Analysis of the long-term actions of gabapentin and pregabalin in dorsal root ganglia and substantia gelatinosa

The α2δ-ligands pregabalin (PGB) and gabapentin (GBP) are used to treat neuropathic pain. We used whole cell recording to study their long-term effects on substantia gelatinosa and dorsal root ganglion (DRG) neurons. Spinal cord slices were prepared from embryonic day 13 rat embryos and maintained in organotypic culture for >5 wk (neuronal age equivalent to young adult rats). Exposure of similarly aged DRG neurons (dissociated and cultured from postnatal day 19 rats) to GBP or PGB for 5–6 days attenuated high-voltage-activated calcium channel currents (HVA ICa). Strong effects were seen in medium-sized and in small isolectin B4-negative (IB4−) DRG neurons, whereas large neurons and small neurons that bound isolectin B4 (IB4+) were hardly affected. GBP (100 μM) or PGB (10 μM) were less effective than 20 μM Mn2+ in suppression of HVA ICa in small DRG neurons. By contrast, 5–6 days of exposure to these α2δ-ligands was more effective than 20 μM Mn2+ in reducing spontaneous excitatory postsynaptic currents at synapses in substantia gelatinosa. Spinal actions of gabapentinoids cannot therefore be ascribed to decreased expression of HVA Ca2+ channels in primary afferent nerve terminals. In substantia gelatinosa, 5–6 days of exposure to PGB was more effective in inhibiting excitatory synaptic drive to putative excitatory neurons than to putative inhibitory neurons. Although spontaneous inhibitory postsynaptic currents were also attenuated, the overall long-term effect of α2δ-ligands was to decrease network excitability as monitored by confocal Ca2+ imaging. We suggest that selective actions of α2δ-ligands on populations of DRG neurons may predict their selective attenuation of excitatory transmission onto excitatory vs. inhibitory neurons in substantia gelatinosa.

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Dorsal Root Rhizotomy and Avulsion in the Cat: A Comparison of Long Term Effects on Dorsal Horn Neuronal Activity

Neurosurgery ◽

10.1097/00006123-198412000-00030 ◽

1984 ◽

Vol 15 (6) ◽

pp. 921-927

Author(s):

Janice Ovelmen-Levitt ◽

Betty Johnson ◽

Purvis Bedenbaugh ◽

Blaine S. Nashold

Keyword(s):

Spinal Cord ◽

Neuronal Activity ◽

Dorsal Root ◽

Receptive Fields ◽

Substantia Gelatinosa ◽

Inhibitory Influence ◽

Long Term Effects ◽

Avulsion Injury ◽

Dorsal Horns

Abstract We performed an extracellular microelectrode analysis of the neuronal activity of cells located in deeper laminae of dorsal horns that had been deafferented by ipsilateral lumbar dorsal root rhizotomy or avulsion. Special attention was given to those cells that were recorded in preparations that were more than 6 weeks chronic. We compared the results to those obtained in nondenervated controls and in experiments in which the spinal cord was acutely transected at a midthoracic level, but had intact dorsal roots. There was an increase in ipsilateral flank and contralateral input in the chronically deafferented as compared to nondenervated controls. Differences were observed between long term rhizotomized and avulsed dorsal horns. Receptive fields extended on to flank and thoracic dermatomes after rhizotomy, often requiring only light cutaneous stimuli. Receptive fields were more restricted with avulsion injury, generally requiring moderate to strong, superficial or deep pinch. Histological analysis revealed consistent differential damage to the medial portion of Lissauer's tract with avulsion injury and subsequently more gliosis in the substantia gelatinosa. The loss of this propriospinal pathway may explain the lack of receptive field expansion on to the thoracic dermatomes and the stronger natural stimuli that were required. A higher percentage of cells with bilateral and inhibitory receptive fields was found in experiments in which the spinal cord was transected at a midthoracic level than in the controls. Ipsilateral excitatory receptive fields were also expanded as compared with control observations, but were not found on the flank. It is concluded that descending fibers have an inhibitory influence on both excitatory and inhibitory receptive fields, both ipsilaterally and contralaterally, which can be released by acute spinal cord transection. These alterations or release from inhibition may form a substrate for observations made after dorsal root denervations.

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Suppression of pituitary-testis function in rats treated neonatally with a gonadotrophin-releasing hormone agonist and antagonist: acute and long-term effects

Journal of Endocrinology ◽

10.1677/joe.0.1230083 ◽

1989 ◽

Vol 123 (1) ◽

pp. 83-91 ◽

Cited By ~ 10

Author(s):

K.-L. Kolho ◽

I. Huhtaniemi

Keyword(s):

Body Weight ◽

Gnrh Agonist ◽

Gnrh Antagonist ◽

Long Term Effects ◽

Adult Rats ◽

Releasing Hormone ◽

Serum Lh ◽

Accessory Sex Organs ◽

Gonadotrophin Releasing Hormone

ABSTRACT The acute and long-term effects of pituitary-testis suppression with a gonadotrophin-releasing hormone (GnRH) agonist, d-Ser(But)6des-Gly10-GnRH N-ethylamide (buserelin; 0·02, 0·1, 1·0 or 10 mg/kg body weight per day s.c.) or antagonist, N-Ac-d-Nal(2)1,d-p-Cl-Phe2,d-Trp3,d-hArg(Et2)6,d-Ala10-GnRH (RS 68439; 2 mg/kg body weight per day s.c.) were studied in male rats treated on days 1–15 of life. The animals were killed on day 16 (acute effects) or as adults (130–160 days; long-term effects). Acutely, the lowest dose of the agonist decreased pituitary FSH content and testicular LH receptors, but with increasing doses pituitary and serum LH concentrations, intratesticular testosterone content and weights of testes were also suppressed (P< 0·05–0·01). No decrease was found in serum FSH or in weights of accessory sex organs even with the highest dose of the agonist, the latter finding indicating continuing secretion of androgens. The GnRH antagonist treatment suppressed pituitary LH and FSH contents and serum LH (P< 0·05–0·01) but, as with the agonist, serum FSH remained unaltered. Testicular testosterone and testis weights were decreased (P <0·01) but testicular LH receptors remained unchanged. Moreover, the seminal vesicle and ventral prostate weights were reduced, in contrast to the effects of the agonists. Pituitary LH and FSH contents had recovered in all adult rats treated neonatally with agonist and there was no effect on serum LH and testosterone concentrations or on fertility. In contrast, in adult rats treated neonatally with antagonist, weights of testis and accessory sex organs remained decreased (P <0·01–0·05) but hormone secretion from the pituitary and testis had returned to normal except that serum FSH was increased by 80% (P <0·01). Interestingly, 90% of the antagonist-treated animals were infertile. It is concluded that treatment with a GnRH agonist during the neonatal period does not have a chronic effect on pituitary-gonadal function. In contrast, GnRH antagonist treatment neonatally permanently inhibits the development of the testis and accessory sex organs and results in infertility. Interestingly, despite the decline of pituitary FSH neonatally, neither of the GnRH analogues was able to suppress serum FSH values and this differs from the concomitant changes in LH and from the effects of similar treatments in adult rats. Journal of Endocrinology (1989) 123, 83–91

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Gender-related long-term effects in adult rats by perinatal dietary ratio of n-6/n-3 fatty acids

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00342.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. R575-R579 ◽

Cited By ~ 70

Author(s):

Marina Korotkova ◽

Britt G. Gabrielsson ◽

Agneta Holmäng ◽

Britt-Marie Larsson ◽

Lars Å. Hanson ◽

...

Keyword(s):

Fatty Acids ◽

Linseed Oil ◽

Maternal Diet ◽

Perinatal Period ◽

Late Gestation ◽

Male Rats ◽

Long Term Effects ◽

Adult Rats ◽

Serum Leptin

Epidemiological studies in humans have shown that perinatal nutrition affects health later in life. We have previously shown that the ratio of n-6 to n-3 polyunsaturated fatty acids (PUFA) in the maternal diet affects serum leptin levels and growth of the suckling pups. The aim of the present study was to investigate the long-term effects of various ratios of the dietary n-6 and n-3 PUFA during the perinatal period on serum leptin, insulin, and triacylglycerol, as well as body growth in the adult offspring. During late gestation and throughout lactation, rats were fed an isocaloric diet containing 7 wt% fat, either as linseed oil (n-3 diet), soybean oil (n-6/n-3 diet), or sunflower oil (n-6 diet). At 3 wk of age, the n-6/n-3 PUFA ratios in the serum phospholipids of the offspring were 2.5, 8.3, and 17.5, respectively. After weaning, all pups were given a standard chow. At the 28th postnatal wk, mean body weight and fasting insulin levels were significantly increased in the rats fed the n-6/n-3 diet perinatally compared with the other groups. The systolic blood pressure and serum triacylglycerol levels were only increased in adult male rats of the same group. These data suggest that the balance between n-6 and n-3 PUFA during perinatal development affects several metabolic parameters in adulthood, especially in the male animals.

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Transcriptomics Analysis of Porcine Caudal Dorsal Root Ganglia in Tail Amputated Pigs Shows Long-Term Effects on Many Pain-Associated Genes

Frontiers in Veterinary Science ◽

10.3389/fvets.2019.00314 ◽

2019 ◽

Vol 6 ◽

Cited By ~ 5

Author(s):

Dale A. Sandercock ◽

Mark W. Barnett ◽

Jennifer E. Coe ◽

Alison C. Downing ◽

Ajit J. Nirmal ◽

...

Keyword(s):

Dorsal Root Ganglia ◽

Dorsal Root ◽

Long Term Effects

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Dorsal Root Rhizotomy and Avulsion in the Cat: A Comparison of Long Term Effects on Dorsal Horn Neuronal Activity

Neurosurgery ◽

10.1227/00006123-198412000-00030 ◽

1984 ◽

Vol 15 (6) ◽

pp. 921-927 ◽

Cited By ~ 21

Author(s):

Janice Ovelmen-Levitt ◽

Betty Johnson ◽

Purvis Bedenbaugh ◽

Blaine S. Nashold

Keyword(s):

Dorsal Horn ◽

Neuronal Activity ◽

Dorsal Root ◽

Long Term Effects

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Baclofen inhibition of dorsal root-evoked inhibitory postsynaptic currents in substantia gelatinosa neurons of rat spinal cord slice

Brain Research ◽

10.1016/s0006-8993(01)02293-4 ◽

2001 ◽

Vol 900 (2) ◽

pp. 320-323 ◽

Cited By ~ 9

Author(s):

Kun Yang ◽

Yu-Peng Feng ◽

Yun-Qing Li

Keyword(s):

Spinal Cord ◽

Dorsal Root ◽

Substantia Gelatinosa ◽

Rat Spinal Cord ◽

Spinal Cord Slice ◽

Inhibitory Postsynaptic Currents ◽

Postsynaptic Currents

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Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00408.2001 ◽

2002 ◽

Vol 283 (3) ◽

pp. L555-L562 ◽

Cited By ~ 254

Author(s):

Timothy D. Le Cras ◽

Neil E. Markham ◽

Rubin M. Tuder ◽

Norbert F. Voelkel ◽

Steven H. Abman

Keyword(s):

Pulmonary Hypertension ◽

Vegf Receptor ◽

Newborn Rats ◽

Long Term Effects ◽

Adult Rats ◽

Rat Pups ◽

Lung Structure ◽

Vegfr Inhibitor ◽

And Function

To determine whether disruption of vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling in the newborn has long-term effects on lung structure and function, we injected 1-day-old newborn rat pups with a single dose of Su-5416, a VEGFR inhibitor, or vehicle (controls). Lungs from infant (3-wk-old) and adult (3- to 4-mo-old) rats treated with Su-5416 as newborns showed reductions in arterial density (82 and 31%, respectively) and alveolar counts (45 and 29%) compared with controls. Neonatal treatment with Su-5416 increased right ventricle weight to body wt ratios (4.2-fold and 2.0-fold) and pulmonary arterial wall thickness measurements (2.7-fold and 1.6-fold) in infant and adult rats, respectively, indicating marked pulmonary hypertension. We conclude that treatment of newborn rats with the VEGFR inhibitor Su-5416 impaired pulmonary vascular growth and postnatal alveolarization and caused pulmonary hypertension and that these effects were long term, persisting well into adulthood.

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