dermorphin and Neuralgia

Chronic pain states are clinically relevant and yet unsolved conditions impacting on quality of life and representing an important social and economic burden; these diseases are poorly treated with the currently available drugs, being urgent the need of innovative analgesics. In this frame, novel analogues of endomorphin-1 and dermorphin emerge as promising starting points to develop innovative, more effective analgesics to treat neuropathic pain.. An extensive and structured search of bibliographic databases for peer-reviewed research literature was undertaken using focused review questions; all the retrieved papers were published on prestigious international journals by the experts of the field and were carefully analyzed to collect all the information and data necessary to the conceptual framework of this review.. One hundred papers were included in this review; forty-one defined the up-to-date findings on neuropathic pain etiopathogenesis and its currently available treatment options. Thirty-five papers described all the advantages and drawbacks of using endomorphin-1 (23) or dermorphin (12) in the frame of neuropathic pain and outlined the most relevant advances in developing endomorphin-1 and dermorphin analogs useful as potential, innovative analgesics. Twenty-four papers provided the latest insights into exploiting biased agonism at opioid receptor as an innovative strategy to develop more effective and safer analgesics.. This review reports that innovative opioid peptides will be of great help in better understanding the multifaceted scenario of neuropathic pain treatment, providing very interesting opportunities for the identification of novel and more effective opioid analgesics to be employed as medications.

Topics: Amino Acid Sequence; Analgesics, Opioid; Animals; Chronic Pain; Humans; Ligands; Male; Neuralgia; Oligopeptides; Opioid Peptides; Receptors, Opioid

Opioids have long been regarded as the most effective drugs for the treatment of severe acute and chronic pain. Unfortunately, their therapeutic efficacy and clinical utility have been limited because of central and peripheral side effects.. To determine the therapeutic value of peripheral μ-opioid receptors as a target for neuropathic pain treatment, the authors examined the effects of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a hydrophilic, peripherally acting μ-opioid receptor agonist, in male and female rats with spinal nerve ligation-induced neuropathic pain. The authors also utilized behavioral, pharmacologic, electrophysiologic, and molecular biologic tools to characterize DALDA's possible mechanisms of action in male rats.. DALDA, administered subcutaneously, had 70 times greater efficacy for inhibiting thermal (n = 8 to 11/group) than mechanical hypersensitivity (n = 6 to 8/group) in male rats. The pain inhibitory effects of DALDA on mechanical and heat hypersensitivity were abolished in animals pretreated with systemic methylnaltrexone (n = 7 to 9/group), a peripheral μ-opioid receptor antagonist. In the spinal wide-dynamic range neurons, systemic DALDA inhibited C-fiber-mediated, but not A-fiber-mediated, response in neuropathic male rats (n = 13). In primary sensory neurons, DALDA inhibited the capsaicin-induced [Ca2+] increase more than the β-alanine-induced [Ca] increase (n = 300); capsaicin and β-alanine activate subpopulations of neurons involved in the signaling of heat and mechanical pain, respectively. DALDA-treated rats (n = 5 to 8/group) did not exhibit motor deficits and locomotor impairment suggesting that it does not induce central side effects.. These findings suggest that DALDA may represent a potential alternative to current opioid therapy for the treatment of neuropathic pain and is likely to be associated with minimal adverse effects.

Topics: Analgesics, Opioid; Animals; Female; Male; Neuralgia; Opioid Peptides; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

Descending input from the rostral ventromedial medulla (RVM) provides positive and negative modulation of spinal nociceptive transmission and has been proposed to be critical for maintaining neuropathic pain. This study tests the hypothesis that neuropathic pain requires the activity of a subset of RVM neurons that are distinguished by co-expression of mu opioid receptor (MOR) and cholecystokinin type 2 receptor (CCK2). Using male Sprague-Dawley rats, we demonstrate that discrete RVM neurons express MOR and CCK2; over 80% of these cells co-express both receptors. Agonist-directed cell lesion in the RVM with the cytotoxin, saporin, using either CCK-saporin to target CCK receptor expressing cells, or dermorphin-saporin to target MOR expressing cells, resulted in concomitant loss of CCK2 and MOR expressing cells, did not alter the basal sensory thresholds but abolished the hyperalgesia induced by microinjection of CCK into the RVM. The findings suggest that these CCK2-MOR co-expressing RVM neurons facilitate pain and can be directly activated by CCK input to the RVM. Furthermore, lesion of these RVM neurons did not affect the initial development of neuropathic pain in the hind paw upon injury to the sciatic nerve, but the abnormal pain states were short lived such that by about day 9 the sensory thresholds had reverted to pre-injury baselines despite the existing neuropathy. These data support our hypothesis and identify CCK2-MOR co-expressing neurons in the RVM as potential therapeutic targets for neuropathic pain.

Topics: Analgesics, Opioid; Animals; Brain Stem; Immunotoxins; In Situ Hybridization; Male; Medulla Oblongata; Microinjections; Morphine; Neuralgia; Neurons; Opioid Peptides; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Opioid, mu; Ribosome Inactivating Proteins, Type 1; RNA, Messenger; Saporins; Sincalide; Synaptic Transmission

Nerve injury-induced afferent discharge is thought to elicit spinal sensitization and consequent abnormal pain. Experimental neuropathic pain, however, also depends on central changes, including descending facilitation arising from the rostral ventromedial medulla (RVM) and upregulation of spinal dynorphin. A possible intersection of these influences at the spinal level was explored by measuring evoked, excitatory transmitter release in tissues taken from nerve-injured animals with or without previous manipulation of descending modulatory systems. Spinal nerve ligation (SNL) produced expected tactile and thermal hyperesthesias. Capsaicin-evoked calcitonin gene-related peptide (CGRP) release was markedly enhanced in lumbar spinal tissue from SNL rats when compared with sham-operated controls. Enhanced, evoked CGRP release from SNL rats was blocked by anti-dynorphin A(1-13) antiserum; this treatment did not alter evoked release in tissues from sham-operated rats. Dorsolateral funiculus lesion (DLF) or destruction of RVM neurons expressing mu-opioid receptors with dermorphin-saporin, blocked tactile and thermal hypersensitivity, as well as SNL-induced upregulation of spinal dynorphin. Spinal tissues from these DLF-lesioned or dermorphin-saporin-treated SNL rats did not exhibit enhanced capsaicin-evoked CGRP-IR release. These data demonstrate exaggerated release of excitatory transmitter from primary afferents after injury to peripheral nerves, supporting the likely importance of increased afferent input as a driving force of neuropathic pain. The data also show that modulatory influences of descending facilitation are required for enhanced evoked transmitter release after nerve injury. Thus, convergence of descending modulation, spinal plasticity, and afferent drive in the nerve-injured state reveals a mechanism by which some aspects of nerve injury-induced hyperesthesias may occur.

Topics: Afferent Pathways; Analgesics, Opioid; Animals; Calcitonin Gene-Related Peptide; Capsaicin; Disease Models, Animal; Dynorphins; Enkephalins; Hyperesthesia; Ligation; Lumbosacral Region; Male; Medulla Oblongata; Microinjections; N-Glycosyl Hydrolases; Nerve Compression Syndromes; Neuralgia; Neuronal Plasticity; Neurotransmitter Agents; Oligopeptides; Opioid Peptides; Pain Measurement; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Recombinant Fusion Proteins; Ribosome Inactivating Proteins, Type 1; Saporins; Sensory Thresholds; Spinal Cord; Spinal Nerves

Neurons in the rostroventromedial medulla (RVM) project to spinal loci where the neurons inhibit or facilitate pain transmission. Abnormal activity of facilitatory processes may thus represent a mechanism of chronic pain. This possibility and the phenotype of RVM cells that might underlie experimental neuropathic pain were investigated. Cells expressing mu-opioid receptors were targeted with a single microinjection of saporin conjugated to the mu-opioid agonist dermorphin; unconjugated saporin and dermorphin were used as controls. RVM dermorphin-saporin, but not dermorphin or saporin, significantly decreased cells expressing mu-opioid receptor transcript. RVM dermorphin, saporin, or dermorphin-saporin did not change baseline hindpaw sensitivity to non-noxious or noxious stimuli. Spinal nerve ligation (SNL) injury in rats pretreated with RVM dermorphin-saporin failed to elicit the expected increase in sensitivity to non-noxious mechanical or noxious thermal stimuli applied to the paw. RVM dermorphin or saporin did not alter SNL-induced experimental pain, and no pretreatment affected the responses of sham-operated groups. This protective effect of dermorphin-saporin against SNL-induced pain was blocked by beta-funaltrexamine, a selective mu-opioid receptor antagonist, indicating specific interaction of dermorphin-saporin with the mu-opioid receptor. RVM microinjection of dermorphin-saporin, but not of dermorphin or saporin, in animals previously undergoing SNL showed a time-related reversal of the SNL-induced experimental pain to preinjury baseline levels. Thus, loss of RVM mu receptor-expressing cells both prevents and reverses experimental neuropathic pain. The data support the hypothesis that inappropriate tonic-descending facilitation may underlie some chronic pain states and offer new possibilities for the design of therapeutic strategies.

Topics: Animals; Behavior, Animal; Brain Stem; Disease Models, Animal; Immunotoxins; Ligation; Male; Medulla Oblongata; Microinjections; N-Glycosyl Hydrolases; Naltrexone; Neuralgia; Neurons; Oligopeptides; Opioid Peptides; Pain Measurement; Physical Stimulation; Plant Proteins; Radioligand Assay; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid, mu; Recombinant Fusion Proteins; Ribosome Inactivating Proteins, Type 1; Saporins; Spinal Nerves