adrenomedullin and Pain

The CGRP system has emerged as a key pharmacological target for the treatment of migraine. However, some individuals who suffer from migraine have low or no response to anti-CGRP or other treatments, suggesting the need for additional clinical targets. CGRP belongs to the calcitonin family of peptides, which includes calcitonin, amylin, adrenomedullin and adrenomedullin 2. These peptides display a range of pro-nociceptive and anti-nociceptive actions, in primary headache conditions such as migraine. Calcitonin family peptides also show expression at sites relevant to migraine and pain. This suggests that calcitonin family peptides and their receptors, beyond CGRP, may be therapeutically useful in the treatment of migraine and other pain disorders. This review considers the localisation of the calcitonin family in peripheral pain pathways and discusses how they may contribute to migraine and pain. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Topics: Adrenomedullin; Calcitonin; Calcitonin Gene-Related Peptide; Headache; Humans; Migraine Disorders; Pain; Peptide Hormones; Receptors, Calcitonin Gene-Related Peptide

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Ghrelin; Humans; Inflammation; Inflammation Mediators; Leptin; Macrophage Activation; Microglia; Neuralgia; Neurodegenerative Diseases; Neuroglia; Neuropeptide Y; Neuropeptides; Pain; Pro-Opiomelanocortin; Tachykinins; Vasoactive Intestinal Peptide

Mas-related genes (Mrgs) belong to a large family of G protein-coupled receptor genes found in rodents. Human MRGX proteins are G protein-coupled 7-transmembrane proteins sharing 41-52% amino acid identity with each other, but have no orthologs in rodents. MrgX2 is a member of the MrgX family. MRGX2 is expressed in the small neurons of sensory ganglia and mast cells. It can interact with a series of factors and genes such as the peptides substance P, vasoactive intestinal peptide, cortistatin (CST), proadrenomedullin N-terminal peptide (PAMP), LL-37, PMX-53 and β-defensins. MRGX2 is related to nociception, adrenal gland secretion and mast cell degranulation. Recent research on MrgX2 provides insights into its role in nociception and anti-microbial activities. This article reviewed the origin, expression and function of MrgX2, and discussed possible future research focus.

Topics: Adrenomedullin; Cell Degranulation; Dextrorphan; Evolution, Molecular; Ganglia, Sensory; Gene Expression Regulation; Humans; Mast Cells; Nerve Tissue Proteins; Neuropeptides; Nociception; Pain; Protein Isoforms; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Signal Transduction; Substance P; Vasoactive Intestinal Peptide

The increase of pronociceptive mediators in the dorsal root ganglia (DRG) and spinal dorsal horn is an important mechanism in the pathogenesis of inflammatory pain and opioid tolerance. Adrenomedullin (AM) belongs to calcitonin gene-related peptide (CGRP) family and has been recently demonstrated to be a pain-related peptide. It has also been shown that the expression and release of AM are increased in the DRG and spinal dorsal horn during inflammation and repeated use of morphine. Intrathecal administration of the selective AM receptor antagonist AM22-52 abolishes inflammatory pain and morphine tolerance, suggesting that enhanced AM receptor signaling in the DRG and spinal dorsal horn contributes to the induction of inflammatory pain and morphine tolerance. The present review highlights the recent developments regarding the involvement of AM in these two disorders. The neurological mechanisms of AM's actions are also discussed.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Drug Tolerance; Ganglia, Spinal; Inflammation; Morphine; Pain; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Adrenomedullin

Vasovagal syncope is defined as a reflex loss of consciousness related to reaction to various stimuli as orthostatic stress, pain or emotions connected with loss of muscle postural tone. The aetiology of this disorder is still unknown. The imbalance between the parts of autonomic nervous system and other homeostasis-related systems as renin-angiotensin-aldosterone system, peptides as endothelin, neuropeptide Y, vasopressin, adrenomedullin and cAMP, adenosine and AMP can play an important role in the development of vasovagal syncope. In the first part of the paper the authors describe the mechanisms involved in the development of vasovagal reaction, pathophysiology of the head-up tilt test and the role of autonomic nervous system.

Topics: Adrenomedullin; Cyclic AMP; Endothelins; Humans; Muscle Hypotonia; Neuropeptide Y; Pain; Peptides; Posture; Receptors, Neurotransmitter; Renin-Angiotensin System; Syncope, Vasovagal; Vasopressins

The pain peptide adrenomedullin (AM) plays a pivotal role in pathological pain. The present study was designed to investigate the effect of blockade of AM receptor on bone cancer pain (BCP) and its mechanism. BCP was developed by inoculation of Walker 256 mammary gland carcinoma cells in the tibia medullary cavity of Sprague Dawley rats. The selective AM receptor antagonist AM

Topics: Adrenomedullin; Animals; Bone Neoplasms; Chemokine CCL2; Ganglia, Spinal; Hyperalgesia; Pain; Pain Threshold; Peptide Fragments; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Adrenomedullin

The calcitonin gene-related peptide (CGRP) family mainly includes CGRPα, CGRPβ, adrenomedullin, calcitonin and amylin. The members of CGRP family and their receptors are widely distributed in the central and peripheral nervous systems. Studies show that members of CGRP family such as CGRP and adrenomedullin play important roles in the transmission of nociceptive information. At spinal level, CGRP promotes the transmission of nociceptive information, spinal morphine tolerance, migraine, inflammatory pain and neuropathic pain. At superspinal level, CGRP suppresses the transmission of nociceptive information. Adrenomedullin is a pain-related neuropeptide which has recently been demonstrated. It facilitates the transmission of nociceptive information and is involved in the development and maintenance of opioid tolerance. The involvement of amylin and calcitonin in pain is not clear yet.

Topics: Adrenomedullin; Analgesics, Opioid; Animals; Calcitonin Gene-Related Peptide; Drug Tolerance; Humans; Islet Amyloid Polypeptide; Nociception; Pain

Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pronociceptive mediator. This study was undertaken to investigate the role of AM in acute inflammatory pain induced by formalin injection in rats. Interestingly Cerebrospinal fluid (CSF) levels of AM increased 45 min after formalin injection and a selective AM receptor antagonist, AM22-52, administered intrathecally (i.t.) decreased phase 2 flinching in a dose-dependent manner but not phase 1 flinching during the formalin test. This anti-hyperalgesic effect of i.t. AM22-52 lasted for 4 h or more. AM in the CSF contributes to the modulation of acute inflammatory pain in the formalin test, and blocking downstream signaling effects of the AM receptor has the potential to relieve pain associated with acute inflammation.

Topics: Adrenomedullin; Animals; Dose-Response Relationship, Drug; Humans; Inflammation; Injections, Spinal; Male; Pain; Pain Measurement; Peptide Fragments; Rats; Receptors, Adrenomedullin

Endothelin-1 (ET-1) has been suggested to be involved in different types of pain due to its neuromodulatory nature. However, its role in inflammatory pain processing, specifically the origin-specific effect, has not yet been clearly defined. Therefore, the aim of this study is to determine the role of cell-type specific ET-1 induction in the modulation of inflammatory pain processing.. The current study assesses the effects of ET-1 over-expression specifically targeted to astrocytes (GET-1) or endothelial cells (TET-1) on the expression of pain-like behaviors induced by a model of inflammatory pain, consisting of a formalin injection into the hind paw.. The baseline sensitivity thresholds of GET-1 and TET-1 mice to the response elicited by tactile and radiant heat stimulation were similar to those observed in age-matched non-transgenic (NTg) controls. Relative to the NTg controls, GET-1 mice displayed a marked decrease in pain-like behavioral responses during the second phase of formalin-induced pain (i.e., 15-20 min after injection), whereas the responses elicited in TET-1 mice were unaltered. The levels of mRNA encoding adrenomedullin, calcitonin gene-related peptide and calcitonin-like receptor were elevated in the spinal cord of saline-injected GET-1 mice compared to those of NTg mice.. The current results support a suppressor role for astrocyte-derived ET-1 in inflammatory pain and suggest that the study of GET-1 mice might provide mechanistic insights for improving the treatment of inflammatory pain.

Topics: Adrenomedullin; Animals; Astrocytes; Behavior, Animal; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Disease Models, Animal; Endothelial Cells; Endothelin-1; Formaldehyde; Gene Expression Regulation; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; RNA, Messenger; Spinal Cord

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.

Topics: Adrenomedullin; Animals; Behavior, Animal; Central Nervous System; Ganglia, Spinal; Hyperalgesia; Male; Mice; Mice, Knockout; Neuropeptides; Organ Specificity; Pain; Pain Measurement; Receptors, Adrenomedullin; Receptors, Peptide; Reflex; Somatosensory Disorders; Spinal Cord

Adrenomedullin (AM) belongs to the calcitonin gene-related peptide (CGRP) family and is a well known potent vasodilator. We show here that AM is a powerful pain-inducing neuropeptide. AM-like immunoreactivity is widely distributed in both CGRP-containing and lectin IB4-binding nociceptors in dorsal root ganglion and axon terminals in the superficial dorsal horn of the rat spinal cord. Specific binding sites for the radioligand, [(125)I]AM13-52 as well as immunoreactivity for receptor markers such as the calcitonin receptor-like receptor and three receptor-activity-modifying proteins are localized in the superficial dorsal horn, demonstrating the existence of AM/CGRP receptors in this region. Intrathecal injection of rat AM1-50, dose- and time-dependently, induced long-lasting heat hyperalgesia and increased the phosphorylation of Akt and GSK3beta in the dorsal horn. Pre- and posttreatments with the AM receptor antagonist AM22-52 and PI3 kinase inhibitors (LY294002 and Wortmannin) significantly blocked or reversed AM-induced heat hyperalgesia. Pre- and posttreatments with AM22-52 and Wortmannin also significantly blocked or reversed intraplantar capsaicin-induced heat hyperalgesia. Taken together, our results demonstrate that AM acts as a pain-inducing peptide in the dorsal horn. By activating specific receptors (likely AM2) and the PI3K/Akt/GSK3beta signaling pathway, AM could play a significant role in long-lasting heat hypersensitivity and inflammatory heat hyperalgesia.

Topics: Adrenomedullin; Animals; Behavior, Animal; Binding Sites; Calcitonin Gene-Related Peptide; Capsaicin; Enzyme Activation; Ganglia, Spinal; Inflammation; Injections, Spinal; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Nociceptors; Pain; Phosphotransferases; Rats; Rats, Sprague-Dawley; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Peptide; Signal Transduction