Pain Medicine  |   August 2016
Intrathecal Catheterization and Drug Delivery in Guinea Pigs: A Small-animal Model for Morphine-evoked Granuloma Formation
Author Notes
  • 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.).
  • Submitted for publication December 1, 2015. Accepted for publication April 5, 2016.
    Submitted for publication December 1, 2015. Accepted for publication April 5, 2016.×
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • This work was presented in part as a poster and oral presentation at the North American Neuromodulation Society meeting in Las Vegas, Nevada, December 10–13, 2015.
    This work was presented in part as a poster and oral presentation at the North American Neuromodulation Society meeting in Las Vegas, Nevada, December 10–13, 2015.×
  • Address correspondence to Dr. Yaksh: Department of Anesthesiology 0818, University of California, San Diego, 9500 Gilman Dr. (CTF C-312), La Jolla, California. tyaksh@ucsd.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Basic Science / Pain Medicine / Pharmacology / Technology / Equipment / Monitoring
Pain Medicine   |   August 2016
Intrathecal Catheterization and Drug Delivery in Guinea Pigs: A Small-animal Model for Morphine-evoked Granuloma Formation
Anesthesiology 8 2016, Vol.125, 378-394. doi:10.1097/ALN.0000000000001166
Anesthesiology 8 2016, Vol.125, 378-394. doi:10.1097/ALN.0000000000001166
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.