Antibiotic for Central Pain?

Any time Hains and Waxman at Yale talk, we listen.


Although some related articles were noted with interest, such as by

Nikodemova et al in J Neurochem. 2006 Jan;96(2):314-23. “Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IkappaBalpha degradation in a stimulus-specific manner in microglia.”

Lai et al “Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines.” Glia. 2006 Mar 15;53(8):809-816 and

Seabrook et al “Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice.” to be published in Glia. 2006 May;53(7):776-82, no one openly anticipated direct results in CP so quickly.

Hains and Waxman, reporting in J Neurosci. 2006 Apr 19;26(16):4308-17 really got everyone’s attention by showing that minocycline helps CP. Here at painonline, you have already read about what is termed the neuroimmune synapse. This term was described to us by Carl Saab, one of Hains’ former classmates at UTMB and an author at this site.

As odd as it may seem, there is very solid evidence building that non-neuronal immune cells play a role in the maintenance of central pain. This conclusion led to the rather amazing article cited above, wherein the microglia (immune type cells around neurons) were suppressed by an ANTIBIOTIC, namely minocycline. Laboratory induced injury to the lumbar region of Sprague Dawley rats led to predictable central pain, or what the scientists prefer to call mechanical and thermal hyperalgesia. About a month after injury was delivered, and Central Pain had been observed, the microglia were suppressed with minocycline and amazingly, p38 ERK activity was REDUCED, and the mechanical and thermal hyperalgesia was reduced significantly.

The really good news is that minocycline has been around for a very long time and we know a great deal about how the body handles it. It is relatively free of side effects, although like all tetracycline related drugs turns toxic rapidly at the expiration date. It is not particularly expensive and usually well tolerated over long periods of time. In fact, it is so well tolerated that it has been used in such conditions as acne, where years long treatment is sometimes needed.

The BAD news is that the minocycline in the study was given INTRATHECALLY. This means into the spinal fluid. We have seen a recent surge in interest in the pumps which inject into spinal fluid with acquisition of smaller manufacturers by the bigger companies. It would appear we may be moving into an era of more pumps. These are very expensive, they plug up, they malfunction, and they can be a real pain to maintain. However, it is not impossible that suppression of non neuronal cells in the central nervous system may benefit central pain. Minocycline has good tissue penetration so we wonder if adequate quantities for microglial supression might be built up over time with oral administration.

We encourage you to go back and read the articles on neuroinflammation at this site. At this point, you may begin to realize why we included them. Here’s hoping this line of research bears fruit rapidly.

We also note the finding by Adaka et al in Eur J Pharmacol. 2006 Mar 14 which showed that one of the piperidins, ie M58373, or 4-[2-(4-hydroxy-4-{[N-(4-isopropoxyphenyl)-N-methylamino]methyl}piperidin-1-yl)ethyl]benzonitrile monohydrochloride acts as a blocker of sodium channels at what is known as site 2 in voltage gated sodium channels. Acting in the late phase of the model of peripheral pain, the substance had strong inhibition of release of Substance P from pain neurons in the dorsal root ganglion and marked reduction in pain behavior in the rats so treated.

You may recall that in an action potential, or neuronal voltage spike ( see diagram at http://staff.washington.edu/chudler/ap.html ) the sodium channels open first, leading to a loss of the negativity inside the cell due to the inflow of the positive sodium ions, followed by flow in the potassium channels which restores the voltage back to resting normal, so that the neuron is ready to fire another action potential. “Polarization” refers to the negative voltage maintained inside the cell, (creating a sort of battery) which sets up the electricity flow by ions in an action potential. Blocking sodium flow should stop depolarization, which is at the core of an action potential, or nerve firing