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.

Adrenomedullin as a Growth and Cell Fate Regulatory Factor for Adult Neural Stem Cells

“…Furthermore, lack of AM expression has behavioral consequences when pain sensitivity was tested with the tail-flick and the hotplate latency paradigms. The results of the test suggest the possibility that AM acts as a nociceptive modulator in spinal reflexes, whereas it may have an analgesic function at higher cognitive levels [99]. This study confirms the important role of AM in pain sensitivity processing, but presents a more complex function of AM than previously described.…”

“…Following this line of thought, Fernández et al [99] explored pain sensitivity in a mouse conditional KO model for AM in neurons of the CNS, including the spinal cord and dorsal root ganglia. Elimination of the AM gene in the CNS of the mouse results in expression changes for several sensory neurotransmitters, including CGRP, substance P, and enkephalin, in the dorsal root ganglia and the spinal cord.…”

Central Administration of C-X-C Chemokine Receptor Type 4 Antagonist Alleviates the Development and Maintenance of Peripheral Neuropathic Pain in Mice

“…SP is locally expressed by secondary sensory neuron at the lumbar spinal cord [25], and spinal SP expression is inducible following neuropathy, implicating that SP may account for the pain signaling to higher level of nociceptive structure [26]. AM is a pain-related neuropeptide with partial homology to CGRP, and recent research with transgenic technology unveiled its central role in pain processing was more complicated than previously surmised [27]. Because the presence of pre-synaptic and post-synaptic CXCR4 receptor implicates the potential interaction of CXCR4 signaling and the release of neurotransmitters [9], our results verified this hypothesis that neuronal CXCR4 may modulate SP and AM-mediated synaptic activity in central nociception.…”

Adrenomedullin and the calcitonin receptor-like receptor system mRNA expressions in the rat heart and sensory ganglia in experimentally-induced long-term diabetes

“…it increases in DRG neurons within hours after injection of complete Freund's adjuvant (CFA) into the rat hind paw (Hong et al 2009). AM is coexpressed with CGRP in DRG neurons (Fernández et al 2010), and it influences CGRP expression as CGRP content is diminished in DRG from neuron specific AM knockout mice (Fernández et al 2010) and the blockade of AM receptors abrogates changes in CGRP expression in the hind paw-CFA model (Hong et al 2009). We are not aware, however, on previous reports on AM expression and potential regulation in vagal sensory neurons.…”