Editorial: Apoptosis is Critical to Pain Control

Dear Readers—Pain frequently involves a neural circuit that can either magnify or suppress pain, depending on the way the brain processes the pain signals and depend- ing on the pain causing or pain suppressing compounds that are secreted in the skin. Pain is essential to life, since it helps us to avoid damaging situations. The most abun- dant pain sensors are in the skin, and are called the tra- nsient receptor potential cation channels (TRP). The TRP family contains many members such as the vanillloid receptors (TRPV), the canonical receptors (TRPC), the ankyrin repeat receptors (TRPA), the polycystin - recaptors (TRPP), the melastatin receptors (TRPM) and the mucolipin receptors (TRPML) [1]. These cation channels allow cations to cross the plasma membrane, such as so- dium andcalcium. In the skin, these recetors are found pon small unmyelinated (C-type) or thinly myelinated (A delta-type) nerve terminals [2]. Their cell bodies are in the dorsal root ganglion with dendrites that form syn- apses in the spinal cord. These synapses are formed with ascending CNS neurons that have cell bodies in the hy- pothalamus, hippocampus and other areas. These CNS neurons form synapses with other CNS descending neu- rons that form synapses in the spinal cord with descend- ing neurons that have nerve terminals in the skin[2]. These descending neurons are neurotrophin secreting neurons. TRP channels are activated by histamine, bradykinin, fatty acid metabolites, endocannabinoids, cannabinoids, ATP, acid, heat, cold, prostaglandins, cytokines, capsai- cin, monoterpenoids and other stimuli. The initial sensa- tion can be heat, cold, pain or itching that can be several minutes in duration. Usually, prolonged activation of the TRP channels, for more than 20 30 minutes or so, r- e- sults in long term deactivation and pain relief. This is how capsaicin and the monoterpenoids, such as menthol, relieve pain [2]. Initial receptor activation is followed by long term deactivation. Arachidonic acid produces pain causing prostaglandins and pain relievingresolvins, in a balance. Resolvins deactivate TRP channels resulting in pain relief [3]. Endocannabinoids, prostaglandins, re- solvins, histamine, bradykinin, cytokines, ATP and other endogenous compounds are produced where they are needed and have short durations of action. This natural pain controlling system can be altered by nonsteroidal anti-inflammatory drugs (NSAIDS) and other drugs, re- sulting in the inability to control pain naturally. This can be disastrous for patients. Pain can be blocked at any point in the neural circuit. Opioids block pain in the brain. NSAIDS block pain in the skin and other sites. Menthol and other monoterp- enoids block pain in the skin, where they are applied. Monoterpenoids are probably safer than opioids and NSAIDS since monoterpenoids are applied in small amounts to the skin. Opioids and NSAIDS are taken orally in large doses and penetrate into many organs of the body. As of 2013, prescription opioids kill 14,000 patients yearly. As of 2009, NSAIDS cause 100,000 ul- cers and 10,000 deaths annually. TRP channels allow calcium to penetrate into nerve terminals. This can activate apoptosis mechanisms that result in nerve terminal destruction [4]. This nerve ter- minal destruction in the skin is a prominent feature of Adams disease, a disease that involves severe pain from over activation of TRP channels by cold and other stim- uli [5]. Adams disease appears to be caused by dysfunc- tional TRP receptors in the skin. Destruction of nerve terminals in the skin may cause long term pain relief. The descending neurons that terminate in the skin se- crete neurotrophins that are essential for the regrowth of TRP containing nerve terminals. The neurotrophin se- creting nerve terminals help reestablish the neural circuit involved in pain sensation.