Divergent peripheral effects of pituitary adenylate cyclase-activating polypeptide-38 on nociception in rats and mice

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and its receptors have been shown in the spinal dorsal horn, on capsaicin-sensitive sensory neurons and inflammatory cells. The role of PACAP in central pain transmission is controversial, and no data are available on its function in peripheral nociception. Therefore, the aim of the present study was to analyze the effects of locally or systemically administered PACAP-38 on nocifensive behaviors, inflammatory/neuropathic hyperalgesia and afferent firing. Intraplantar PACAP-38 (0.2 nmol) injection inhibited carrageenan-evoked inflammatory mechanical allodynia, mild heat injury-induced thermal hyperalgesia, as well as nocifensive behaviors in the early and late phases of the formalin test in rats. However, the above dose did not alter basal mechanical or heat thresholds. In mice, PACAP-38 (0.2 nmol/kg s.c.) significantly diminished acetic acid-induced abdominal contractions, but exerted no effect on sciatic nerve ligation-induced neuropathic mechanical hyperalgesia. In contrast, local PACAP-38 injection markedly increased rotation-induced afferent firing in the inflamed rat knee joint clearly demonstrating a peripheral sensitization in this organ. These actions were blocked by VPAC1/VPAC2 receptor antagonist pretreatment, but were not altered by PAC1 receptor antagonism. This paper presents the first data for the peripheral actions of PACAP-38 on nociceptive transmission mediated by VPAC receptors. These effects seem to be divergent depending on the mechanisms of nociceptor activation and the targets of PACAP actions. In acute somatic and visceral inflammatory pain models, PACAP exerts anti-nociceptive, anti-hyperalgesic and anti-allodynic effects. It has no significant peripheral role in traumatic mononeuropathy, but induces mechanical sensitization of knee joint primary afferents.