Intrathecal Catheterization and Drug Delivery in Guinea Pigs: A Small-animal Model for Morphine-evoked Granuloma Formation

Kelly A. Eddinger, Eric S. Rondon, Veronica I. Shubayev, Marjorie Grafe, Miriam Scadeng, Keith R. Hildebrand, Linda M. Page, Shelle A. Malkmus, Joanne J. Steinauer, Tony L. Yaksh

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

BACKGROUND:: Intrathecal infusion of opioids in dogs, sheep, and humans produces local space-occupying masses. To develop a small-animal model, the authors examined effects of intrathecal catheterization and morphine infusion in guinea pigs. METHODS:: Under isoflurane, polyethylene or polyurethane catheters were advanced from the cisterna magna to the lumbar enlargement. Drugs were delivered as a bolus through the externalized catheter or continuously by subcutaneous minipumps. Hind paw withdrawal to a thermal stimulus was assessed. Spinal histopathology was systematically assessed in a blinded fashion. To assist in determining catheter placement, ex vivo images were obtained using magnetic resonance imaging in several animals. Canine spinal tissue from previous intrathecal morphine studies was analyzed in parallel. RESULTS:: (1) Polyethylene (n = 30) and polyurethane (n = 25) catheters were implanted in the lumbar intrathecal space. (2) Bolus intrathecal morphine produced a dose-dependent (20 to 40 μg/10 μl) increase in thermal escape latencies. (3) Absent infusion, a catheter-associated distortion of the spinal cord and a fibrotic investment were noted along the catheter tract (polyethylene > polyurethane). (4) Intrathecal morphine infusion (25 mg/ml/0.5 μl/h for 14 days) resulted in intrathecal masses (fibroblasts, interspersed collagen, lymphocytes, and macrophages) arising from meninges proximal to the catheter tip in both polyethylene- and polyurethane-catheterized animals. This closely resembles mass histopathology from intrathecal morphine canine studies. CONCLUSIONS:: Continuous intrathecal infusion of morphine leads to pericatheter masses that morphologically resemble those observed in dogs and humans. This small-animal model may be useful for studying spinal drug toxicology in general and the biology of intrathecal granuloma formation in particular.

Original languageEnglish (US)
JournalAnesthesiology
DOIs
StateAccepted/In press - Jun 6 2016

Fingerprint

Granuloma
Catheterization
Morphine
Guinea Pigs
Catheters
Animal Models
Polyurethanes
Polyethylene
Pharmaceutical Preparations
Canidae
Hot Temperature
Dogs
Cisterna Magna
Meninges
Isoflurane
Toxicology
Opioid Analgesics
Spinal Cord
Sheep
Collagen

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Intrathecal Catheterization and Drug Delivery in Guinea Pigs : A Small-animal Model for Morphine-evoked Granuloma Formation. / Eddinger, Kelly A.; Rondon, Eric S.; Shubayev, Veronica I.; Grafe, Marjorie; Scadeng, Miriam; Hildebrand, Keith R.; Page, Linda M.; Malkmus, Shelle A.; Steinauer, Joanne J.; Yaksh, Tony L.

In: Anesthesiology, 06.06.2016.

Research output: Contribution to journalArticle

Eddinger, KA, Rondon, ES, Shubayev, VI, Grafe, M, Scadeng, M, Hildebrand, KR, Page, LM, Malkmus, SA, Steinauer, JJ & Yaksh, TL 2016, 'Intrathecal Catheterization and Drug Delivery in Guinea Pigs: A Small-animal Model for Morphine-evoked Granuloma Formation', Anesthesiology. https://doi.org/10.1097/ALN.0000000000001166
Eddinger, Kelly A. ; Rondon, Eric S. ; Shubayev, Veronica I. ; Grafe, Marjorie ; Scadeng, Miriam ; Hildebrand, Keith R. ; Page, Linda M. ; Malkmus, Shelle A. ; Steinauer, Joanne J. ; Yaksh, Tony L. / Intrathecal Catheterization and Drug Delivery in Guinea Pigs : A Small-animal Model for Morphine-evoked Granuloma Formation. In: Anesthesiology. 2016.
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abstract = "BACKGROUND:: Intrathecal infusion of opioids in dogs, sheep, and humans produces local space-occupying masses. To develop a small-animal model, the authors examined effects of intrathecal catheterization and morphine infusion in guinea pigs. METHODS:: Under isoflurane, polyethylene or polyurethane catheters were advanced from the cisterna magna to the lumbar enlargement. Drugs were delivered as a bolus through the externalized catheter or continuously by subcutaneous minipumps. Hind paw withdrawal to a thermal stimulus was assessed. Spinal histopathology was systematically assessed in a blinded fashion. To assist in determining catheter placement, ex vivo images were obtained using magnetic resonance imaging in several animals. Canine spinal tissue from previous intrathecal morphine studies was analyzed in parallel. RESULTS:: (1) Polyethylene (n = 30) and polyurethane (n = 25) catheters were implanted in the lumbar intrathecal space. (2) Bolus intrathecal morphine produced a dose-dependent (20 to 40 μg/10 μl) increase in thermal escape latencies. (3) Absent infusion, a catheter-associated distortion of the spinal cord and a fibrotic investment were noted along the catheter tract (polyethylene > polyurethane). (4) Intrathecal morphine infusion (25 mg/ml/0.5 μl/h for 14 days) resulted in intrathecal masses (fibroblasts, interspersed collagen, lymphocytes, and macrophages) arising from meninges proximal to the catheter tip in both polyethylene- and polyurethane-catheterized animals. This closely resembles mass histopathology from intrathecal morphine canine studies. CONCLUSIONS:: Continuous intrathecal infusion of morphine leads to pericatheter masses that morphologically resemble those observed in dogs and humans. This small-animal model may be useful for studying spinal drug toxicology in general and the biology of intrathecal granuloma formation in particular.",
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AU - Hildebrand, Keith R.

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AU - Yaksh, Tony L.

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