Chromaffin allografts into arachnoid of spinal cord reduce basal pain responses in rats

Vaquero, J.; Arias, A. Bagües; Oya, S.; Zurita, Mercedes

doi:10.1097/00001756-199103000-00010

Cited by 29 publications

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“…Previous studies in our and other laboratories have demonstrated that transplants of adrenal medullary chromaffin cells into the subarachnoid space of the spinal cord can attenuate pain responses in a variety of animal models and offers a promising avenue for clinical pain management (Brewer and Yezierski 1998;Buchser et al 1996;Burgess et al 1996;Décosterd et al 1998;Hains et al 1998;Hama and Sagen 1993;Lazorthes et al 1995;Ortega-Alvaro et al 1997;Sagen et al 1990;Siegan and Sagen 1997;Vaquero et al 1991;Winnie et al 1993;Yu et al 1998). 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).…”

Section: Discussionmentioning

confidence: 98%

“…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).…”

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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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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

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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“…Adrenergic and opioid agonists are antinociceptive when intrathecally injected either alone or in combination (Kuraishi et al, 1985;Przesmycki et al, 1997;Sherman et al, 1988). Likewise, chromaffin cells release catecholamines and opioid peptides and the antinociceptive effects are blocked with either phentolamine or naloxone (Czech and Sagen, 1995;Siegan and Sagen, 1997;Vaquero et al, 1991). There are other less well-characterized substances that are synthesized and released by chromaffin cells that may have antinociceptive effects as well (Lemaire et al, 1995;.…”

Section: Discussionmentioning

confidence: 99%

“…Transplanted into the lumbar spinal subarachnoid space, these cells have been shown to reduce pain-related behaviors in a number of rat pain models, including the formalin test (Hama and Sagen, 1994a;Sagen et al, 1986;Siegan and Sagen, 1997;Sol et al, 2004;Vaquero et al, 1991;Wang and Sagen, 1995). The opioid receptor antagonist naloxone and α-adrenoreceptor antagonist phentolamine attenuate the antinociceptive effects of the transplant, indicating that the primary action of these cells is to attenuate the activity of dorsal horn nociceptive neurons (Hentall et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Spinal subarachnoid adrenal medullary transplants reduce hind paw swelling and peripheral nerve transport following formalin injection in rats

2008

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Previous studies have demonstrated that adrenal medullary chromaffin cells transplanted into the spinal subarachnoid space significantly reduced pain-related behavior following hind paw plantar formalin injection in rats. The data suggests a centrally mediated antinociceptive mechanism. The spinal transplants may have effects on sciatic nerve function as well. To address this, the current study examined the effects of spinal adrenal transplants on hind paw edema and the anterograde transport of substance P (SP) that occur following formalin injection. Robust formalin-evoked edema, as well as hind paw flinching, was observed in striated muscle control-transplanted rats, which were not observed in adrenal-transplanted rats. To visualize transport of SP, the sciatic nerve was ligated ipsilateral to formalin injection and the nerve was processed 48 h later for immunocytochemistry. A significant formalin-induced accumulation of SP immunoreactivity (IR) was observed proximal to the ligation in control-transplanted rats. In contrast, there was significantly less SP IR observed from nerve of adrenal-transplanted rats, suggesting a diminution of anterograde axoplasmic transport by adrenal transplants. The change in SP IR may have been due to an alteration of transport due to formalin injection, thus, transport was visualized by the accumulation of growth-associated protein 43 (GAP43) at the ligation site. Formalin injection did not significantly increase proximal accumulation of GAP43 IR, indicating that formalin does not increase anterograde transport. Surprisingly, however, adrenal transplants significantly diminished GAP43 IR accumulation compared to control-transplanted rats. These data demonstrate that spinal adrenal transplants can attenuate the formalin-evoked response by modulating primary afferent responses.

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“…Most of this work has focused on the transplantation of adrenal medullary chromaffin cells in the spinal subarachnoid space, as these cells produce numerous agents with analgesic or antinociceptive activity, including opioid peptides, catecholamines, and endogenous Nmethyl-D-aspartate (NMDA) antagonists. Adrenal medullary tissue or isolated chromaffin cell transplants have shown efficacy in various preclinical pain models, including the formalin test [1][2][3][4][5], chronic inflammation [6][7][8], neuropathic pain models [9][10][11][12][13][14], central pain models [15][16][17][18], and wind-up [19]. Our laboratory at the University of Illinois at Chicago (UIC) published the first papers on the use of this approach in preclinical acute rodent pain models in 1986 [20][21].…”

Section: Adrenal Medullary Transplants For Pain: Previous Clinical Exmentioning

confidence: 99%

Cellular therapies for spinal cord injury: What will the FDA need to approve moving from the laboratory to the human?

Sagen¹

2003

JRRD

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Abstract-The transplantation of living cells and tissues to restore function and/or provide therapeutic molecules has been an active and ongoing area of research interest for over 25 years. Several of these potential therapies have reached initial clinical trials, and it is likely that applications will continue to expand, and that novel and improved approaches will be explored over the next several years. In the past, many of these experimental approaches were tested in early clinical trials without the oversight of regulatory agencies such as the Food and Drug Administration. However, as novel cellular therapies move from preclinical laboratory findings to the clinical arena, researchers and regulators face new and continually evolving issues and uncertainties involving long-term safety and efficacy. Using adrenal medullary transplantation in the spinal cord for pain as an example, this review presents an overview of past and current regulatory guidelines for moving these promising, novel cellular transplantation therapies from the laboratory to the human.

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Chromaffin allografts into arachnoid of spinal cord reduce basal pain responses in rats

Cited by 29 publications

References 0 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

Spinal subarachnoid adrenal medullary transplants reduce hind paw swelling and peripheral nerve transport following formalin injection in rats

Cellular therapies for spinal cord injury: What will the FDA need to approve moving from the laboratory to the human?

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