Update: Channelopathies and paradoxical response to opioids

Things have been a little slow lately in pain research, but two areas deserve mention.

Whether it is real or imagined, there seems to have been a lull in pain articles that shake things up. Not to despair, the pauses usually indicate someone is working out something new and important.

One area receiving attention is opioid hypersensitivity. It is being reported mainly in patients with uncontrolled cancer pain, where rapidly increasing opioids may cause a sudden increase in pain. Some authors recommend opioid switching to a different medicine in lower dose. There is no solid data yet on the effectiveness of this method. Once the hypersensitization is noted, there are also reports of successful detoxification under general anesthesia, but the patient is then expected to go on WITHOUT opioids.

Next, we have written much on the TRPV1 channel. Recently, another transient receptor potential channel has received attention, the TRPA1 channel. It was initially reported to the be the channel modulating noxious cold response (exaggerated cold response is a common feature of central pain), but another study in knockout rats* failed to confirm that TRPA is necessary for initial sensing of noxious cold. We will await more word, since these kinds of things generally sort out into something concrete that makes sense.

Andrade et al in Neuroscience. 2008 Jan 9 have noted that allyl isothiocyanate seems to do for TRPA what capsaicin does for TRPV1. Interestingly, ruthenium red blocks BOTH channels. Additionally, TRPV1 fibers which are sensitive to capsaicin are also the ones which carry TRPA1 which can be activated (agonized) by allyl isothiocyanate.

The expanding knowledge of ion channels has created a new branch of medical illness, known as “channelopathies”. The transient receptor potential channels are comprised of 28 known channels permeable to monovalent [single charge] cations [the charge is positive], which are divided into several groups. TRPV channels are among those permeable to divalent calcium ions [Ca2+]. Such channels are the ones concerned with pain. TRPV stands for TRPvanilloid, which is thought to be the primary channel afflicting central pain patients, at least as to dyesthetic burning. Since cold allodynia is so common in central pain, we might have to make room for another tormentor, TRPA1.

The method is being developed of blocking these channels by intrathecal injection of antisense oligodeoxynucleotides, which are counterfeit bits of DNA-like material which gum up the works of a channel. Selective blockade of the TRPV1 channel can be achieved by SB 366791, while TRPA is selctively blocked by the antisense oligonucleotides. Significantly, both TRPV1 activity and TRPA1 activity are blocked by the selective neurokinin 1 receptor antagonist N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbony-1-l-prolyl]-N-methyl-N-phenylmethyl-3-2-(2-naphtyl)-l-alaninamide.

Studies indicate that after TRPA1 activation with allyl isothiocyanate, mast cells release histamine, which involves tachykinins, such as bradykinin.These steps are part of classic neurinflammation. Sympathetic blockade with guanethidine did NOT stop the pain (nociception) from channel activation. A fair number of patients with central pain after spinal cord injury also display sympathetically mediated pain. Such patients are sometimes identifiable clinially by developing thinned shiny skin at the ends of their extremities (eg feet) and loss of hair there, or by response to IV sympathetic blockade. Time should demonstrate whether a dual therapeutic approach is indicated in these people, one for the TRP channels and one to block sympathetically maintained pain.

Yang, et al in J Pharmacol Sci. 2008 Feb 9 have developed a method of isolating the omental fat apron of the gut in anesthetized rats which exploits the reflex hypertensive response to pain agents. This approach may yield better ways to suppress bradykinin participation in inflammation. Already the use of the reflex hypertensive response has allowed the determination of whether one agent is acting peripherally or centrally. The technique compares application of an agent topically to the exposed omentum and then giving it intravenously or intrathecally.

The authors state, “Topical administration of a non-acidic analgesic, mepirizole, inhibited the RHR by topical BK [bradykinin[ by only 20%, but intravenous mepirizole inhibited topical BK by 96.2%, indicating its major CENTRAL action” Central pain patients are frequently left alone in skepticism as to their pain. The bradykinin test may provide another avenue for identifying real pain of at least one variety. Admittedly, the neuroinflammation is going on at a cryptic level, inside the brain or cord, so gut fat may not help us establish what we want to establish, namely, the reality of central pain.

On another topic, scientists in Iran have reported that extract from leaves of Danae racemosa relieve pain when they have a high content of quercetin and kaempferol.

Additionally, Wydenkeller has reported a new method of using ordinary contact heat points to measure evoked potentials, but this is not clinical yet. Laser has long been used, without really pinning down who has neuropathic pain, so it is unknown whether this is a breakthrough or a mere simplification of existing study method.

*A knockout rat is one in which the gene producing a given protein structure has been disabled. Knocking out a gene allows us to determine the function of the gene, as well as study the results of failure of the protein that gene produces. The technique is powerful and the inventor, Mario Capecchi at the Univ. of Utah, won the Nobel prize in Medicine last year.