Antinociceptive effects of intrathecally administered human β-endorphin in the rat and cat

1978 ◽  
Vol 56 (5) ◽  
pp. 754-759 ◽  
Author(s):  
Tony L. Yaksh ◽  
James L. Henry
Keyword(s):  
Subarachnoid Space ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Opiate Receptor ◽  
Tail Flick ◽  
Dose Ratio ◽  
Response Curves ◽  
Indwelling Catheter ◽  
Spinal Subarachnoid Space

Rats chronically implanted with intrathecal catheters displayed a dose-dependent increase in the hot-plate and tail-flick response latencies following the injection of human β-endorphin into the lumbar spinal subarachnoid space through the indwelling catheter. β-Endorphin was approximately 25 times more potent than morphine on a molar basis. Matching morphine and β-endorphin doses such that approximately equal submaximal effects occurred, it was observed that the antinociception produced by β-endorphin lasted approximately three times longer than that produced by morphine. Experiments with intrathecal injection of β-endorphin into the spinal subarachnoid space of cats fitted with intrathecal catheters also revealed a potent antinociceptive effect which was completely antagonized by naloxone. In the rats, naloxone administered systemically in doses of 10–100 μg/kg produced a parallel shift in the dose–response curves of both nociceptive measures suggesting a competitive antagonism. Using a dose ratio analysis, an in vivo pA2 of 7.1 for naloxone was obtained. These data and those derived from previous work based on the pA2 suggest that the interaction of morphine, certain pentapeptides, and β-endorphin is the same with regard to the spinal opiate receptor population mediating behavioraily defined analgesia.

scholarly journals Buprenorphine Metabolites, Buprenorphine-3-glucuronide and Norbuprenorphine-3-glucuronide, Are Biologically Active

2011 ◽  
Vol 115 (6) ◽  
pp. 1251-1260 ◽  
Author(s):  
Sarah M. Brown ◽  
Michael Holtzman ◽  
Thomas Kim ◽  
Evan D. Kharasch
Keyword(s):  
Radioligand Binding ◽  
Competitive Inhibition ◽  
Antinociceptive Effect ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Biologically Active ◽  
Whole Body ◽  
Tail Flick ◽  
High Affinity

Background The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine. Methods Competitive inhibition of radioligand binding to human μ, κ, and δ opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in SwissWebster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing. Results Buprenorphine-3-glucuronide had high affinity for human μ (Ki [inhibition constant] = 4.9 ± 2.7 pM), δ (Ki = 270 ± 0.4 nM), and nociceptin (Ki = 36 ± 0.3 μM) but not κ receptors. Norbuprenorphine-3-glucuronide had affinity for human κ (Ki = 300 ± 0.5 nM) and nociceptin (Ki = 18 ± 0.2 μM) but not μ or δ receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation. Conclusions Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures, which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.

scholarly journals Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels

2019 ◽  
Vol 216 (11) ◽  
pp. 2492-2502 ◽  
Author(s):  
Qiaoli Ma ◽  
Yann Decker ◽  
Andreas Müller ◽  
Benjamin V. Ineichen ◽  
Steven T. Proulx
Keyword(s):  
Cerebrospinal Fluid ◽  
Subarachnoid Space ◽  
Near Infrared ◽  
Cranial Nerves ◽  
Lymphatic Vessels ◽  
Intraventricular Injection ◽  
Spinal Subarachnoid Space ◽  
Cord Injury ◽  
Sacral Spine

The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end of the spine. Outflow of CSF tracers from the spinal subarachnoid space occurred predominantly from intravertebral regions of the sacral spine to lymphatic vessels, leading to sacral and iliac LNs. Clearance of CSF from the spine to lymphatic vessels may have significance for many conditions, including multiple sclerosis and spinal cord injury.

scholarly journals Altered Cerebrospinal Fluid Clearance and Increased Intracranial Pressure in Rats 18 h After Experimental Cortical Ischaemia

2021 ◽  
Vol 14 ◽  
Author(s):  
Steven W. Bothwell ◽  
Daniel Omileke ◽  
Rebecca J. Hood ◽  
Debbie-Gai Pepperall ◽  
Sara Azarpeykan ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Intracranial Pressure ◽  
Lymph Nodes ◽  
Subarachnoid Space ◽  
Ex Vivo ◽  
Bimodal Distribution ◽  
Cervical Lymph Nodes ◽  
Post Stroke ◽  
Spinal Subarachnoid Space

Oedema-independent intracranial pressure (ICP) rise peaks 20–22-h post-stroke in rats and may explain early neurological deterioration. Cerebrospinal fluid (CSF) volume changes may be involved. Cranial CSF clearance primarily occurs via the cervical lymphatics and movement into the spinal portion of the cranio-spinal compartment. We explored whether impaired CSF clearance at these sites could explain ICP rise after stroke. We recorded ICP at baseline and 18-h post-stroke, when we expect changes contributing to peak ICP to be present. CSF clearance was assessed in rats receiving photothrombotic stroke or sham surgery by intraventricular tracer infusion. Tracer concentration was quantified in the deep cervical lymph nodes ex vivo and tracer transit to the spinal subarachnoid space was imaged in vivo. ICP rose significantly from baseline to 18-h post-stroke in stroke vs. sham rats [median = 5 mmHg, interquartile range (IQR) = 0.1–9.43, n = 12, vs. −0.3 mmHg, IQR = −1.9–1.7, n = 10], p = 0.03. There was a bimodal distribution of rats with and without ICP rise. Tracer in the deep cervical lymph nodes was significantly lower in stroke with ICP rise (0 μg/mL, IQR = 0–0.11) and without ICP rise (0 μg/mL, IQR = 0–4.47) compared with sham rats (4.17 μg/mL, IQR = 0.74–8.51), p = 0.02. ICP rise was inversely correlated with faster CSF transit to the spinal subarachnoid space (R = −0.59, p = 0.006, Spearman’s correlation). These data suggest that reduced cranial clearance of CSF via cervical lymphatics may contribute to post-stroke ICP rise, partially compensated via increased spinal CSF outflow.

scholarly journals Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1370 ◽  
Author(s):  
Ferenc Zádor ◽  
Amir Mohammadzadeh ◽  
Mihály Balogh ◽  
Zoltán S. Zádori ◽  
Kornél Király ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Antinociceptive Effect ◽  
Gastrointestinal Transit ◽  
Inhibitory Effect ◽  
In Vitro Tests ◽  
Tail Flick ◽  
The Novel ◽  
Gastrointestinal Side Effects

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund’s Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.

Robot-assisted endoscopic exploration of the spinal cord

2010 ◽  
Vol 224 (7) ◽  
pp. 1515-1529 ◽  
Author(s):  
L Ascari ◽  
C Stefanini ◽  
U Bertocchi ◽  
P Dario
Keyword(s):  
Spinal Cord ◽  
Subarachnoid Space ◽  
Ex Vivo ◽  
Hierarchical Control ◽  
Three Dimensional ◽  
Robot Assisted ◽  
Actuation System ◽  
Spinal Subarachnoid Space

This work presents the design and development of an integrated image-guided robot-assisted endoscopic system for the safe navigation within the spinal subarachnoid space, providing the surgeon with the direct vision of the structures (i.e. spinal cord, roots, vessels) and the possibility of performing some particularly useful operations, like local electrostimulation of nerve roots. The modelling, micro-fabrication, fluidic sustentation, and cable-based actuation system of a steerable tip for a multilumen flexible catheter is described; the hierarchical control system shared between the surgeon and the computer, and based on machine vision techniques and a simple but effective three-dimensional reconstruction is detailed. The Blind Expected Perception sensory-motor scheme is proposed in robot-assited endoscopy. Results from in vitro, ex vivo, and in vivo experiments show that the described model can accurately predict the shape of the catheter given the tension distribution on the cables, that the proposed actuation system can assure smooth and precise control of the catheter tip, that the fluidic sustentation of the catheter is essential in in vivo navigation, and that the proposed rear view mirror interface to show non-visible obstacles is appropriate; in conclusion, the results proved the validity of the proposed solution to develop an intrinsically safe robotic system for navigation and intervention in a narrow and challenging environment such as the spinal subarachnoid space.

Noninvasive optical imaging of the subarachnoid space and cerebrospinal fluid pathways based on near-infrared fluorescence

1997 ◽  
Vol 87 (5) ◽  
pp. 738-745 ◽  
Author(s):  
Kaoru Sakatani ◽  
Masaki Kashiwasake-Jibu ◽  
Yoshinori Taka ◽  
Shijie Wang ◽  
Huancong Zuo ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Injection Site ◽  
Fluorescence Imaging ◽  
Subarachnoid Space ◽  
Near Infrared ◽  
Content Type ◽  
Spinal Subarachnoid Space ◽  
Lumbar Spinal ◽  
Fine Print

✓ The authors have developed a noninvasive optical method to image the subarachnoid space and cerebrospinal fluid pathways in vivo based on the near-infrared fluorescence of indocyanine green (ICG). The ICG was bound to purified lipoproteins (ICG—lipoprotein) and injected into the subarachnoid space of neonatal and adult rats. The ICG fluorescence was detected by a cooled charge-coupled device camera. After injection of ICG—lipoprotein into the cerebral subarachnoid space of the neonatal rat, ICG fluorescence was clearly detected at the injection site through the skull and skin. The ICG fluorescence was observed in the cerebellum and the lumbar spinal cord 1 and 8 hours postinjection, respectively. After injection of ICG—lipoprotein into the lumbar spinal subarachnoid space of an adult rat, ICG fluorescence was observed from the injection site to the thoracic levels along the spinal subarachnoid space. In addition, with the rat's head tilted downward, ICG fluorescence had extended to the cerebral subarachnoid space by 1 hour postinjection. The ICG fluorescence imaging of the cerebral subarachnoid space demonstrated an increase in fluorescence intensity around the lambdoid suture and the forebrain. On dissection of the rat brain the former location was identified as the supracerebellar cistern and the latter as the olfactory cistern. The results of this study are the first to demonstrate that an optical technique is applicable to imaging of the subarachnoid space and cerebrospinal fluid pathways in vivo. In addition, ICG—lipoprotein provides a sensitive optical tracer for imaging extravascular biological structures. Finally, ICG fluorescence imaging does not require an intricate imaging system because ICG is localized near the surface of the body.

Nitrous Oxide Produces Antinociceptive Response via α2Band/or α2CAdrenoceptor Subtypes in Mice 

1999 ◽  
Vol 90 (2) ◽  
pp. 470-476 ◽  
Author(s):  
Tian-Zhi Guo ◽  
Frances M. Davies ◽  
Wade S. Kingery ◽  
Andrew J. Patterson ◽  
Lee E. Limbird ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Transgenic Mice ◽  
Time Course ◽  
Antinociceptive Effect ◽  
Opiate Receptors ◽  
Opiate Receptor ◽  
Tail Flick ◽  
Wild Type ◽  
Tail Flick Latency ◽  
In The Wild

Background Opiate receptors in the periaqueductal gray region and alpha2 adrenoceptors in the spinal cord of the rat mediate the antinociceptive properties of nitrous oxide (N2O). The availability of genetically altered mice facilitates the detection of the precise protein species involved in the transduction pathway. In this study, the authors establish the similarity between rats and mice in the antinociceptive action of N2O and investigate which alpha2 adrenoceptor subtypes mediate this response. Methods After obtaining institutional approval, antinociceptive dose-response and time-course to N2O was measured in wild-type and transgenic mice (D79N), with a nonfunctional alpha2A adrenoceptor using tail-flick latency. The antinociceptive effect of N2O was tested after pretreatment systemically with yohimbine (nonselective alpha2 antagonist), naloxone (opiate antagonist), L659,066 (peripheral alpha2-antagonist) and prazosin (alpha2B- and alpha2C-selective antagonist). The tail-flick latency to dexmedetomidine (D-med), a nonselective alpha2 agonist, was tested in wild-type and transgenic mice. Results N2O produced antinociception in both D79N transgenic and wild-type litter mates, although the response was less pronounced in the transgenic mice. Antinociception from N2O decreased over time with continuing exposure, and the decrement was more pronounced in the transgenic mice. The antinociceptive response could be dose dependently antagonized by opiate receptor and selective alpha2B-/alpha2C-receptor antagonists but not by a central nervous system-impermeant alpha2 antagonist (L659,066). Whereas dexmedetomidine exhibited no antinociceptive response in the D79N mice, the robust antinociceptive response in the wild-type litter mates could not be blocked by a selective alpha2B-/alpha2C-receptor antagonist. Conclusion These data confirm that the antinociceptive response to an exogenous alpha2-agonist is mediated by an alpha2A adrenoceptor and that there appears to be a role for the alpha2B- or alpha2C-adrenoceptor subtypes, or both, in the analgesic response to N2O.

Dexmedetomidine Injection into the Locus Ceruleus Produces Antinociception

1996 ◽  
Vol 84 (4) ◽  
pp. 873-881. ◽  
Author(s):  
Tian-Zhi Guo ◽  
Jian-Yu Jiang ◽  
Ann E. Buttermann ◽  
Mervyn Maze
Keyword(s):  
Spinal Cord ◽  
Pertussis Toxin ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Locus Ceruleus ◽  
Tail Flick ◽  
Sprague Dawley ◽  
Tail Flick Latency ◽  
Pharmacologically Active ◽  
Sites Of Action

Background Alpha(2)-Adrenergic agonists such as clonidine and dexmedetomidine are known to produce sedation and analgesia in humans. The sedative effect of these agents is thought to occur through supraspinal pathways, involving the locus ceruleus (LC) and its projections in rats. While the antinociceptive response to alpha(2) agonists, given intrathecally, is mediated predominantly in the spinal cord, other sites of action have not been systematically studied. The authors examined whether alpha(2)-adrenergic receptors in the LC mediate an antinociceptive effect. Methods For administration of different drugs into the LC, guide cannulas were placed with their tips in the LC in male Sprague-Dawley rats. Dexmedetomidine (3.5 micrograms/0.2 microliter) was microinjected into the LC through the cannula, or given systemically by intraperitoneal injecton (50 micrograms/kg). The antinociceptive effect of dexmedetomidine was measured using the tail-flick latency response. To determine the sites through which dexmedetomidine injection into the LC produces antinociception, the authors examined whether this response could be perturbed by the specific alpha(2)-adrenergic antagonists atipamezole and L659,066 and pertussis toxin administered either into the LC or intrathecally before injection of dexmedetomidine systemically or directly into the LC. To eliminate the possibility that drug administered in one site (LC or intrathecal) could reach the other site, the dispositional characteristics of radiolabeled dexmedetomidine (LC) or atipamezole (intrathecal) were studied. Results Dexmedetomidine placed into the LC produces a dose-dependent increase in the tail-flick latency. This antinociceptive effect was blocked by pertussis toxin and by the alpha(2) antagonists atipamezole and L659,066 placed in the LC. Intrathecal administration of atipamezole and pertussis toxin also blocked the antinociceptive effect of dexmedetomidine placed in the LC. (3)H-dexmedetomidine introduced into the LC did not reach the spinal cord in pharmacologically active concentrations; also, intrathecally administered (3)H-atipamezole did not reach the LC in appreciable amounts. The systemic administration of dexmedetomidine produced an increase in tail-flick latency, and this effect was attenuated by the injection of atipamezole and L659,066 into the LC. Conclusions Part of the mechanism by which dexmedetomidine produces an antinociceptive effect is by an action directly on the LC, demonstrated by these studies in which antinociception produced by injection of this drug into the LC can be blocked by specific alpha(2) antagonists injected into the LC. Furthermore, the action of dexmedetomidine in the LC in turn may result in an increase in activation of alpha(2) adrenoceptors in the spinal cord, because the antinociceptive effect of LC dexmedetomidine injection also can be blocked by intrathecal injection of antipamezole and pertussis toxin.

scholarly journals Cerebrospinal fluid drainage kinetics across the cribriform plate are reduced with aging

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Molly Brady ◽  
Akib Rahman ◽  
Abigail Combs ◽  
Chethana Venkatraman ◽  
R. Tristan Kasper ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Cerebrospinal Fluid ◽  
Subarachnoid Space ◽  
Ex Vivo ◽  
Cribriform Plate ◽  
Cervical Lymph Nodes ◽  
Spinal Subarachnoid Space ◽  
Ex Vivo Tissues ◽  
The Brain

Abstract Background Continuous circulation and drainage of cerebrospinal fluid (CSF) are essential for the elimination of CSF-borne metabolic products and neuronal function. While multiple CSF drainage pathways have been identified, the significance of each to normal drainage and whether there are differential changes at CSF outflow regions in the aging brain are unclear. Methods Dynamic in vivo imaging of near infrared fluorescently-labeled albumin was used to simultaneously visualize the flow of CSF at outflow regions on the dorsal side (transcranial and -spinal) of the central nervous system. This was followed by kinetic analysis, which included the elimination rate constants for these regions. In addition, tracer distribution in ex vivo tissues were assessed, including the nasal/cribriform region, dorsal and ventral surfaces of the brain, spinal cord, cranial dura, skull base, optic and trigeminal nerves and cervical lymph nodes. Results Based on the in vivo data, there was evidence of CSF elimination, as determined by the rate of clearance, from the nasal route across the cribriform plate and spinal subarachnoid space, but not from the dorsal dural regions. Using ex vivo tissue samples, the presence of tracer was confirmed in the cribriform area and olfactory regions, around pial blood vessels, spinal subarachnoid space, spinal cord and cervical lymph nodes but not for the dorsal dura, skull base or the other cranial nerves. Also, ex vivo tissues showed retention of tracer along brain fissures and regions associated with cisterns on the brain surfaces, but not in the brain parenchyma. Aging reduced CSF elimination across the cribriform plate but not that from the spinal SAS nor retention on the brain surfaces. Conclusions Collectively, these data show that the main CSF outflow sites were the nasal region across the cribriform plate and from the spinal regions in mice. In young adult mice, the contribution of the nasal and cribriform route to outflow was much higher than from the spinal regions. In older mice, the contribution of the nasal route to CSF outflow was reduced significantly but not for the spinal routes. This kinetic approach may have significance in determining early changes in CSF drainage in neurological disorder, age-related cognitive decline and brain diseases.

scholarly journals Antinociception Following Implantation of AtT-20 and Genetically Modified AtT-20/hENK Cells in Rat Spinal Cord

1993 ◽  
Vol 4 (1) ◽  
pp. 15-26 ◽  
Author(s):  
Hope H. Wu ◽  
Steven C. McLoon ◽  
George L. Wilcox
Keyword(s):  
Spinal Cord ◽  
Antinociceptive Effect ◽  
Alternative Therapy ◽  
Immunohistochemical Analysis ◽  
Opioid Antagonist ◽  
Control Group ◽  
Tail Flick ◽  
Rat Spinal Cord ◽  
Adrenergic Agonist ◽  
Spinal Subarachnoid Space

AtT-20 cells, which produceß-endorphin, and AtT-20/hENK cells, which are AtT-20 cells transfected with a proenkephalin gene, were implanted in the rat spinal subarachnoid space in an effort to produce an antinociceptive effect. Host rats were tested for antinociceptive activity by standard nociceptive tests, tail flick and hot plate. Although cell implants had minimal effect on the basal response to thermal nociceptive stimuli, administration of theß2-adrenergic agonist isoproterenol produced antinociception in the cell-implanted group but not in the control group. The antinociceptive effect of isoproterenol was dose-related and could be blocked by the opioid antagonist naloxone. Immunohistochemical analysis of spinal cords revealed the presence of enkephalin-negative cells surrounding the spinal cord of rats receiving AtT-20 cell implants, and enkephalinpositive cells surrounding the spinal cord of rats. receiving AtT-20/hENK cell implants. These results suggest that opioid-releasing cells implanted around rat spinal cord can produce antinociception and may provide an alternative therapy for chronic pain.

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