William Schmidt, NorthStar Consulting
I read the article by Hackel et al. and then did a PubMed search "(perineurium OR perineurial barrier)," which identified 1,451 articles going back to the dawn of Medline that discuss a protective blood-nerve barrier for both myelinated and non-myelinated neurons that is similar to the blood-brain barrier. When I added the PubMed search terms “AND (analgesia or analgesic),” the results showed 63 references going back to 1969.
This has not entered into any of the preclinical testing strategies or chemical design issues that I’ve worked on during my career in pain medicine, so either I’ve been sleeping or this concept has not taken fire until recently. It may also be that inflammation-induced disruption of the blood-nerve barrier provides a suitable entry for hydrophilic drugs to peripheral nerves, so that this barrier does not have much functional or clinical significance under most painful conditions. This would be a greater problem in peripheral pathological pain conditions that are not associated with inflammation or mechanical disruption of the perineurium (Stein, 1991; Schulte-Steinberg et al., 1995). Migraine prophylaxis may be the best example where an intact perineurial barrier may limit drug actions (Gupta, 2006). This has also been shown in some experimental acute pain models in humans that do not involve inflammation (Tegeder et al., 2003).
It would be interesting to speculate that it would be possible to develop a drug that had no efficacy and no on-target adverse effects (e.g., abuse liability, adverse GI effects) if it did not pass the BBB or the perineurial barrier in the periphery under conditions where the barriers were intact in a normal patient. Under pathological conditions, the perineurial barrier would be opened by inflammation and permit the drug to enter. As inflammation subsides, the drug would no longer have access. Under ideal conditions, this sounds like an ideal way to limit drug activity to only those conditions where it could have benefit.
Peripheral analgesic actions of opioids.
J Pain Symptom Manage. 1991 Apr; 6(3):119-24.PMID: 1849945.
Intraperitoneal versus interpleural morphine or bupivacaine for pain after laparoscopic cholecystectomy.
Schulte-Steinberg H, Weninger E, Jokisch D, Hofstetter B, Misera A, Lange V, Stein C.
Anesthesiology. 1995 Mar; 82(3):634-40.
Botulinum toxin--a treatment for migraine? A systematic review.
Gupta V K.
Pain Med. 2006 Sep-Oct; 7(5):386-94.
Peripheral opioid analgesia in experimental human pain models.
Tegeder I, Meier S, Burian M, Schmidt H, Geisslinger G, Lötsch J.
Brain. 2003 May; 126(Pt 5):1092-102.
Related recent papers:
Transient opening of the perineurial barrier for analgesic drug delivery.
Hackel D, Krug SM, Sauer R-S, Mousa SA, Böcker A, Pflücke D, Wrede E-J, Kistner K, Hoffmann T, Niedermirtl B, Sommer C, Bloch L, Huber O, Blasig IE, Amasheh S, Reeh PW, Fromm M, Brack A, Rittner HL.
Proc Natl Acad Sci U S A. 2012 Jun 25.
Modulation of Tight Junction Proteins in the Perineurium to Facilitate Peripheral Opioid Analgesia.
Rittner HL, Amasheh S, Moshourab R, Hackel D, Yamdeu R-S, Mousa SA, Fromm M, Stein C, Brack A.
Anesthesiology. 2012 Apr 24.
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