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



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.



(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.



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.
From the Departments of Anesthesiology (K.A.E., E.S.R., V.I.S., S.A.M., J.J.S., T.L.Y.) and Radiology (M.S.), University of California, San Diego, La Jolla, California; Departamento de Medicina Veterinária, Universidade Federal de Mato Grosso do Sul, Campo Grande, Brazil (E.S.R.); Department of Anesthesiology, Veterans Affairs San Diego Healthcare System, La Jolla, California (V.I.S.); Department of Pathology, Oregon Health Sciences University, Portland, Oregon (M.R.G.); and Departments of Global Research and Neuromodulation, Medtronic, Inc., Minneapolis, Minnesota (K.R.H., L.M.P.).
Kelly A
KA
Eddinger
Eric S
ES
Rondon
Veronica I
VI
Shubayev
Marjorie R
MR
Grafe
Miriam
M
Scadeng
Keith R
KR
Hildebrand
Linda M
LM
Page
Shelle A
SA
Malkmus
Joanne J
JJ
Steinauer
Tony L
TL
Yaksh
D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D002404:Catheterization / Q000379:methods*; D057785:Catheters; D002946:Cisterna Magna; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D006099:Granuloma / Q000139:chemically induced* / Q000473:pathology; D006168:Guinea Pigs; D007278:Injections, Spinal / Q000379:methods*; D008279:Magnetic Resonance Imaging; D008297:Male; D008578:Meninges / Q000473:pathology; D009020:Morphine / Q000009:adverse effects*; D020959:Polyethylene; D011140:Polyurethanes; D013118:Spinal Cord Diseases / Q000139:chemically induced* / Q000473:pathology
D000701:Analgesics, Opioid; D011140:Polyurethanes; D009020:Morphine; D020959:Polyethylene