Morphine Directly Inhibits Nociceptors in Inflamed Skin

2006 ◽  
Vol 95 (4) ◽  
pp. 2083-2097 ◽  
Author(s):  
Heather N. Wenk ◽  
Jill-Desiree Brederson ◽  
Christopher N. Honda
Keyword(s):  
Opioid Receptors ◽  
Average Rate ◽  
Receptive Fields ◽  
Thermal Hyperalgesia ◽  
Experimental Models ◽  
Spontaneous Discharge ◽  
Intraplantar Injection ◽  
Response Properties ◽  
Peripheral Opioid Receptors

Peripherally delivered opiates attenuate mechanical and thermal hyperalgesia in experimental models of inflammation, suggesting that activation of peripheral opioid receptors decreases the excitability of nociceptors in inflamed tissues. The current study examines the effects of peripheral morphine sulfate on response properties of sensory neurons in healthy and inflamed skin. Afferent units (185) were isolated from tibial nerve of rats using an in vitro glabrous skin-nerve teased-fiber preparation. Of these, 107 units were from normal healthy skin, and 78 were from inflamed skin 18 h after intraplantar injection of complete Freund's adjuvant. As a population, C-fiber units innervating inflamed skin exhibited properties characteristic of sensitization when compared with units innervating healthy control skin. Mechanical thresholds were lowered, responses to noxious mechanical and thermal stimuli were elevated, a greater proportion of units was spontaneously active, and the average rate of spontaneous discharge was higher. Response properties in other conduction velocity groups remained unchanged. Fifty-eight percent of C and C/Aδ nociceptors innervating inflamed skin were opiate-sensitive, and their excitability was attenuated by direct application of morphine to their receptive fields. All morphine-sensitive units were nociceptors from inflamed skin with conduction velocities <1.3 m/s. Morphine effects were concentration-dependent and naloxone-sensitive, indicating that the effects were receptor-mediated. These findings provide direct evidence that morphine acts through peripheral opioid receptors to inhibit the activity of cutaneous nociceptors under conditions of inflammation.

scholarly journals Subcellular Pathways of β-Endorphin Synthesis, Processing, and Release from Immunocytes in Inflammatory Pain

Endocrinology ◽  
2004 ◽  
Vol 145 (3) ◽  
pp. 1331-1341 ◽  
Author(s):  
Shaaban A. Mousa ◽  
Mehdi Shakibaei ◽  
Nicolle Sitte ◽  
Michael Schäfer ◽  
Christoph Stein
Keyword(s):  
Opioid Receptors ◽  
Immune Cells ◽  
Inflammatory Pain ◽  
Secretory Granules ◽  
Inflammatory Cells ◽  
Opioid Peptide ◽  
Active Peptides ◽  
Carboxypeptidase E ◽  
Peripheral Opioid Receptors

Abstract The opioid peptide β-endorphin (END) as well as mRNA for its precursor proopiomelanocortin (POMC) are found not only in the pituitary gland, but also within various types of immune cells infiltrating inflamed sc tissue. During stressful stimuli END is released and interacts with peripheral opioid receptors to inhibit pain. However, the subcellular pathways of POMC processing and END release have not yet been delineated in inflammatory cells. The aim of the present study was to examine the presence of POMC, carboxypeptidase E, the prohormone convertases 1 (PC1), and 2 (PC2), PC2-binding protein 7B2, and the release of END from inflammatory cells in rats. Using immunohistochemistry we detected END and POMC alone or colocalized with PC1, PC2, carboxypeptidase E, and 7B2 in macrophages/monocytes, granulocytes, and lymphocytes of the blood and within inflamed sc paw tissue. Immunoelectron microscopy revealed that END is localized within secretory granules packed in membranous structures in macrophages, monocytes, granulocytes, and lymphocytes. Finally, END is released by noradrenaline from immune cells in vitro. Taken together, our results indicate that immune cells express the entire machinery required for POMC processing into functionally active peptides such as END and are able to release these peptides from secretory granules.

scholarly journals Development of an Effective Topical Liposomal Formulation for Localized Analgesia and Antiinflammatory Actions in the Complete Freund’s Adjuvant Rodent Model of Acute Inflammatory Pain

2014 ◽  
Vol 6;17 (6;12) ◽  
pp. E719-E735
Author(s):  
Susan Hua
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Inflammatory Pain ◽  
Time Course ◽  
Control Groups ◽  
Intact Skin ◽  
Intraplantar Injection ◽  
Anti Inflammatory ◽  
Peripheral Opioid Receptors ◽  
Antiinflammatory Effects

Background: Peripheral opioid receptor targeting has been well established as a novel target in clinical pain management for acute and chronic peripheral inflammatory pain. The physiochemical properties of the peripheral mu-opioid receptor agonist, loperamide HCl, limit the use of the free drug as an analgesic or anti-inflammatory agent, particularly for dermal delivery across intact skin. Objective: Our objective was to manufacture an effective topical formulation containing loperamide using liposomal delivery that would allow loperamide to produce analgesia and anti-inflammatory effects, by penetrating the epidermis to reach peripheral opioid receptors within the dermis of intact skin. Study Design: A randomized, double blind, controlled animal trial. Methods: Thirty-five adult male Wistar rats (200 – 250 g) were randomly divided into 5 groups: loperamide HCl-encapsulated liposomal gel, naloxone methiodide + loperamide HCl-encapsulated liposomal gel, free loperamide gel, empty liposomal gel, and 1% diclofenac gel (Voltaren®). Diclofenac gel was used as a positive control as it is clinically used as a topical analgesic and anti-inflammatory drug. Animals received an intraplantar injection of 150 µl Complete Freund’s Adjuvant (CFA) into the right hindpaw and experiments were performed 5 days post-CFA injection, which corresponded to the peak inflammatory response. All manufactured formulations were applied topically on both hind paws twice daily, whereas Voltaren gel was applied 3 times a day in accordance with the manufacturer’s instructions. The dose administered was 50 µl, which equated to 0.4 mg of loperamide HCl for the loperamide HCl treatment groups (low dose). Naloxone methiodide (1 mg/kg) was administered via intraplantar injection, 15 minutes prior to application of loperamide HCl-encapsulated liposomal gel to determine opioid receptor dependent activity. An investigator blinded to the treatment administered assessed time course of the antinociceptive and antiinflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively. Results: Application of loperamide HCl in a liposomal gel formulation exerted analgesic and antiinflammatory effects exclusively in peripheral painful inflamed tissue. This formulation produced highly significant analgesic and anti-inflammatory effects over the 48-hour time course studied following topical administration in rats with CFA-induced inflammation of the paw. As expected, the diclofenac gel group showed significant antinociception over the duration of the study; however, this effect was lower in comparison to the loperamide HCl liposomal gel formulation. All other control groups showed no significant antinociceptive effects. In addition, all control groups (1% diclofenac gel, free loperamide gel, and empty liposomal gel) did not demonstrate a significant change in paw volume over 48 hours. Limitations: In vivo studies were performed in the well-established rodent model of acute inflammatory pain. We are currently studying this approach in chronic pain models known to have clinical activation of the peripheral immune-derived opioid response. Conclusions: The study demonstrates that topically applied loperamide encapsulated within liposomal systems has improved therapeutic efficacy over conventional formulations for the local treatment of acute peripheral inflammatory pain conditions where the skin has remained intact. Once in the inflamed peripheral tissue, loperamide provides analgesic and anti-inflammatory effects in a similar manner to peripheral endogenous opioids. This preparation optimises the retention of drug at the site where action is required. Key words: Pain, inflammation, opioids, loperamide, liposomes, topical drug delivery, peripheral opioid receptors

scholarly journals Polyglycerol-opioid conjugate produces analgesia devoid of side effects

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sara González-Rodríguez ◽  
Mohiuddin A Quadir ◽  
Shilpi Gupta ◽  
Karolina A Walker ◽  
Xuejiao Zhang ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Side Effects ◽  
Opioid Receptors ◽  
Analgesic Efficacy ◽  
Injured Tissue ◽  
Hyperbranched Polyglycerol ◽  
Peripheral Opioid Receptors ◽  
The Brain ◽  
Inflamed Tissue

Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects.

Spatial response properties of acoustically responsive neurons in the superior colliculus of the ferret: a map of auditory space

1987 ◽  
Vol 57 (2) ◽  
pp. 596-624 ◽  
Author(s):  
A. J. King ◽  
M. E. Hutchings
Keyword(s):  
Superior Colliculus ◽  
Stimulus Intensity ◽  
Free Field ◽  
Receptive Fields ◽  
Stimulus Onset ◽  
Spontaneous Discharge ◽  
Auditory Neurons ◽  
Response Properties ◽  
Deep Layers ◽  
Stimulus Offset

Extracellular single-unit recordings were made from auditory neurons in the superior colliculus of ferrets anesthetized with either a neuroleptic or a combination of barbiturate with paralysis. The response properties of these neurons were studied using white-noise bursts presented under free-field conditions in an anechoic chamber. Auditory neurons were found throughout the intermediate and deep layers of the superior colliculus. All neurons were spontaneously active, the rates of discharge varying from 0.1 to 61.1 spikes X s-1. Although the spontaneous discharge interspike-interval histograms for many units approximated to exponential distributions, the histograms of 44% had clear secondary peaks, indicating more than one preferred interval, and could not be modeled by a simple process. Most neurons (50%) responded only at stimulus onset, whereas 12% exhibited sustained discharges and 38% gave onset responses followed by a period of silence or reduced activity and then a period of elevated discharge, which was not apparently related to stimulus offset. Neurons with multipeaked response patterns were concentrated in the stratum griseum profundum. The latencies from arrival of the stimulus at the ear to the onset of neural activity ranged from 6 to 49 ms and decreased with increasing stimulus intensity. Although responsive to sounds over a large region of space, most neurons had clearly defined best positions at which the strongest response was obtained. The response declined as the speaker was moved away from this position, and nearly all units had peaked response profiles. The spatial tuning varied between different neurons, but most were more sharply tuned in elevation than in azimuth. Increasing the stimulus intensity did not, in general, alter the best positions of these neurons, but usually resulted in a broadening of the receptive fields, although other units became more sharply tuned. The best positions of auditory neurons varied systematically in azimuth from 20 degrees into the ipsilateral hemifield to 130 degrees into the contralateral hemifield as the electrode was moved from the rostrolateral to the caudomedial end of the superior colliculus. The best positions shifted in elevation along a rostromedial to caudolateral axis from 60 degrees above to 50 degrees below the visuoaural plane.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Local administration of mu or kappa opioid agonists attenuates capsaicin-induced thermal hyperalgesia via peripheral opioid receptors in rats

2000 ◽  
Vol 148 (2) ◽  
pp. 180-185 ◽  
Author(s):  
M. C. H. Ko ◽  
J. E. Tuchman ◽  
M. D. Johnson ◽  
K. Wiesenauer ◽  
J. H. Woods ◽  
...  
Keyword(s):  
Opioid Receptors ◽  
Thermal Hyperalgesia ◽  
Local Administration ◽  
Kappa Opioid ◽  
Opioid Agonists ◽  
Peripheral Opioid Receptors

Neutralization of a Low Molecular Weight Heparin (LHN-1) and Conventional Heparin by Protamine Sulfate in Rats

1986 ◽  
Vol 56 (03) ◽  
pp. 318-322 ◽  
Author(s):  
V Diness ◽  
P B Østergaard
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Thrombus Formation ◽  
Experimental Models ◽  
Protamine Sulfate ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
Higher Doses

SummaryThe neutralization of a low molecular weight heparin (LHN-1) and conventional heparin (CH) by protamine sulfate has been studied in vitro and in vivo. In vitro, the APTT activity of CH was completely neutralized in parallel with the anti-Xa activity. The APTT activity of LHN-1 was almost completely neutralized in a way similar to the APTT activity of CH, whereas the anti-Xa activity of LHN-1 was only partially neutralized.In vivo, CH 3 mg/kg and LHN-1 7.2 mg/kg was given intravenously in rats. The APTT and anti-Xa activities, after neutralization by protamine sulfate in vivo, were similar to the results in vitro. In CH treated rats no haemorrhagic effect in the rat tail bleeding test and no antithrombotic effect in the rat stasis model was found at a protamine sulfate to heparin ratio of about 1, which neutralized APTT and anti-Xa activities. In LHN-1 treated rats the haemorrhagic effect was neutralized when APTT was close to normal whereas higher doses of protamine sulfate were required for neutralization of the antithrombotic effect. This probably reflects the fact that in most experimental models higher doses of heparin are needed to induce bleeding than to prevent thrombus formation. Our results demonstrate that even if complete neutralization of APTT and anti-Xa activities were not seen in LHN-1 treated rats, the in vivo effects of LHN-1 could be neutralized as efficiently as those of conventional heparin. The large fall in blood pressure caused by high doses of protamine sulfate alone was prevented by the prior injection of LHN-1.

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

Epithelial Organotypic Cultures: A Viable Model to Address Mechanisms of Carcinogenesis by Epitheliotropic Viruses

2018 ◽  
Vol 18 (4) ◽  
pp. 246-255 ◽  
Author(s):  
Lara Termini ◽  
Enrique Boccardo
Keyword(s):  
Three Dimensional ◽  
Cell Types ◽  
Experimental Models ◽  
Biological Research ◽  
Specific Gene ◽  
Specific Cell ◽  
Organotypic Cultures ◽  
Skin Physiology

In vitro culture of primary or established cell lines is one of the leading techniques in many areas of basic biological research. The use of pure or highly enriched cultures of specific cell types obtained from different tissues and genetics backgrounds has greatly contributed to our current understanding of normal and pathological cellular processes. Cells in culture are easily propagated generating an almost endless source of material for experimentation. Besides, they can be manipulated to achieve gene silencing, gene overexpression and genome editing turning possible the dissection of specific gene functions and signaling pathways. However, monolayer and suspension cultures of cells do not reproduce the cell type diversity, cell-cell contacts, cell-matrix interactions and differentiation pathways typical of the three-dimensional environment of tissues and organs from where they were originated. Therefore, different experimental animal models have been developed and applied to address these and other complex issues in vivo. However, these systems are costly and time consuming. Most importantly the use of animals in scientific research poses moral and ethical concerns facing a steadily increasing opposition from different sectors of the society. Therefore, there is an urgent need for the development of alternative in vitro experimental models that accurately reproduce the events observed in vivo to reduce the use of animals. Organotypic cultures combine the flexibility of traditional culture systems with the possibility of culturing different cell types in a 3D environment that reproduces both the structure and the physiology of the parental organ. Here we present a summarized description of the use of epithelial organotypic for the study of skin physiology, human papillomavirus biology and associated tumorigenesis.

scholarly journals Organoids of the female reproductive tract

2021 ◽  
Vol 99 (4) ◽  
pp. 531-553 ◽  
Author(s):  
Cindrilla Chumduri ◽  
Margherita Y. Turco
Keyword(s):  
Reproductive Tract ◽  
Personalised Medicine ◽  
Three Dimensional ◽  
In Vitro Models ◽  
Experimental Models ◽  
Female Reproductive Tract ◽  
Cellular Heterogeneity ◽  
Dynamic Regulation ◽  
Pregnancy And Childbirth

AbstractHealthy functioning of the female reproductive tract (FRT) depends on balanced and dynamic regulation by hormones during the menstrual cycle, pregnancy and childbirth. The mucosal epithelial lining of different regions of the FRT—ovaries, fallopian tubes, uterus, cervix and vagina—facilitates the selective transport of gametes and successful transfer of the zygote to the uterus where it implants and pregnancy takes place. It also prevents pathogen entry. Recent developments in three-dimensional (3D) organoid systems from the FRT now provide crucial experimental models that recapitulate the cellular heterogeneity and physiological, anatomical and functional properties of the organ in vitro. In this review, we summarise the state of the art on organoids generated from different regions of the FRT. We discuss the potential applications of these powerful in vitro models to study normal physiology, fertility, infections, diseases, drug discovery and personalised medicine.

scholarly journals Nociceptive Sensitization by Activation of Protease-Activated Receptor 2 in a Rat Model of Incisional Pain

2021 ◽  
Vol 11 (2) ◽  
pp. 144
Author(s):  
Kanta Kido ◽  
Norika Katagiri ◽  
Hiromasa Kawana ◽  
Shigekazu Sugino ◽  
Masanori Yamauchi ◽  
...  
Keyword(s):  
Postoperative Pain ◽  
Inflammatory Responses ◽  
Early Period ◽  
Intraplantar Injection ◽  
C Fibers ◽  
Nociceptive Responses ◽  
Incisional Pain ◽  
Protease Activated Receptor 2

Postoperative pain and consequent inflammatory responses after tissue incision adversely affects many surgical patients due to complicated mechanisms. In this study, we examined whether activation of protease-activated receptor 2 (PAR-2), which is stimulated by tryptase from mast cells, elicits nociception and whether the PAR-2 antagonist could reduce incisional nociceptive responses in vivo and in vitro. The effects of a selective PAR-2 antagonist, N3-methylbutyryl-N-6-aminohexanoyl-piperazine (ENMD-1068), pretreatment on pain behaviors were assessed after plantar incision in rats. The effects of a PAR-2 agonist, SLIGRL-NH2, on nociception was assessed after the injection into the hind paw. Furthermore, the responses of C-mechanosensitive nociceptors to the PAR-2 agonist were observed using an in vitro skin–nerve preparation as well. Intraplantar injection of SLIGRL-NH2 elicited spontaneous nociceptive behavior and hyperalgesia. Local administration of ENMD-1068 suppressed guarding behaviors, mechanical and heat hyperalgesia only within the first few hours after incision. SLIGRL-NH2 caused ongoing activity in 47% of C-mechanonociceptors in vitro. This study suggests that PAR-2 may support early nociception after incision by direct or indirect sensitization of C-fibers in rats. Moreover, PAR-2 may play a regulatory role in the early period of postoperative pain together with other co-factors to that contribute to postoperative pain.

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