Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts

Ibuki, Takae; Hama, Aldric; Wang, X T; Pappas, George D.; Sagen, Jacqueline

doi:10.1016/s0306-4522(96)00341-7

Cited by 265 publications

(185 citation statements)

References 40 publications

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“…Thus, a more tenable explanation is that the transplanted cells have altered local spinal CNS pain transmission pathways, indirectly leading to sustained release of ␤-endorphin from higher centers. A possible route for these effects is the spinohypothalamic tract, which has been shown to originate in part from nociceptive neurons in the lumbar superficial dorsal horn and gray matter surrounding the central canal in rats (Burstein et al 1987(Burstein et al , 1990, regions previously showing neurochemical and morphological alterations following adrenal medullary transplantation (Hama and Sagen 1994;Ibuki et al 1997;Sagen and Wang 1995).The second effect of adrenal medullary transplants revealed in the present studies was blockade of increased ␤-endorphin release in response to noxious stimuli. Previous findings showed a consistent and marked transiently evoked increase in ␤-endorphin release from the internal arcuate nucleus, which paralleled increased pain behaviors in response to intraplantar formalin injection (Zangen et al 1998).…”

supporting

confidence: 49%

“…Although the transplanted cells appear to produce some of their antinociceptive effects via local release of pain-reducing analgesic agents, including catecholamines and opioid peptides, into the host spinal CSF (Sagen and Kemmler 1989;Sagen et al 1991), recent studies have indicated that these transplants can also produce neuroplastic changes in the pain processing circuitry of the spinal cord, including restoration of spinal inhibitory neurons and decreased c-fos activation in response to persistent pain (Ibuki et al 1997;Sagen and Wang 1995). Thus, cellular transplants in the spinal cord may result in long-term and widespread alterations in host CNS pain modulatory systems.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Alterations in Endogenous Brain β-Endorphin Release by Adrenal Medullary Transplants in the Spinal Cord

Yadid

Zangen

Herzberg

et al. 2000

Neuropsychopharmacology

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While transplants of adrenal medullary cells into the spinal subarachnoid space may produce antinociception via inhibition of spinal pain transmission pathways, alterations at higher central nervous system (CNS) centers have not been addressed. Recent findings suggest that prolonged noxious stimulation results in release of endogenousTransplantation of adrenal medullary chromaffin cells in the subarachnoid space of the spinal cord has been shown to reduce pain behaviors in several animal models, including inflammatory pain (Ortega-Alvaro et al. 1997;Sagen et al. 1990;Siegan and Sagen 1997;Vaquero et al. 1991;Wang and Sagen 1995), neuropathic pain (Décosterd et al. 1998;Ginzburg and Seltzer 1990; Sagen 1993, 1994), and central pain models (Brewer and Yezierski 1998;Hains et al. 1998;Yu et al. 1998). This has led to the initiation of clinical trials at several centers, with promising outcomes (Buchser et al. 1996;Burgess et al., 1996;Lazorthes et al. 1995;Winnie et al. 1993). Since chromaffin cells produce and secrete several potential pain-reducing neuroactive substances, including opioid peptides and catecholamines, a possible mechanism for this pain reduction is via inhibition of spinal pain transmission pathways. In support for this, adrenal medullary transplants in the rat lumbar spinal subarachnoid space suppress flinching responses 23 , NO . 6 in the formalin pain model, an effect which is partially reversed by opioid antagonist naloxone or ␣ -adrenergic antagonist phentolamine (Siegan and Sagen 1997).While local spinal actions of cellular implants have been the focus of the majority of previous studies, effects on higher central nervous system (CNS) pain processing centers have been largely ignored. In particular, recent findings by our group have demonstrated markedly increased levels of endogenous ␤ -endorphin secretion in the hypothalamic arcuate nucleus coincident with pain behaviors in response to hindpaw injections of formalin (Zangen et al. 1998). As the arcuate nucleus is the principal source of this potent opioid peptide in the CNS (Bach 1997), this finding may be indicative of a compensatory mechanism in response to prolonged noxious stimuli. In support for this, noxious stimuli or persistent pain have been shown to increase activity in the arcuate nucleus as indicated by increased c-fos (Bullitt 1990;Pan et al. 1994), 2-deoxyglucose (Mao et al. 1993, and blood flow (Morrow et al. 2000) in that region. In addition, intense activation of spinal nociceptive pathways by intrathecal capsaicin results in increased ␤ -endorphin release in brain lateral ventricular perfusates (Bach and Yaksh 1995a).The hypothalamic arcuate nucleus may also play a role in endogenous analgesic responses. For example, this region is activated by analgesic low frequency electroacupuncture (Lee and Beitz 1993;Pan et al. 1994;Takeshige et al. 1992; Wang et al. 1990a,b;Zhang et al. 1996), and local stimulation of the arcuate nucleus or ␤ -endorphin microinjection can reduce pain responses to noxious stimuli (Bach and Yak...

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supporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Alterations in Endogenous Brain β-Endorphin Release by Adrenal Medullary Transplants in the Spinal Cord

Yadid

Zangen

Herzberg

et al. 2000

Neuropsychopharmacology

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“…Activity-dependent central sensitization (heterosynaptic facilitation) is evident within seconds of a nociceptive conditioning stimulus and can outlast the stimulus for hours (Woolf and Wall, 1986). Within the dorsal horn, increases in excitatory amino acid concentrations (Somers et al, 2002) and reduction of GABA concentrations (Ibuki et al, 1997;Stiller et al, 1996) may also contribute to allodynia and hyperalgesia after nerve injury. The present results also suggest that upregulated expression of Na v 1.3 contributes to hyperresponsiveness of these central neurons after nerve injury.…”

Section: Discussionmentioning

confidence: 99%

Altered Sodium Channel Expression in Second-Order Spinal Sensory Neurons Contributes to Pain after Peripheral Nerve Injury

Hains

Saab²,

Klein³

et al. 2004

J. Neurosci.

248

156

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Peripheral nerve injury is known to upregulate the rapidly repriming Na v 1.3 sodium channel within first-order spinal sensory neurons. In this study, we hypothesized that (1) after peripheral nerve injury, second-order dorsal horn neurons abnormally express Na v 1.3, which (2) contributes to the responsiveness of these dorsal horn neurons and to pain-related behaviors. To test these hypotheses, adult rats underwent chronic constriction injury (CCI) of the sciatic nerve. Ten days after CCI, allodynia and hyperalgesia were evident. In situ hybridization, quantitative reverse transcription-PCR, and immunocytochemical analysis revealed upregulation of Na v 1.3 in dorsal horn nociceptive neurons but not in astrocytes or microglia, and unit recordings demonstrated hyperresponsiveness of dorsal horn sensory neurons. Intrathecal antisense oligodeoxynucleotides targeting Na v 1.3 decreased the expression of Na v 1.3 mRNA and protein, reduced the hyperresponsiveness of dorsal horn neurons, and attenuated pain-related behaviors after CCI, all of which returned after cessation of antisense delivery. These results demonstrate for the first time that sodium channel expression is altered within higher-order spinal sensory neurons after peripheral nerve injury and suggest a link between misexpression of the Na v 1.3 sodium channel and central mechanisms that contribute to neuropathic pain after peripheral nerve injury.

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“…The GABA-immunoreactivity in the spinal dorsal horn decreases once peripheral nerve and spinal ischemic injuries occur [12,26]. The spinal administration of GABA-A receptor antagonist, bicuculline, induces hyperexcitability of spinal dorsal horn neurons in naïve rats [27].…”

Section: Discussionmentioning

confidence: 99%

Transplantation of GABAergic Neurons from ESCs Attenuates Tactile Hypersensitivity Following Spinal Cord Injury

et al. 2010

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We investigated the therapeutic potential of mouse ESCderived gamma-amino butyric acid (GABA)ergic neurons ($74% of total neurons in vitro) to reduce neuropathic pain following spinal cord injury (SCI) in rats. Spinal cord hemisection at the T13 segment, which is used as a rat SCI pain model, induced tactile hypersensitivity of the hind paw, as evidenced by decreased paw withdrawal thresholds in response to von Frey filaments, and also induced hyperexcitability of wide dynamic range neurons in the lumbar spinal cord in response to natural cutaneous stimuli. At 2 weeks posthemisection, GABAergic neurons (500,000 cells) were transplanted into the subarachnoid space of the spinal lumbar enlargement via a modified lumbar puncture technique. The transplantation of GABAergic neurons led to long-term attenuation of hemisection-induced tactile hypersensitivity and neuronal hyperexcitability as compared with vehicle-treated controls. These attenuations were reversed by the application of bicuculline and CGP52432, GABA-A and GABA-B receptor antagonists, respectively, but not by application of the serotonergic receptor antagonist methylsergide, indicating a specific restoration of spinal GABAergic inhibition. Histological data from sections of the lumbar cord in grafts demonstrated that 43.5% of surviving engrafted cells were neurons and located densely in the lower-medial portion of the dorsal funiculi in the spinal white matter. Among the observed neurons, 26.2% were GABAergic. The results suggest that subarachnoid transplantation of ESC-derived GABAergic neurons appear to restore spinal GABAergic inhibitory tone and can be a promising strategy to treat SCI-induced pain.

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Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts

Cited by 265 publications

References 40 publications

Alterations in Endogenous Brain β-Endorphin Release by Adrenal Medullary Transplants in the Spinal Cord

Alterations in Endogenous Brain β-Endorphin Release by Adrenal Medullary Transplants in the Spinal Cord

Altered Sodium Channel Expression in Second-Order Spinal Sensory Neurons Contributes to Pain after Peripheral Nerve Injury

Transplantation of GABAergic Neurons from ESCs Attenuates Tactile Hypersensitivity Following Spinal Cord Injury

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