Reversal of Peripheral Nerve Injury-induced Hypersensitivity in the Postpartum Period

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.

C-tactile afferents: Cutaneous mediators of oxytocin release during affiliative tactile interactions?

“…In addition, oxytocin, through effects on GABA responses in nociceptive neurons, has an analgesic effect in newborn rat pups during delivery (Mazzuca et al, 2011). There is also evidence of up-regulation of oxytocin in plasma and CNS as well as an analgesic effect in rodent models of inflammatory (Eliava et al, 2016;Matsuura et al, 2015) and neuropathic pain (Gutierrez et al, 2013).…”

Chronic Pain Secondary to Childbirth

“…To investigate a potential mechanism for reduced pain sensitivity during pregnancy and/or the postnatal period, Gutierrez et al 5 performed a second study using a rat model to test whether pregnancy or nursing affected the development of spinal nerve ligation-induced hypersensitivity to a mechanical stimulus. The authors hypothesized that physiologic changes in pregnancy and/or the puerperium may protect against the development of hypersensitivity, and that oxytocin may play a role in this protective effect.…”

“…4,5 The first article reports the results of a multicenter longitudinal cohort study of pain and depression after human childbirth. 4 The second study uses a rat model to investigate the potential protective effect of oxytocin on the development of neuropathic hypersensitivity.…”

“…4 The second study uses a rat model to investigate the potential protective effect of oxytocin on the development of neuropathic hypersensitivity. 5 For the human study, the investigators recruited more than 2,500 women from two major U.S. institutions and two European institutions. 4 Study subjects were interviewed about chronic, pregnancy-associated, and acute postpartum pain within 36 h of delivery; scripted pain questionnaires were administered at 2-, 6-, and 12-months after delivery.…”

Phase 1 Safety Assessment of Intrathecal Oxytocin

“…4 Additionally, we recently showed that pain and hypersensitivity following surgery recovers more quickly in animals and humans when the surgery occurs near the time of delivery, and that this is reversed by spinal injection of an oxytocin receptor-preferring antagonist. 5,6 Oxytocin receptors are present in the superficial dorsal horn of human spinal cord 7 where it engages inhibitory circuits. 3,8,9 Thus, there is a clear rationale to test the efficacy of intrathecal oxytocin for analgesia in humans.…”