Mechanical pain hypersensitivity after incisional surgery is enhanced in rats subjected to neonatal peripheral inflammation: Effects of N-methyl-D-aspartate receptor antagonists

BACKGROUND: Neonatal pain and inflammation may lead to a long-term effect on nociceptive processing in adults. The current study examined the characteristics of postoperative incisional pain behaviors in adult rats that were subjected to neonatal peripheral inflammation. METHODS: Rat pups received a subcutaneous injection of saline or carrageenan into the plantar surface of the left hind paw at postnatal day 1. Naive pups were used as the control. Paw withdrawal thresholds to punctuate mechanical stimuli were examined at postnatal days 35, 42, and 49. After rats received a plantar incision on the left or right hind paw at postnatal day 50, paw withdrawal thresholds were measured at 4 h, 1 day, 2 days, 3 days, 5 days, and 7 days after incision. In addition, spinal cord Fos expression was detected at 2 h after incision. Finally, the effects of intrathecal N-methyl-d-aspartate receptor antagonists dl-2-amino-5-phosphonovaleric acid and dizocilpine and the nitric oxide synthase inhibitor l-N-nitro-arginine methylester on incisional pain were examined at 4 h after incision. RESULTS: Although the rats subjected to neonatal peripheral carrageenan injection developed mechanical hypoalgesia in bilateral hind paws at baseline, they displayed increased spinal cord Fos expression at 2 h and exaggerated mechanical pain hypersensitivity at 4 h (but not at other time points) after plantar incision. Intrathecal dl-2-amino-5-phosphonovaleric acid, dizocilpine, and l-N-nitro-arginine methylester significantly attenuated incision-induced mechanical pain hypersensitivity at 4 h after incision in the neonatally carrageenan-treated rats, but not in the naive or neonatally saline-treated rats. CONCLUSIONS: The authors' results suggest that early inflammatory insults during the neonatal period could produce excessive incision-associated mechanical pain hypersensitivity in adult rats. Spinal cord N-methyl-d-aspartate receptors and downstream nitric oxide signaling might contribute to this abnormal pain hypersensitivity, although the mechanisms underlying the long-term effect of neonatal inflammation are still unclear.