Age- and Sex-Specific Nociceptive Response to Endothelin-1

Endothelin-1 (ET-1) is a chemical mediator released by the body at sites of injury and disease. This study tests the hypothesis that ET-1–induced nociception changes with age and sex. Intraplantar ET-1 (1.1 and 3.3 nmol) produced age-specific paw flinching and licking (postnatal day 7 > 21 > 60). The onset and duration of the nociceptive responses was dependent on age. Postnatal day (P) 21 and 60 rats displayed an immediate onset of behavior that subsided with time, whereas the P7 rats had a delayed behavioral response that onset at 20 minutes after ET-1 administration and continued beyond the 75 minute observation period. P7 males showed greater paw flinching compared with females. In addition to spontaneous nociceptive behaviors, ET-1 produced mechanical allodynia in all ages. As with spontaneous nociception, ET-1–induced mechanical allodynia was of a longer duration in the younger aged rats compared with adult rats. These findings show that ET-1 produces both spontaneous nociceptive behaviors and evoked mechanical allodynia in both young and adult rats but that the temporal profile and the size of the responses are age- and sex-dependent. These findings are the first description of age- and sex-specific ET-1–induced nociception.PerspectiveEndothelin-1 is a vasoactive peptide released into the systemic circulation after stress and cold pain as well as locally in tissue after injury and disease. These findings suggest greater pain to stimuli that release endogenous endothelin in younger versus older organisms. This developmental approach to studying ET-1–induced pain further illustrates the need for understanding pain mechanisms as a function of the development of the organism so as to better treat pain across the life span.