Intravenous Morphine Increases Release of Nitric Oxide From Spinal Cord by an α-Adrenergic and Cholinergic Mechanism

1997 ◽  
Vol 78 (4) ◽  
pp. 2072-2078 ◽  
Author(s):  
Zemin Xu ◽  
Chuanyao Tong ◽  
Hui-Lin Pan ◽  
Sergio E. Cerda ◽  
James C. Eisenach
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Dorsal Horn ◽  
Cervical Spinal Cord ◽  
Intrathecal Injection ◽  
Spinal Cord Tissue ◽  
Cholinergic Mechanism ◽  
Adrenergic Antagonist ◽  
Opioid Administration ◽  
Intravenous Morphine

Xu, Zemin, Chuanyao Tong, Hui-Lin Pan, Sergio E. Cerda, and James C. Eisenach. Intravenous morphine increases release of nitric oxide from spinal cord by an α-adrenergic and cholinergic mechanism. J. Neurophysiol. 78: 2072–2078, 1997. Systemic opioids produce analgesia in part by activating bulbospinal noradrenergic pathways. Spinally released norepinephrine (NE) has been suggested to produce analgesia in part by stimulating α2-adrenoceptors on cholinergic spinal interneurons to release acetylcholine (ACh). We hypothesized that this spinally released ACh would stimulate synthesis of nitric oxide (NO), and that spinally released NO after intravenous (IV) opioid injection thus would depend on a cascade of noradrenergic and cholinergic receptor stimulation. To test these hypotheses, IV morphine was administered to anesthetized sheep, and neurotransmitters in dorsal horn interstitial fluid were measured by microdialysis. IV morphine increased NE and ACh in dorsal horn microdialysates, and these increases were inhibited by IV naloxone or cervical spinal cord transection. IV morphine also increased dorsal horn microdialysate concentrations of nitrite, a stable metabolite of NO. Increases in NE, ACh, and nitrite were antagonized by prior intrathecal injection of the α2-adrenergic antagonist idazoxan, the muscarinic antagonist atropine, or the NO synthase inhibitor N-methyl-l-arginine (NMLA). To examine the concentration-dependent effects of spinal adrenergic stimulation, isolated rat spinal cord tissue was perfused with the α2-adrenergic agonist clonidine. Clonidine increased nitrite in the spinal cord tissue perfusate, an effect blocked by coadministration of idazoxan, atropine, and NMLA. These data support a previously hypothesized cascade of spinally released NE and ACh after systemic opioid administration. These data also suggest that spinally released NO plays a role in the analgesic effects of systemic opioids. In addition, these data imply a positive feedback whereby spinally released nitric oxide increases NE release and that has not previously been described.

Spinal Nitric Oxide Mediates Antinociception from Intravenous Morphine 

1998 ◽  
Vol 89 (1) ◽  
pp. 215-221 ◽  
Author(s):  
Ho-Kyung Song ◽  
Hui-Lin Pan ◽  
James C. Eisenach
Keyword(s):  
Nitric Oxide ◽  
Intravenous Injection ◽  
Intrathecal Injection ◽  
No Synthase ◽  
Male Rats ◽  
Adrenergic Antagonist ◽  
Spinal Opioids ◽  
Intravenous Morphine ◽  
Intrathecal Space ◽  
Dose Dependent

Introduction Spinal nitric oxide (NO) is thought in many circumstances to play a pronociceptive role, because spinal injection of NO synthase inhibitors block hypersensitivity after nerve injury and enhance antinociception from spinal opioids. Conversely, intravenous injection of morphine has been demonstrated to activate descending noradrenergic pathways and to increase spinal synthesis of NO. This study examined the role of spinal NO in antinociception produced by intravenously administered morphine. Methods Polyethylene catheters were inserted with tips in the lumbar intrathecal space and in a jugular vein in male rats. Antinociception in response to intravenous injection of morphine was determined by latency to withdrawal of the hind paw from a heat source. Animals received an intrathecal injection of saline, an alpha2-adrenergic antagonist (idazoxan), a muscarinic antagonist (atropine), two NO synthase inhibitors, or an NO scavenger after intravenously administered morphine. Results Intravenously administered morphine produced dose-dependent antinociception, which was stable for 45 min and unaffected by intrathecally administered saline or atropine injection. In contrast, idazoxan, each of the NO synthase inhibitors, and the NO scavenger produced dose-dependent attenuation of intravenously administered morphine-induced antinociception. Discussion These results confirm a spinal alpha2-adrenergic mechanism of antinociception from intravenously administered morphine, consistent with morphine's activation of descending noradrenergic pathways. Further, these data suggest that spinal NO mediates antinociception produced by intravenous morphine.

scholarly journals Anatomical organization of the lateral cervical nucleus in Artiodactyls

2021 ◽  
Author(s):  
Annamaria Grandis ◽  
Anna Gardini ◽  
Claudio Tagliavia ◽  
Giulia Salamanca ◽  
Jean-Marie Graïc ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Cervical Spinal Cord ◽  
Synaptic Activity ◽  
Immunoperoxidase Method ◽  
Somatosensory Information ◽  
Lateral Cervical Nucleus ◽  
Neuronal Processes ◽  
Calbindin D28k ◽  
Oxide Synthase

AbstractThe presence of the lateral cervical nucleus (LCN) in different mammals, including humans, has been established in a number of anatomical research works. The LCN receives its afferent inputs from the spinocervical tract, and conveys this somatosensory information to the various brain areas, especially the thalamus. In the present study, the organization of the calf and pig LCN was examined through the use of thionine staining and immunohistochemical methods combined with morphometrical analyses. Specifically, the localization of calbindin-D28k (CB-D28k) and neuronal nitric oxide synthase (nNOS) in the LCN was investigated using the immunoperoxidase method. Calf and pig LCN appear as a clearly defined column of gray matter located in the three cranial segments of the cervical spinal cord. Thionine staining shows that polygonal neurons represent the main cell type in both species. The calf and pig LCN contained CB-D28k-immunoreactive (IR) neurons of varying sizes. Large neurons are probably involved in the generation of the cervicothalamic pathway. Small CB-D28k-IR neurons, on the other hand, could act as local interneurons. The immunoreactivity for nNOS was found to be mainly located in thin neuronal processes that could represent the terminal axonal portion of nNOS-IR found in laminae III e IV. This evidence suggests that nitric oxide (NO) could modulate the synaptic activity of the glutamatergic spinocervical tracts. These findings suggest that the LCN of Artiodactyls might play an important role in the transmission of somatosensory information from the spinal cord to the higher centers of the brain.

scholarly journals Mechanical Properties of Cervical Spinal Cord in Neonatal Piglet: In Vitro

2020 ◽  
pp. 1-3
Author(s):  
Anita Singh ◽  
Anita Singh ◽  
Rachel Magee ◽  
Sriram Balasubramanian
Keyword(s):  
Spinal Cord ◽  
Maximum Stress ◽  
Cervical Spinal Cord ◽  
Tensile Loading ◽  
Maximum Load ◽  
Spinal Cord Tissue ◽  
Prevention Strategies ◽  
Biomechanical Behavior ◽  
Injury Mechanisms

The response of neonatal spinal cord tissue to tensile loading is not well-studied. In this study, isolated fresh neonatal cervical spinal cord samples, obtained from twelve 2-4 days old piglets, were tested in uniaxial tension at a rate of 500 mm/min until failure. Maximum load, maximum stress, percentage strain at maximum stress and modulus of elasticity were reported to be 14.6±3.4 N, 0.34±0.11 MPa, 29.3±5.4% and 1.52±0.8 MPa, respectively. These data can help understand the biomechanical behavior of the spinal cord in neonates and can be further used in computational modeling to understand injury mechanisms better and help develop injury prevention strategies.

Attenuation of reflex pressor and ventilatory responses to static contraction by an NK-1 receptor antagonist

1992 ◽  
Vol 73 (4) ◽  
pp. 1389-1395 ◽  
Author(s):  
J. M. Hill ◽  
J. G. Pickar ◽  
M. P. Kaufman
Keyword(s):  
Spinal Cord ◽  
Substance P ◽  
Receptor Antagonist ◽  
Dorsal Horn ◽  
Intrathecal Injection ◽  
Muscular Contraction ◽  
Muscle Afferents ◽  
Neurokinin A ◽  
Ventilatory Responses ◽  
Static Contraction

The chemical messengers released onto second-order dorsal horn neurons from the spinal terminals of contraction-activated group III and IV muscle afferents have not been identified. One candidate is the tachykinin substance P. Related to substance P are two other tachykinins, neurokinin A (NKA) and neurokinin B (NKB), which, like substance P, have been isolated in the dorsal horn of the spinal cord and have receptors there. Whether NKA or NKB plays a transmitter/modulator role in the spinal processing of the exercise pressor reflex is unknown. Therefore, we tested the following hypotheses. After the intrathecal injection of a highly selective NK-1 (substance P) receptor antagonist onto the lumbosacral spinal cord, the reflex pressor and ventilatory responses to static muscular contraction will be attenuated. Likewise, after the intrathecal injection either of an NK-2 (NKA) receptor antagonist or an NK-3 (NKB) receptor antagonist onto the lumbrosacral spinal cord, the reflex pressor and ventilatory responses to static contraction will be attenuated. We found that, 10 min after the intrathecal injection of 100 micrograms of the NK-1 receptor antagonist, the pressor and ventilatory responses to contraction were significantly (P < 0.05) attenuated. Mean arterial pressure was attenuated by 13 +/- 3 mmHg (48%) and minute volume of ventilation by 120 +/- 38 ml/min (34%). The cardiovascular and ventilatory responses to contraction before either 100 micrograms of the NK-2 receptor antagonist or 100 micrograms of the NK-3 receptor antagonist were not different (P > 0.05) from those after the NK-2 or the NK-3 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

A5 noradrenergic neurons and the carotid sympathetic chemoreflex

1994 ◽  
Vol 267 (2) ◽  
pp. R519-R526 ◽  
Author(s):  
N. Koshiya ◽  
P. G. Guyenet
Keyword(s):  
Spinal Cord ◽  
Neural Activity ◽  
Adrenergic Receptor ◽  
Intrathecal Injection ◽  
Noradrenergic Neurons ◽  
Alpha Adrenergic Receptor ◽  
Adrenergic Antagonist ◽  
A5 Area ◽  
6 Hydroxydopamine ◽  
Nerve Discharge

Inhibition of neural activity in the caudal ventrolateral pons (A5 area) by microinjection of muscimol (Mus) attenuates (-65%) the carotid sympathetic chemoreflex (SChR) without altering the concomitant activation of the phrenic nerve (PND). The present study, performed in urethan-anesthetized rats, explores the possibility that activation of the noradrenergic (NE) neurons of the A5 area is involved in the SChR. The NE neuron-selective toxin 6-hydroxydopamine (6-OHDA) was microinjected bilaterally into the spinal cord at T2 level (4 micrograms). This dose reduced the SChR by 55% (n = 5) 90 min after injection, while 0.4 microgram of 6-OHDA produced no effect (n = 5). In seven rats that had received 250 micrograms 6-OHDA intracisternally 2 wk before, Mus injections into the A5 area failed to attenuate the SChR. These rats also had a lower resting mean arterial pressure than controls (97 vs. 112 mmHg). Spinal intrathecal injection of alpha-adrenergic receptor antagonists (prazosin, 10 and 20 micrograms) or phentolamine (20 and 40 micrograms) attenuated resting sympathetic nerve discharge (SND) and SChR in a roughly proportional manner (25-40%); the beta-adrenergic antagonist nadolol (10 and 20 microgram(s) intrathecally) attenuated the SChR selectively but modestly (-10%). The results are generally compatible with the hypothesis that A5 NE neurons and particularly their spinal cord projection could play a facilitating role in the SChR. However, clear evidence that A5 cells contribute selectively to sympathoactivation during chemoreceptor stimulation by releasing NE in the spinal cord could not be obtained.

Location and Characteristics of Nitric Oxide Synthase in Sheep Spinal Cord and Its Interaction with α2-Adrenergic and Cholinergic Antinociception

1996 ◽  
Vol 84 (4) ◽  
pp. 890-899. ◽  
Author(s):  
Zemin Xu ◽  
Ping Li ◽  
Chuanyao Tong ◽  
Jorge Figueroa ◽  
Joseph R. Tobin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Nitric Oxide Synthase ◽  
Dorsal Horn ◽  
Spinal Cord Dorsal Horn ◽  
Soluble Form ◽  
Superficial Dorsal Horn ◽  
Cell Column ◽  
Oxide Synthase ◽  
Nitric Oxide Synthase Activity

Background Nitric oxide synthase is located in the spinal cord dorsal horn and intermediolateral cell column, where it may modulate sensory and sympathetic neuronal activity. However, the biochemical characteristics of this enzyme have not been examined in these different areas in the spinal cord. Although alpha(2)-adrenergic agonists, muscarinic agonists, and nitric oxide may interact in the spinal cord to produce antinociception, these interactions have not been characterized. Methods Sheep spinal cord tissue was homogenized ad centrifuged at high sped to separate soluble and membrane-bound fractions. Nitric oxide synthase activity was determined by conversion of [(14)C]-L-arginine to [(14)C]-L-citrulline and its kinetic characteristics, dependency on cofactors, and sensitivity to inhibitors determined. Sheep spinal cord was stained for nicotinamide adenine dinucleotide phosphate diaphorase as a marker for nitric oxide synthase. Antinociception to a mechanical stimulus from intrathecal clonidine alone and with neostigmine was determined and the effects of L-arginine and n-methyl-L-arginine were determined. Results More than 85% of nitric oxide synthase activity was present in the soluble form and its kinetic, cofactor, and antagonist properties were similar to those of the neuronal isoform of nitric oxide synthase. Biochemical and histochemical studies localized nitric oxide synthase to the superficial dorsal horn and the intermediolateral cell column. Clonidine antinociception was enhanced by L-arginine and neostigmine, but not by D-arginine. Neostigmine's enhancement of clonidine antinociception was blocked by n-methyl-L-arginine. Conclusions These results confirm those of previous studies demonstrating localization of nitric oxide synthase to superficial dorsal horn and intermediolateral cell column of mammalian spinal cord, and suggesting its identity as the neuronal isoform. Spinal alpha(2)-adrenergic agonist antinociception may be partly dependent on cholinergic and nitric oxide mechanisms.

scholarly journals ML-05 A CASE OF NEUROLYMPHOMATOSIS ARISED SECONDARILY FROM PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii33-ii33
Author(s):  
Keishi Horiguchi ◽  
Hirofumi Asano ◽  
Tadashi Osawa ◽  
Masahiko Tosaka ◽  
Yuhei Yoshimoto
Keyword(s):  
Spinal Cord ◽  
Fdg Pet ◽  
Peripheral Nerves ◽  
Initial Treatment ◽  
Cervical Spinal Cord ◽  
Intrathecal Injection ◽  
Cranial Nerves ◽  
Central Nervous System Lymphoma ◽  
High Dose ◽  
Whole Brain Irradiation

Abstract A woman in her 40s. A biopsy of multiple intracranial lesions was performed, and the patient was diagnosed with DLBCL. As an initial treatment, 6 courses of high dose MTX therapy were performed and CR was achieved. Radiation therapy was not desired by the patient. On the 19th month after initial treatment, tumor recurrence was confirmed by MRI and added 2 courses of HD-MTX. On the 23rd month, second recurrence around the left basal ganglia were observed. One additional course of HD-MTX was performed, but due to the appearance of renal damage that was thought to be acute tubular necrosis, additional HD-MTX was not performed and whole brain irradiation was performed. She began complaining of pain in the trunk and extremities during radiation. When MRI and FDG-PET were performed in the 25th month, multiple lesions were found in the ganglia, plexus, and peripheral nerves from the cervical spinal cord to the sacral spinal cord. Cerebrospinal fluid cytology revealed atypical lymphocytes and lymphoma dissemination in the spinal cord. When intrathecal administration of the anticancer agent was performed nine times weekly, the CSF cytology was negative. Imaging findings showed that the lesions relapsed, although the lesions were temporarily reduced. After confirming that the renal function had recovered, two additional courses of HD-MTX were performed. Accumulation of FDG-PET in the lesion disappeared in the 29th month. However, peripheral neuropathic pain and paraplegia remained. Discussion: Neurolymphomatosis is considered to be a clinically rare disease that presents invasion of lymphoma into peripheral nerves including the cranial nerves, nerve roots or plexus. Diagnosis of NL has been required to be proved by nerve biopsy or autopsy, but noninvasive FDG-PET has been reported to be effective. In this case, CR was not obtained with anticancer drug intrathecal injection, and HD-MTX therapy was successful.

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