dynorphins and Pruritus

There have been many exciting recent advances in our understanding of the molecular and cellular basis of itch. These discoveries cover diverse aspects of itch sensation, from the identification of new receptors to the characterization of spinal cord itch circuits. A common thread of these studies is that they demonstrate that itch sensory signals are segregated from input for other somatosensory modalities, such as pain, touch, and thermosensation. This specificity is achieved by the expression of dedicated receptors and transmitters in a select population of sensory neurons which detect pruritogens. Further, recent studies show that itch specificity is maintained in a spinal cord circuit by the utilization of specific neurotransmitters and cognate receptors to convey input along a distinct cellular pathway.

Topics: Animals; Dynorphins; Humans; Pruritus; Receptors, Cytokine; Receptors, G-Protein-Coupled; Sensory Receptor Cells

Several chemically diverse pruritogens, including bombesin, compound 48/80, norbinaltorphimine, and 5'-GNTI, cause rodents to scratch excessively in a stable, uniform manner and consequently provide convenient animal models of itch against which potential antipruritics may be evaluated, structure-activity relationships established, and the nature of spontaneous, repetitive behavior itself analyzed. Decreasing the number of scratching bouts in these apparently simple models has been the requisite first step in the progress of kappa opioid agonists such as nalbuphine, asimadoline, and CR845 toward clinical testing as antipruritics. Nalfurafine is the prime example of a kappa agonist spanning the developmental divide between scratching mice models and commercialization within 10 years. Patients undergoing hemodialysis and suffering from the itching associated with uremic pruritus, and potentially those inflicted with atopic dermatitis, are the beneficiaries.

Topics: Animals; Dynorphins; Guanidines; Humans; Ligands; Mice; Morphinans; Naltrexone; p-Methoxy-N-methylphenethylamine; Peptide Fragments; Pruritus; Receptors, Opioid, kappa; Spiro Compounds

To explore the mechanism of Chinese medicinal therapy for nourishing blood and softening Gan in treating senile pruritus through observing the impact of Guishen Zhiyang Recipe (GZR) on serum levels of stem cell factor (SCF) and dynorphin (DYN) in patients suffered from the disease of blood-deficiency and Gan-hyperactive syndrome type (BDGH).. Sixty patients with senile pruritus were equally randomized into two groups, the patients in the treated group (33 cases) were treated by GZR, and those in the control group (28 cases) were treated by Fuyang Granule, all for 8 weeks. Changes of symptoms and skin lesions as well as blood levels of SCF and DYN were observed before and after treatment.. Three patients were rejected from the treated group. Twenty patients in the treated group were cured after treatment, the cure rate being 66.7%, which was significantly higher than that in the control group (10 patients, 35.7%, P < 0.05). Levels of SCF and DYN in the treated group significantly lowered after treatment (all P < 0.01), and were lower than those in the control group (P < 0.05 and P < 0.01, respectively).. GZR shows favorite effect in treating senile pruritus of BDGH type and it may be achieved by regulating SCF and DYN levels to improve the pruritus associated inflammatory media.

Topics: Aged; Aged, 80 and over; Drugs, Chinese Herbal; Dynorphins; Female; Humans; Male; Middle Aged; Phytotherapy; Pruritus; Stem Cell Factor; Syndrome

Morphine-induced itch is a very common and debilitating side effect that occurs in laboring women who receive epidural analgesia and in patients who receive spinal morphine for relief of perioperative pain. Although antihistamines are still widely prescribed for the treatment of morphine-induced itch, their use is controversial because the cellular basis for morphine-induced itch remains unclear. Here, we used animal models and show that neuraxial morphine causes itch through neurons and not mast cells. In particular, we found that spinal dynorphin (Pdyn) neurons are both necessary and sufficient for morphine-induced itch in mice. Agonism of the kappa-opioid receptor alleviated morphine-induced itch in mice and nonhuman primates. Thus, our findings not only reveal that morphine causes itch through a mechanism of disinhibition but also challenge the long-standing use of antihistamines, thereby informing the treatment of millions worldwide.

Topics: Analgesics, Opioid; Animals; Dynorphins; Humans; Mice; Morphine; Neurons; Pruritus

Topics: Aged; Biomarkers; Case-Control Studies; Dynorphins; Female; Humans; Liver Diseases; Male; Middle Aged; Preliminary Data; Pruritus; Severity of Illness Index

Topics: Animals; Dynorphins; Female; Ganglia, Spinal; Male; Mice; Mice, Inbred C57BL; Neural Pathways; Optogenetics; Pain; Pruritus; Receptors, Atrial Natriuretic Factor; Receptors, Purinergic; Receptors, Somatostatin; Sensory Receptor Cells; Somatostatin; Spinal Cord

How neuropeptides in the primate spinal cord regulate itch and pain is largely unknown. Here we elucidate the sensory functions of spinal opioid-related peptides and gastrin-releasing peptide (GRP) in awake, behaving monkeys. Following intrathecal administration, β-endorphin (10-100 nmol) and GRP (1-10 nmol) dose-dependently elicit the same degree of robust itch scratching, which can be inhibited by mu-opioid peptide (MOP) receptor and GRP receptor (BB2) antagonists, respectively. Unlike β-endorphin, which produces itch and attenuates inflammatory pain, GRP only elicits itch without affecting pain. In contrast, enkephalins (100-1000 nmol) and nociceptin-orphanin FQ (3-30 nmol) only inhibit pain without eliciting itch. More intriguingly, dynorphin A(1-17) (10-100 nmol) dose-dependently attenuates both β-endorphin- and GRP-elicited robust scratching without affecting pain processing. The anti-itch effects of dynorphin A can be reversed by a kappa-opioid peptide (KOP) receptor antagonist nor-binaltorphimine. These nonhuman primate behavioral models with spinal delivery of ligands advance our understanding of distinct functions of neuropeptides for modulating itch and pain. In particular, we demonstrate causal links for itch-eliciting effects by β-endorphin-MOP receptor and GRP-BB2 receptor systems and itch-inhibiting effects by the dynorphin A-KOP receptor system. These studies will facilitate transforming discoveries of novel ligand-receptor systems into future therapies as antipruritics and/or analgesics in humans.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; beta-Endorphin; Dynorphins; Female; Gastrin-Releasing Peptide; Hyperalgesia; Injections, Spinal; Macaca mulatta; Male; Neuropeptides; Pain; Pruritus; Spinal Cord

Electroacupuncture (EA) is used as a prescription to treat pruritus and atopic dermatitis. Whether EA affects experimental itch in rat models of immunologic or neuronal damages, however, is unknown.. The present study was designed to determine the therapeutic effects of high-frequency EA on atopic dermatitis-like lesions in rats.. Capsaicin (50mg/kg) was subcutaneously administered rat pups within 48h after birth. Rats then underwent 30min of EA at six acupoints (bilateral BL13, and unilateral LI11, ST36, SP10, SP6) every other day (EA group) for 3 weeks. Measurements of IgE, mast cells, scratching behavior, dynorphin release, skin thickness and dermatitis score were obtained.. Only the dermatitis score and dynorphin expression were decreased in the EA group compared with the control non-EA group.. We suggest that high-frequency EA alleviates pruritus of atopic dermatitis-like lesions in rats induced by capsaicin injection, via the release of dynorphin. These findings indicate a new potential therapeutic approach for the amelioration of symptoms of atopic dermatitis.

Topics: Animals; Animals, Newborn; Body Weight; Capsaicin; Dermatitis; Dermatitis, Atopic; Disease Models, Animal; Dynorphins; Electroacupuncture; Immunoglobulin E; Male; Mast Cells; Phenotype; Pruritus; Rats; Skin; Treatment Outcome

It has been shown previously that norbinaltorphimine (norBNI) and 5'-guanidinonaltrindole (5'-GNTI), long-acting kappa opioid receptor (KOPR) antagonists, cause frenzied scratching in mice [1,2]. In the current study, we examined if zyklophin, a short-acting cyclic peptide KOPR antagonist, also elicited scratching behavior. When injected s.c. in the nape of the neck of male Swiss-Webster mice, zyklophin at doses of 0.1, 0.3 and 1mg/kg induced dose-related hindleg scratching of the neck between 3 and 15 min after injection. Pretreating mice with norBNI (20mg/kg, i.p.) at 18-20 h before challenge with zyklophin (0.3mg/kg) did not markedly affect scratching. Additionally, KOPR-/- mice given 0.3mg/kg of zyklophin displayed similar levels of scratching as wild-type animals. The absence of KOPR in KOPR-/- mice was confirmed with ex vivo radioligand binding using [(3)H]U69,593. Taken together, our data suggest that the presence of kappa receptors is not required for the excessive scratching caused by zyklophin. Thus, zyklophin, similar to the structurally different KOPR antagonist 5'-GNTI, appears to act at other targets to elicit scratching and potentially the sensation of itch.

Topics: Animals; Benzeneacetamides; Dose-Response Relationship, Drug; Dynorphins; Injections, Subcutaneous; Male; Mice; Mice, Knockout; Naltrexone; Peptide Fragments; Pruritus; Pyrrolidines; Radioligand Assay; Receptors, Opioid, kappa

Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5(-/-) mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.

Topics: Analgesics, Opioid; Animals; Capsaicin; Dynorphins; Interneurons; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Inhibition; Octreotide; Organ Culture Techniques; Posterior Horn Cells; Pruritus; Receptors, Opioid, kappa; Spinal Cord

Itch is immensely frustrating. Most studies focus on the cause of itch. In this issue of Neuron, Kardon et al. (2014) find that itch can be modulated by inhibitory neurons that produce dynorphin, an endogenous agonist of κ-opioid receptors.

Topics: Animals; Dynorphins; Interneurons; Male; Neural Inhibition; Posterior Horn Cells; Pruritus

Psoriasis is a complex, multifactorial inflammatory skin disease with genetic and environmental interactions. Patients with psoriasis exhibit erythematous plaques with itch, but the mechanisms of psoriatic itch are poorly understood.. This study was performed to investigate epidermal nerve density and opioid receptor levels in psoriatic skin with or without itch.. Twenty-four patients with psoriasis aged between 39 and 82 years were included in this study. The number of epidermal nerve fibres, the levels of semaphorin 3A (Sema3A) and the expression patterns of μ- and κ-opioid systems were examined immunohistologically in skin biopsies from psoriatic patients with or without itch and healthy volunteers as controls.. The number of epidermal nerve fibres tended to increase in approximately 40% of psoriatic patients with itch compared with healthy controls, while such intraepidermal nerves were not observed in other itchy patients. In comparison with healthy controls, Sema3A levels also tended to decrease in the epidermis of psoriatic patients with itch. However, no relationship was found between nerve density and Sema3A levels in the epidermis of psoriatic patients with itch. The levels of μ-opioid receptor and β-endorphin in the epidermis were the same in healthy controls and psoriatic patients with or without itch. The levels of κ-opioid receptor and dynorphin A were significantly decreased in the epidermis of psoriatic patients with itch compared with healthy controls.. Based on Sema3A levels in the epidermis, epidermal opioid systems, rather than hyperinnervation, may be involved in the pathogenesis of psoriatic itch.

Topics: Adult; Aged; beta-Endorphin; Biopsy, Needle; Case-Control Studies; Dynorphins; Epidermis; Female; Humans; Immunohistochemistry; Male; Middle Aged; Nerve Fibers; Pruritus; Psoriasis; Receptors, Opioid; Semaphorin-3A

The micro-opioid (beta-endorphin/micro-opioid receptor) and kappa-opioid (dynorphin A (DynA)/kappa-opioid receptor) systems play pivotal roles in the modulation of pruritus in the central nervous system. The micro-opioid system has also been identified in human epidermis, raising the possibility that the system controls the peripheral itch. However, the precise distribution of the kappa-opioid system has not yet been clarified in human epidermis. To address this issue, reverse transcription-PCR and immunohistochemical analyses were performed on cultured keratinocytes and normal skins from humans. The analyses revealed that epidermal keratinocytes express kappa-opioid receptor and its ligands, DynA (1-17) and DynA (1-8). Moreover, expression for micro- and kappa-opioid systems was examined immunohistochemically in skin biopsies from healthy volunteers and patients with atopic dermatitis (AD) before and after psoralen-ultraviolet A (PUVA) therapy. Our expression analyses showed that only the kappa-opioid system, not the micro-opioid system, was downregulated in the epidermis of AD patients. The downregulation of the micro-opioid system and the restoration of the kappa-opioid system by PUVA therapy were observed in the AD patients, concomitant with a decrease of VAS (visual analogue scale) scores. These results suggest epidermal opioid systems are associated with the modulation of pruritus in AD. This new finding may help us to understand the control mechanism of peripheral itch.

Topics: Adult; Analgesics, Opioid; Biopsy; Dermatitis, Atopic; Dynorphins; Epidermis; Gene Expression Regulation; Humans; Immunohistochemistry; Keratinocytes; Ligands; Male; Pruritus; Receptors, Opioid; Ultraviolet Rays