An artificial knee joint has been implanted in an elderly patient. After surgery, the physicians inject him with a local anesthetic for pain relief. It blocks the pain-transmitting nerve fibers in the surgical area, thus alleviating the pain. However, the drug also disables nerve fibers that are responsible for other sensations or for mobility – resulting in muscle paralysis.
This is an inevitable side effect of pain therapy, which is very undesirable, for it is very important for surgical site healing and post-operative recovery that patients, particularly elderly patients, get back on their feet quickly and are able to move without pain after surgery.
To be sure, there are some very good painkillers (also known as analgesics) on the market that do not affect the mobility of patients. „These include morphine and other opioids, which still are the most effective analgesics known,“ says Heike Rittner of the University Hospital of Würzburg. However, these drugs have the following disadvantage: They do not ease the pain when locally injected at the surgical site or at the nerve – presumably because they cannot penetrate the nerve sheath. This barrier surrounds the nerves like a protective cover.
Publication in the scientific journal PNAS
How to prevent postoperative pain effectively while maintaining mobility after surgery? An answer to this question is now provided in the scientific journal PNAS by the „Molecular pain research“ group of the Department for Anesthesiology at the University Hospital of Würzburg. Heike Rittner, Alexander Brack and Dagmar Hackel discovered the new facts in collaboration with colleagues from Berlin, Jena and Erlangen.
Transient opening of the nerve sheath
The scientists had the idea to open the nerve sheath for opioids and other drugs. For this purpose, they successfully used a 10 percent sodium chloride solution – since such a solution also makes other barriers in the body permeable, as was already known to the scientists. If the sodium chloride solution was injected together with the opioid drugs near a nerve in an animal model, a pain-reducing effect was detectable and the mobility was preserved. If administered alone, however, neither the sodium chloride solution nor the drugs had any such effect.
Molecular signaling pathway described
The scientists also identified the molecular mechanism underlying this effect. The sodium chloride solution releases the enzyme metalloproteinase 9 in the tissue, which leads to a subsequent chain of reactions and finally reduces the production of the protein claudin-1 in the nerve sheath. Without this protein, the barrier loses its function and opens, but closes again only a few hours after treatment. The nerves do not exhibit any detectable structural, immunological or functional damage afterwards.
The scientific importance of the Würzburg research lies in the clarification of this signaling pathway. „For the first time, we have identified the molecular mechanisms in peripheral nerves with which the permeability for drugs is regulated,“ says Heike Rittner. At the same time, this gives rise to an innovative therapeutic concept that can be used for blocking the transmission of pain through the nerves in a targeted way while fully maintaining motor function.
Small peptides under examination
The method is not yet ready for human application, though. The reason: The injection of such a concentrated sodium chloride solution would inflict pain. Therefore, the researchers are looking for an alternative way to induce a transient and specific opening of the nerve sheath without unwelcome side effects.
„The signaling pathway that we have identified is open to several approaches, which are already being investigated,“ the scientists explain. For instance, it is possible to open the barrier by down-regulating the barrier protein claudin-1 directly and specifically with small peptides.
Patent Alliance is looking for license holders
The patent application for these peptides is already pending. The Bavarian Patent Alliance („Bayerische Patentallianz GmbH“) is currently looking for pharmaceutical companies interested in obtaining a license. Conclusion of the researchers: „We expect that our research will help patients towards faster and better recovery after surgery of the arms and legs, because they will no longer be subject to debilitating muscle paralysis.“
Hackel D, Krug SM, Sauer RS, Mousa SA, Boecker A, Pfluecke D, Wrede EJ, Kistner K, Hoffmann T, Bloch L, Huber O, Blasig IE, Amasheh S, Sommer C, Reeh PW Fromm M, Brack A, Rittner HL: Transient opening of the perineurial barrier for analgesic drug delivery. Proc Natl Acad Sci USA 2012, published online before print June 25, DOI: 10.1073/pnas.1120800109
Dr. Heike Rittner, Department of Anesthesia and Critical Care, Würzburg University Hospital, T +49 (0)931 201-30046, firstname.lastname@example.org