PACAP and orphanin FQ/nociceptin -Distribution, importance and regulation in sensory neurons and spinal cord

Sammanfattning: Neuropeptide expression in the nervous system is abundant and plastic, and an altered expression after injury is an example of a functional response, helping the neuron to cope with adverse changes, and involves effects on differentiation, synthesis, repair/regeneration, survival, and modulation of signal transmission. I have investigated the distribution/expression of the neuropeptides, orphanin FQ/nociceptin (OFQ/N) and pituitary adenylate cyclase activating polypeptide (PACAP), under normal conditions, in response to nerve injuries, and also studied sensory responses in mice deficient for the PAC1 receptor (PAC1-/-). Expression of OFQ/N and its receptor is demonstrated in neurons in spinal cord dorsal and ventral horns, DRG and SCG. Expression in specific neurons in these tissues gives a morphological basis supporting their suggested role as modulators of sensory, especially nociceptive, transmission. Further modulatory roles are suggested by expression in motor neurons and SCG. Expression of PACAP in spinal cord dorsal and ventral horn neurons, and induced expression in motor neurons in response to sciatic nerve injury, is demonstrated. Further, PACAP expression is induced in DRG neurons in response to nerve transection, and compression injury. Intrathecal anti-BDNF infusion mitigates this injury induced expression, suggesting that endogenous BDNF can regulate PACAP expression. The injury induced PACAP expression, in DRG and motor neurons, indicates a possible role for PACAP in repair/regeneration and modulation of the sensory/nociceptive and motor transmission. More direct evidence for this is the finding of a pronounced decrease in pain behaviour in PAC1–/– mice, strongly suggesting a role for PACAP in modulation of inflammatory pain.