Analgesic and Antipyretic Activities of a Novel Tetrapeptide in Rats

The efficacy of a novel tetrapeptide sequence, FLPS (Phe-Leu-Pro-Ser), to alleviate severe pain associated with surgical incision is demonstrated in the Brennan model, a model used for developing new drugs for postoperative pain in humans. The tetrapeptide (100 mg/kg dose) administered by subdermal injection completely alleviated post-incisional pain in rats using the hindpaw withdrawal as an endpoint response. When the tetrapeptide (0.15 mg/paw) was topically applied to the vicinity of the surgical wound, it also alleviated pain. Statistically significant increases in pain threshold (assessed by von Frey filaments pressed against the surgical wound, 15–20 min after dosing) were observed on the day of surgery and on the third day post-surgery. Up to a 0.5°C decrease in body temperature under basal conditions and yeast-provoked pyrexia was observed at doses that alleviate pain. The tetrapeptide does not exhibit any significant anti-edema activity in carrageenan-induced hindpaw edema, and does not affect human recombinant cyclooxygenase-2 activity, indicating that the analgesic property of the tetrapeptide is unlikely to be mediated through inflammatory pathways. The tetrapeptide at 10 μM, a dose that is sufficient to increase the pain threshold in rats, does not compete with naloxone for the opioid receptors in membrane preparations from rat brain, indicating that it does not mediate its effect through the opioid receptors. It also does not bind to the vanilloid receptor, indicating that peripheral vanilloid receptors are not involved in pain relief by the tetrapeptide.