Morphine withdrawal is modified in pituitary adenylate cyclase-activating polypeptide type I-receptor-deficient mice.
The pituitary adenylate cyclase-activating polypeptide type I-receptor (PAC1) is a G-protein-coupled receptor that is widely expressed in neurons of the central and peripheral nervous system. The strong expression of PAC1 in the second sensory neuron as well as in brainstem regions such as the locus coeruleus prompted us to elucidate the potential in vivo role of PAC1-mediated signalling in pain perception and opioid addiction using a PAC1-deficient mouse line. We observed a selective involvement of PAC1 in the mediation of visceral pain. While there was no impairment in acute somatic pain perception, PAC1-mutants exhibited a dramatically decreased response in the abdominal writhing test. These data in concert with data from the literature implicate PAC1 in the mediation of visceral and chronic pain. In addition, we observed that PAC1 did not influence the motivational aspects of opioid addictive properties, since morphine-induced rewarding effects and sensitization to locomotor responses were completely maintained in PAC1-deficient mice. However, there was a dramatic increase in physical withdrawal signs after naloxone-precipitated morphine withdrawal in PAC1 mutants. At the cellular level, electrophysiological examinations in locus coeruleus neurons from morphine-dependent wild-type and PAC1-deficient mice did not reveal any differences in firing rates. These data therefore suggested that most likely disruption of PAC1-mediated signalling in afferents towards the locus coeruleus but not within the intrinsic locus coeruleus system led to the enhancement of somatic withdrawal signs.
Martin
Miquel
M
Laboratory of Neuropharmacology, Faculty of Medicine, University Pompeu Fabra, c/ Doctor Aiguader 80, 08003 Barcelona, Spain.
Otto
Christiane
C
Santamarta
Maria Teresa
MT
Torrecilla
Maria
M
Pineda
Joseba
J
Schütz
Günther
G
Maldonado
Rafael
R
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000235:genetics*; D009619:Nociceptors / Q000187:drug effects; D010147:Pain Measurement; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
C495402:Adcyap1 protein, mouse; D000701:Analgesics, Opioid; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D009020:Morphine