished by intrathecal injection of the oxytocin receptor antagonist, atosiban.

Conclusions: These results suggest that the postpartum period rather than pregnancy protects against chronic hypersensitivity from peripheral nerve injury and that this protection may reflect sustained oxytocin signaling in the central nervous system during this period.

Figure 1

Effect of spinal nerve ligation (SNL) surgery, when performed duringpregnancy, on withdrawal threshold. A. Withdrawal threshold over time in pregnant and nonpregnant rats, with surgery performed one week prior to delivery. B. Withdrawal threshold over time in pregnant an nonpregnant rats, with surgery performed one week prior to delivery and pups removed within 24 hr of delivery. Data are presented as mean ± SD, Bonferroni's Multiple Comparison Test: *p <0.05 compared to nonpregnant.

Figure 2

Effect of spinal nerve ligation (SNL) or sham surgery, when performed within 24 hr of delivery, on withdrawal threshold. Withdrawal threshold ipsilateral (A) or contralateral (B) to SNL or sham surgery in virgin, nonpregnant and in postpartum rats when surgery was performed within 24 hr of delivery. Data are presented as mean ± SD, Bonferroni's Multiple Comparison Test: ^*p<0.05 comparing postpartum SNL to nonpregnant SNL; ^{^}p<0.05 comparing postpartum SNL to postpartum Sham, ^&p<0.05 comparing postpartum SNL to nonpregnant Sham; ^{^}p<0.05 comparing nonpregnat SNL to nonpregnant Sham, ^@p<0.05 comparing nonpregnant Sham to postpartum Sham, ^#p<0.05 comparing nonpregnant Sham to postpartum SNL.

Figure 3

Effect of pups separation at the time of weaning on withdrawal threshold. Withdrawal threshold over time before and after weaning and separation of pups 22 days after delivery and with spinal nerve ligation (SNL) or sham surgery performed within 24 hr of delivery. Data are presented as mean ± SD, Bonferroni's Multiple Comparison Test: *p<0.05 comparing nonpregnant Sham to postpartum Sham; ^#p<0.05 comparing nonpregnant Sham to postpartum SNL.

Figure 4

Role of spinal oxytocin in postpartum antihypersensitivity. A. Cerebrospinal fluid (CSF) concentrations of oxytocin in nonpregnant animals (control), postpartum rats 22 days after delivery (With pups) or those 22 days after delivery with pups separated 24 hr earlier (Separated). The Bar represents the Mean. B. Withdrawal threshold over time in postpartum rats with spinal nerve ligation(SNL)following separation of pups and after intrathecal injection, at time 0, of oxytocin or vehicle.*p<0.05 compared to vehicle. C. Withdrawal threshold over time in postpartum rats 3 weeks after SNL at the time ofdelivery and receiving intrathecal injection of saline, the oxytocin receptor antagonist atosiban, or the opioid receptor antagonist, naloxone. For comparison, the effect of intrathecal atosiban in nonpregnant, non-postpartum rats is also shown. Data are presented as mean ± SD. Bonferroni's Multiple Comparison Test: *p<0.05 comparing atosiban SNL to saline SNL; ^@p < 0.05 comparing atosiban normal to atosiban SNL; ^#p<0.05 comparing atosiban normal to saline SNL.