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The individual and global burden of migraine is of such significance that there are accelerated efforts to develop new therapies. New migraine therapeutics are needed to address the current deficiencies that exist in the efficacy and adherence rate of approved anti-migraine medications. The recent discovery of the calcitonin gene related peptide as an add-on to the role of serotonin has markedly increased the range of new treatment options for acute and chronic migraine. Despite this, tackling the complexity of migraine disorders requires a complete understanding of its pathophysiology. Preclinical animal models can shed light on disease-related pathophysiology, including migraine. Indeed, the use of animal models has been instrumental in developing many therapeutics. However, an animal model is limited by the predictive and face validity of that model, and this extends to preclinical migraine models. In this review, a summary of the current understanding of the pathophysiology of migraine is given from both a preclinical and clinical perspective, and an emphasis is placed on the animal models of migraine. We will discuss the strengths and pitfalls of common preclinical migraine models as well as experimental research areas to explore further. [ABSTRACT FROM AUTHOR]

The individual and global burden of migraine is of such significance that there are accelerated efforts to develop new therapies. New migraine therapeutics are needed to address the current deficiencies that exist in the efficacy and adherence rate of approved anti-migraine medications. The recent discovery of the calcitonin gene related peptide as an add-on to the role of serotonin has markedly increased the range of new treatment options for acute and chronic migraine. Despite this, tackling the complexity of migraine disorders requires a complete understanding of its pathophysiology. Preclinical animal models can shed light on disease-related pathophysiology, including migraine. Indeed, the use of animal models has been instrumental in developing many therapeutics. However, an animal model is limited by the predictive and face validity of that model, and this extends to preclinical migraine models. In this review, a summary of the current understanding of the pathophysiology of migraine is given from both a preclinical and clinical perspective, and an emphasis is placed on the animal models of migraine. We will discuss the strengths and pitfalls of common preclinical migraine models as well as experimental research areas to explore further.

AbstractMigraine is a chronic neurologic disease estimated to affect approximately 50 million Americans. It is associated with a range of symptoms, which contribute to disability and substantial negative impacts on quality of life for many patients. Still, migraine continues to be underdiagnosed, undertreated, and optimising treatment for individual patients has proven difficult. As many migraine patients will be seen first in primary care settings, internists and other primary care providers are ideally positioned to improve diagnosis and migraine management for many patients. In this review, we discuss some of the challenges in diagnosing migraine and suggest strategies to overcome them, summarise the current understanding of migraine pathophysiology and clinical evidence on acute and preventive treatment options, and offer practical approaches to diagnosis and contemporary management of migraine in the primary care setting.Key messagesMigraine is a prevalent disease with substantial impact. Primary care providers are ideally positioned to improve care for migraine patients with streamlined approaches to diagnosis and management.A stepwise diagnostic approach to migraine involves taking a thorough headache history, excluding secondary headache, and identifying primary headache disorder using screening tools or ICHD-3 criteria.The FDA approved seven new migraine therapies from 2018 to 2020 (four monoclonal antibodies, two gepants, one ditan), expanding acute and preventive therapeutic options.

Migraine is a chronic neurologic disease estimated to affect approximately 50 million Americans. It is associated with a range of symptoms, which contribute to disability and substantial negative impacts on quality of life for many patients. Still, migraine continues to be underdiagnosed, undertreated, and optimising treatment for individual patients has proven difficult. As many migraine patients will be seen first in primary care settings, internists and other primary care providers are ideally positioned to improve diagnosis and migraine management for many patients. In this review, we discuss some of the challenges in diagnosing migraine and suggest strategies to overcome them, summarise the current understanding of migraine pathophysiology and clinical evidence on acute and preventive treatment options, and offer practical approaches to diagnosis and contemporary management of migraine in the primary care setting. Migraine is a prevalent disease with substantial impact. Primary care providers are ideally positioned to improve care for migraine patients with streamlined approaches to diagnosis and management. A stepwise diagnostic approach to migraine involves taking a thorough headache history, excluding secondary headache, and identifying primary headache disorder using screening tools or ICHD-3 criteria. The FDA approved seven new migraine therapies from 2018 to 2020 (four monoclonal antibodies, two gepants, one ditan), expanding acute and preventive therapeutic options. [ABSTRACT FROM AUTHOR]

The etiology of migraine pain involves sensitized meningeal afferents that densely innervate the dural vasculature. These afferents, with their cell bodies located in the trigeminal ganglion, project to the nucleus caudalis, which in turn transmits signals to higher brain centers. Factors such as chronic stress, diet, hormonal fluctuations, or events like cortical spreading depression can generate a state of “sterile inflammation” in the intracranial meninges resulting in the sensitization and activation of trigeminal meningeal nociceptors. This sterile inflammatory phenotype also referred to as neurogenic inflammation is characterized by the release of neuropeptides (such as substance P, calcitonin gene related peptide) from the trigeminal innervation. This release leads to vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Although neurogenic inflammation has been observed and extensively studied in peripheral tissues, its role has been primarily investigated in the genesis and maintenance of migraine pain. While some aspects of neurogenic inflammation has been disregarded in the occurrence of migraine pain, targeted analysis of factors have opened up the possibilities of a dialogue between the neurons and immune cells in driving such a sterile neuroinflammatory state in migraine pathophysiology. [ABSTRACT FROM AUTHOR]

In migraine attack treatment analgesics such as nonsteroidal anti-inflammatory drugs and triptans can be utilized. The efficacy of acute attack treatment is relevant to prevent migraine chronification. For prophylactic treatment β-blockers, tricyclic antidepressants, flunarizine, antiepileptics and onabotulinumtoxin A are available. There is evidence that some other substances (e. g. sartans) are also efficacious in this regard. Furthermore, nondrug approaches are essential in migraine therapy. Early education and prophylactic treatment of patients at risk may prevent from medication overuse headache. Noninvasive neuromodulatory approaches as supraorbital or vagal nerve stimulation are emerging methods for prophylactic treatment. Ongoing clinical trials investigate an oral calcitonin gene-related peptide (CGRP) antagonist for acute treatment and several prophylactic monoclonal CGRP or CGRP receptor-antibodies regarding safety, side effects and efficacy as new therapeutic options. [ABSTRACT FROM AUTHOR]

Introduction:Cluster headache is the worst primary headache form; it occurs in paroxysmal excruciatingly severe unilateral head pain attacks usually grouped in cluster periods. The familial occurrence of the disease indicates a genetic component but a gene abnormality is yet to be disclosed. Activation of trigeminal afferents and cranial parasympathetic efferents, the so-called trigemino-parasympathetic reflex, can explain pain and accompanying oculo-facial autonomic phenomena. In particular, pain in cluster headache is attributed, at least in part, to the increased CGRP plasma levels released by activated trigeminal system. Posterior hypothalamus was hypothesized to be the cluster generator activating the trigemino-parasympathetic reflex. Efficacy of monoclonal antibodies against CRGP is under investigation in randomized clinical trials. Areas covered:This paper will focus on main findings contributing to consider cluster headache as a neurovascular disorder with an origin from within the brain. Expert commentary:Accumulated evidence with hypothalamic stimulation in cluster headache patients indicate that posterior hypothalamus terminates rather than triggers the attacks. More extensive studies on the genetics of cluster headache are necessary to disclose anomalies behind the increased familial risk of the disease. Results from ongoing clinical trials in cluster headache sufferers using monoclonal antibodies against CGRP will open soon a new era. [ABSTRACT FROM PUBLISHER]

Introduction: Based on animal studies, calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are thought to play a role in neurobiological events such as neuropathic pain, neuroprotection, neurotransmission, neural plasticity, and neurotrophic effects. The aim of the study is to investigate whether there is a change in the blood level of CGRP and PACAP in patients with neuropathic pain and to look for clues about the utility of these peptides as pharmacological targets in the treatment of neuropathic pain in humans., Methods: The study included 60 polyneuropathy patients with neuropathic pain, 30 polyneuropathy patients without neuropathic pain (NNP) and 29 healthy subjects as control group. Polyneuropathy patients with neuropathic pain were divided into two groups as diabetic (D-PNP) and non-diabetic polyneuropathy (ND-PNP) patients. Plasma CGRP and serum PACAP levels were measured from venous blood samples of the patients and healthy controls., Results: The CGRP level was significantly higher in the D-PNP and ND-PNP groups compared to the control and NNP groups (P<0.05). PACAP levels were significantly higher in the D-PNP and ND-PNP groups compared to the control and NNP groups (P<0.05). There was no significant correlation between CGRP and PACAP levels and neuropathic pain scale (NPS)., Conclusions: This study is the first to demonstrate elevated plasma CGRP and serum PACAP levels in polyneuropathy patients with neuropathic pain. The results of this study are important in terms of showing that both CGRP and PACAP can be new pharmacological targets in the treatment of neuropathic pain and polyneuropathy in humans., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

The role of neuropeptides in cardiomyopathy-associated heart failure has been garnering more attention. Several neuropeptides – Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), substance P (SP) and their receptors have been studied in the various types of cardiomyopathies. The data indicate associations with the strength of the association varying depending on the kind of neuropeptide and the nature of the cardiomyopathy – diabetic, ischemic, inflammatory, stress-induced or restrictive cardiomyopathy. Several neuropeptides appear to alter regulation of genes involved in heart failure. Demonstration of an association is an essential first step in proving causality or establishing a role for a factor in a disease. Understanding the complexity of neuropeptide function should be helpful in establishing new or optimal therapeutic strategies for the treatment of heart failure in cardiomyopathies. [ABSTRACT FROM AUTHOR]

Abstract: Airway sensory C-fibres express TRPA1 channels which have recently been identified as a key chemosensory receptor for acrolein, a toxic and highly prevalent component of smoke. TRPA1 likely plays an intermediary role in eliciting a range of effects induced by acrolein including cough and neurogenic inflammation. Currently, it is not known whether acrolein-induced activation of TRPA1 produces other airway effects including relaxation of mouse airway smooth muscle. The aims of this study were to examine the effects of acrolein on airway smooth muscle tone in mouse isolated trachea, and to characterise the cellular and molecular mechanisms underpinning the effects of acrolein. Isometric tension recording studies were conducted on mouse isolated tracheal segments to characterise acrolein-induced relaxation responses. Release of the relaxant PGE2 was measured by EIA to examine its role in the response. Use of selective antagonists/inhibitors permitted pharmacological characterisation of the molecular and cellular mechanisms underlying this relaxation response. Acrolein induced dose-dependent relaxation responses in mouse isolated tracheal segments. Importantly, these relaxation responses were significantly inhibited by the TRPA1 antagonists AP-18 and HC-030031, an NK1 receptor antagonist RP-67580, and the EP2 receptor antagonist PF-04418948, whilst completely abolished by the non-selective COX inhibitor indomethacin. Acrolein also caused rapid PGE2 release which was suppressed by HC-030031. In summary, acrolein induced a novel bronchodilator response in mouse airways. Pharmacologic studies indicate that acrolein-induced relaxation likely involves interplay between TRPA1-expressing airway sensory C-fibres, NK1 receptor-expressing epithelial cells, and EP2-receptor expressing airway smooth muscle cells. [Copyright &y& Elsevier]

Highlights: [•] Defining the circuits which employ CART as neurotransmitter. [•] Analysis of the diverse functions attributed to the neuropeptide CART. [•] Understand the role of CART in disparate neuronal circuitries. [•] CART in the brain of vertebrates and its evolutionary significance. [•] Identify the lacunae in current literature on CART and to seek future directions. [Copyright &y& Elsevier]

Abstract: Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of N/OFQ. Additionally, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present review focuses on the role of N/OFQ in the regulation of feeding, body weight homeostasis, stress, the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit. [Copyright &y& Elsevier]

Highlights: [•] CaV2.2 calcium channels are a prime target for development of novel analgesics. [•] Targeting CaV2.2 complex proteins may avoid side-effects of CaV2.2-targeted drug. [•] Axonal growth protein CRMP2 interacts with and regulates function of CaV2.2. [•] CRMP2 peptide is anti-nociceptive in models of neuropathic pain. [•] Tailored CRMP2 peptides hold promise for next generation analgesics. [ABSTRACT FROM AUTHOR]

Abstract: Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through β2-adrenoceptors (β2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor α (TNFα) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on β2-ARs expressed by non-neuronal satellite cells. This stimulation of β2-ARs decreases the neuropathy-induced production of membrane-bound TNFα, resulting in relief of neuropathic allodynia. This indirect anti-TNFα action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the β2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies. [Copyright &y& Elsevier]

Abstract: Both chronic cough and chronic pain are critical clinical issues in which a large number of patients remain unsatisfied with available treatments. These conditions have considerable effects on sufferers' quality of life, who often show co-morbidities such as anxiety and depression. There is therefore a pressing need to find new effective therapies. The basic neurobiological mechanisms and pathologies of these two conditions show substantial homologies. However, whilst chronic pain has received a great deal of attention over the last few decades, the same cannot be said for the neurological underpinnings of chronic cough. There is a substantial literature around mechanisms of chronic pain which is likely to be useful in advancing knowledge about the pathologies of chronic cough. Here we compare the basic pain and cough pathways, in addition to the clinical features and possible pathophysiologies of each; including mechanisms of peripheral and central sensitisation which may underlie symptoms such as hyperalgesia and allodynia, and hypertussitvity and allotussivity. Due to the substantial overlap that emerges, it is likely that therapies may be effective over both areas. [Copyright &y& Elsevier]

Abstract: The barrier properties of the skin pose a significant but not insurmountable obstacle for development of new effective anti-inflammatory therapies. The objective of this study was to design and evaluate therapeutic efficacy of anti-nociception agent Capsaicin (Cap) and anti-TNFα siRNA (siTNFα) encapsulated cyclic cationic head lipid-polymer hybrid nanocarriers (CyLiPns) against chronic skin inflammatory diseases. Physico-chemical characterizations including hydrodynamic size, surface potential and entrapment efficacies of CyLiPns were found to be 163±9nm, 35.14±8.23mV and 92% for Cap, respectively. In vitro skin distribution studies revealed that CyLiPns could effectively deliver FITC-siRNA up to 360μm skin depth. Further, enhanced (p<0.001) Cap permeation from CyLiPns was observed compared to Capsaicin-Solution and Capzasin-HP. Therapeutic efficacies of CyLiPns were assessed using imiquamod-induced psoriatic plaque like model. CyLiPns carrying both Cap and siTNFα showed significant reduced expression of TNFα, NF-κB, IL-17, IL-23 and Ki-67 genes compared to either drugs alone (p<0.05) and were in close comparison with Topgraf®. Collectively these findings support our notion that novel cationic lipid-polymer hybrid nanoparticles can efficiently carry siTNFα and Cap into deeper dermal milieu and Cap with a combination of siTNFα shows synergism in treating skin inflammation. [Copyright &y& Elsevier]

Many disturbances in electrolyte and hormonal balance in the body induced by functional impairment of renal parenchyma may affect the activity of amine precursor uptake and decarboxylation (APUD) cells, which constitute a very important link in the regulation of homeostasis. The aim of the present study was the morphological, immunohistochemical and ultrastructural estimation of enteroendocrine cells in the stomach of uremic rats. Fragments of gastric pylorus were collected 1, 2 and 4 weeks after nephrectomy. Paraffin embedded sections were stained with H + E and by silver impregnation. For identification of neuroendocrine cells, immunohistochemical reactions were performed using specific antibodies against somatostatin, synaptophysin, neuron-specific enolase and anti-calcitonin gene related peptide. The analysis showed an increased number of APUD cells in the stomach of uremic rats compared to control rats, which may be a morphological expression of their hyperfunction in the functional impairment of renal parenchyma. These results suggest that chronic renal failure can modulate the secretory processes of APUD cells. [Copyright &y& Elsevier]

Intrinsic primary afferent neurons (IPANs) of the enteric nervous system are quite different from all other peripheral neurons. The IPANs are transducers of physiological stimuli, including movement of the villi or distortion of the mucosa, contraction of intestinal muscle and changes in the chemistry of the contents of the gut lumen. They are the first neurons in intrinsic reflexes that influence the patterns of motility, secretion of fluid across the mucosal epithelium and local blood flow in the small and large intestines. In the guinea pig small intestine, where they have been characterized in detail, IPANs have Dogiel type II morphology, that is they are large round or oval neurons with multiple processes, some of which end close to the luminal surface of the intestine, and some of which form synapses with enteric interneurons, motor neurons and with other IPANs. The IPANs have well-defined ionic currents through which their excitability, and their functions in enteric nerve circuits, is determined. These include voltage-gated Na+ and Ca2+ currents, a long lasting calcium-activated K+ current, and a hyperpolarization-activated cationic current. The IPANs exhibit long-term changes in their states of excitation that can be induced by extended periods of low frequency activity in synaptic inputs and by inflammatory mediators, either applied directly or released during an inflammatory challenge. The IPANs may be involved in pathological changes in enteric function following inflammation. [Copyright &y& Elsevier]

Antigen challenge can provoke acute bronchoconstriction, recognized as immediate asthmatic response (IAR), but the evolving events in this reaction are not well defined. Recently, a novel peptide, designated adrenomedullin, was isolated from human pheochromocytoma, and has been shown to have potent systemic and pulmonary vasodilator activity.The purpose of this study was to elucidate the influence of adrenomedullin in the development of IAR. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride, and then artificially ventilated. Ovalbumin was inhaled after an intravenous administration of adrenomedullin. Other studies were performed in naive guinea pigs to investigate the airway responses to inhaled methacholine or histamine after an intravenous administration of adrenomedullin. Antigen challenge caused bronchoconstriction in sensitized guinea pigs. Adrenomedullin did not inhibit the antigen-induced bronchoconstriction in sensitized guinea pigs or the dose-dependent responses to inhaled methacholine or histamine in naive animals in spite of its vasodilating effect. We conclude that an intravenous administration of adrenomedullin does not influence antigen-induced bronchoconstriction or bronchial responsiveness to inhaled methacholine or histamine in vivo. [Copyright &y& Elsevier]

Hexoprenaline is a beta-adrenergic agent used for tocolysis after the 26th week of pregnancy. The purpose of the present study was to demonstrate the site of action of hexoprenaline on the membrane of single isolated smooth muscle cells. The main action of beta-mimetics on the cell is hyperpolarization of the cellular membrane, i.e. beta-mimetics have similar effects as K(+)-ions (Standen et al., 1989). Our results indicate a prolonged and significantly enhanced activity of K(+)-channels in the cell membrane, as may also be demonstrated by the use of the K(+)-channel activator Calcitonin-gene related peptide (CGRP). In control experiments under physiological conditions, we observed a large conductance K(+)-channel with 158 pS. The channel was voltage dependent and Ca++ sensitive indicating that it belongs to the class of big conductance Ca(++)-activated K(+)-channels (BKCa). Hexoprenaline and CGRP both increased the open probability (P(o)) of the channel measured with the patch clamp system in the cell attached configuration. Hexoprenaline was also an activator of the BKCa in the presence of Nitrendipine, indicating that the activation of the Ca++ sensitive channel is not an indirect effect of Ca++ currents via L-type Ca++ channels. [ABSTRACT FROM AUTHOR]

Activation of the trigeminal system causes the release of various neuropeptides, cytokines, and other immune mediators. Calcitonin gene-related peptide (CGRP), which is a potent algogenic mediator, is expressed in the peripheral sensory neurons of trigeminal ganglion (TG). It affects the inflammatory responses and pain sensitivity by modulating the activity of glial cells. The primary aim of this study was to use array analysis to investigate the effect of CGRP on the glial cells of TG in regulating nuclear factor kappa B (NF-κB) signaling genes and to further check if CGRP in the TG can affect neuron-glia activation in the spinal trigeminal nucleus caudalis. The glial cells of TG were stimulated with CGRP or Minocycline (Min) + CGRP. The effect on various genes involved in NF-κB signaling pathway was analyzed compared to no treatment control condition using a PCR array analysis. CGRP, Min + CGRP or saline was directly injected inside the TG and the effect on gene expression of Egr1, Myd88 and Akt1 and protein expression of cleaved Caspase3 (cleav Casp3) in the TG, and c-Fos and glial fibrillary acidic protein (GFAP) in the spinal section containing trigeminal nucleus caudalis was analyzed. Results showed that CGRP stimulation resulted in the modulation of several genes involved in the interleukin 1 signaling pathway and some genes of the tumor necrosis factor pathway. Minocycline pre-treatment resulted in the modulation of several genes in the glial cells, including anti-inflammatory genes, and neuronal activation markers. A mild increase in cleav Casp3 expression in TG and c-Fos and GFAP in the spinal trigeminal nucleus of CGRP injected animals was observed. These data provide evidence that glial cells can participate in neuroimmune interaction due to CGRP in the TG via NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

The role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been highlighted in mechanisms underlying inflammatory and neuropathic pain processes. The present study was designed to investigate whether NF-κB signaling is associated with pain-related neuropeptide expression in patients with chronic back pain related to degenerative disc disease (DDD). Intervertebral disc (IVD) tissues were collected from forty DDD patients undergoing disc replacement or fusion surgery, and from eighteen postmortem (PM) control subjects. RELA, NFKB1, CGRP, TAC1, TRPV1, and MMP-3 gene expression were analyzed by RT-qPCR, while NF-κB subunit RelA and NF-κB1–DNA binding in nuclear extracts and calcitonin gene related peptide (CGRP), substance P (SP), and transient receptor potential, subfamily V, member 1 (TRPV1) protein levels in cytosolic extracts of tissues were assessed by enzyme-linked immunosorbent assay (ELISA). An upregulated NF-κB1–DNA binding, and higher CGRP and TRPV1 protein levels were observed in DDD patients compared to PM controls. In DDD patients, NF-κB1–DNA binding was positively correlated with nuclear RelA levels. Moreover, NF-κB1–DNA binding was positively associated with TRPV1 and MMP-3 gene and SP and TRPV1 protein expression in DDD patients. Our results indicate that the expression of SP and TRPV1 in IVD tissues was associated with NF-κB activation. Moreover, NF-κB may be involved in the generation or maintenance of peripheral pain mechanisms by the regulation of pain-related neuropeptide expression in DDD patients. [ABSTRACT FROM AUTHOR]