Role of Meningeal Mast Cells in Intrathecal Morphine–evoked Granuloma Formation

Abstract

Background Intrathecal morphine forms granulomas that arise from the adjacent arachnoid membrane. We propose that these inflammatory cells exit the meningeal vasculature secondary to meningeal mast cell degranulation. Methods Three sets of experiments were accomplished in dogs. 1) Ex vivo Meningeal mast cell degranulation. Histamine release was measured ex vivo from canine dura incubated with opiates. 2) In vivo cutaneous mast cell degranulation. Flare areas on the dog abdomen were measured after subcutaneous opiates. 3) In vivo granuloma pharmacology. Dogs with lumbar intrathecal catheters received infusion of intrathecal saline or intrathecal morphine. Intrathecal morphine dogs received: i) No other treatment (Control); ii) Twice daily subcutaneous naltrexone; iii) Intrathecal co-infusion of cromolyn; or, iv) Twice daily subcutaneous cromolyn for the 24–28 day study course. Results 1) Morphine but not fentanyl evoked dural histamine release, which was blocked by cromolyn but not naloxone. 2) Wheal/flare was produced by subcutaneous morphine, methadone, hydromorphone, but not fentanyl, and was unaffected by naltrexone but prevented by cromolyn. 3) Granulomas occurred in all dogs receiving intrathecal morphine (15/15); subcutaneous naltrexone had no effect on granulomas (6/6), but was reduced by concurrent intrathecal cromolyn (0/5) or twice daily subcutaneous cromolyn (1 of 5). Conclusions The pharmacology of cutaneous/dural MC degranulation and intrathecal granulomas are comparable, not mediated by opioid receptors, and reduced by agents preventing MC degranulation. If an agent produces cutaneous MC degranulation at concentrations produced by intrathecal delivery, the agent may initiate granulomas.

Primary Hydromorphone-Related Intrathecal Catheter Tip Granulomas: Is There a Role for Dose and Concentration?

“…Thus, several mu opiates (morphine, hydromorphone, methadone) produce the effect, but fentanyl and alfentanil do not. Further, concurrent treatment with opiate antagonists does not alter granuloma mass size or time of onset with intrathecal morphine .…”

“…This hypothesis was further reinforced by the fact that intrathecal or subcutaneous administration of the mast cell stabilizer cromolyn, but not naltrexone, reduced the incidence of ICTG formation in canines . Animal experiments failed to induce ICTG in response to intrathecal fentanyl , an opioid that does not evoke dural histamine release . No ICTG case reports have been ascribed to fentanyl , with the exception of one case description of a patient who was receiving 2.7 mg/day of intrathecal fentanyl at the time he developed a granuloma resulting in motor weakness, urinary retention and back and leg pain.…”

High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs

“…The lumbar IT catheter was surgically placed in anesthetized dogs by passing the catheter from the cisterna magna approximately 40 cm to the lumbar enlargement as described previously 30,44 . For anesthesia, the dogs received a pre-anesthetic intramuscular (IM) dose of atropine (0.04 mg/kg), which was given 10 minutes prior to IM injection of xylazine (1.5 mg/kg) and followed by 3.5% isoflurane in 40% 0 2 / 60% N 2 0 via mask.…”

Unique Intradural Inflammatory Mass Containing Precipitated Morphine: Confirmatory Analysis by LESA‐MS and MALDI‐MS

“…9 The proposed mechanism is that highly concentrated opioids trigger local meningeal mast cell degranulation, causing fibroblast and inflammatory cell migration. 10 …”