title: Lack of adrenomedullin in the central nervous system results in apparently paradoxical alterations on pain sensitivity.
abstract: Adrenomedullin (AM) is a regulatory peptide, coded by the adm gene, which is involved in numerous physiological processes, including pain sensitivity. Previous studies have shown that intrathecal injection of AM induced hyperalgesia in the rat. Here, we explore pain sensitivity in a mouse conditional knockout for adm in neurons of the central nervous system, including the spinal cord and dorsal root ganglia. Double immunofluorescence in wild-type (WT) animals shows that AM immunoreactivity is found in calcitonin gene-related peptide-positive neurons of the dorsal root ganglia but not in neurons that bind isolectin B4. Mice lacking adm had modified expression of canonical sensorial neuropeptides, having significantly more calcitonin gene-related peptide and less substance P and enkephalin than their WT littermates. Furthermore, the spinal cord of adm knockout mice expressed higher levels of the AM receptor components, suggesting a compensation attempt to deal with the lack of afferent AM signaling. Behavioral nociceptive tests also found differences between genotypes. In the tail-flick test, which measures mostly spinal reflexes, the adm-null animals had a longer latency than their WT counterparts. On the other hand, in the hotplate test, which requires encephalic processing, mice lacking adm had shorter latencies than normal littermates. These results suggest that AM acts as a nociceptive modulator in spinal reflexes, whereas it may have an analgesic function at higher cognitive levels. This study confirms the important role of AM in pain sensitivity processing but unveils a more complex scenario than previously surmised.
authors.affiliation: Department of Cellular, Molecular, and Developmental Neurobiology, Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Fernández
authors.forename: Julia
authors.initials: J
authors.lastname: Serrano
authors.forename: Ricardo
authors.initials: R
authors.lastname: Martínez-Murillo
authors.forename: Alfredo
authors.initials: A
authors.lastname: Martínez
mesh_terms: D053607:Adrenomedullin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010146:Pain / Q000235:genetics* / Q000378:metabolism; D010147:Pain Measurement; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000378:metabolism; D012018:Reflex / Q000235:genetics / Q000502:physiology; D020886:Somatosensory Disorders / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D009479:Neuropeptides; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D053607:Adrenomedullin