Inflammatory Pain Mechanisms
Context During cellcommunication processes, endogenous and exogenous signaling affects normal and pathological developmental conditions. Exogenous influences, such as extra low frequency (ELF) electromagnetic fields (EMFs) have been shown to affect pain and inflammation by modulating G protein coupling receptors (GPCRs) downregulating cyclooxygenase 2 (Cox 2) activity, and downregulating inflammatory modulators, such as tumor necrosis factor alpha (TNF a) and interleukin 1 beta (IL 1b) as well as the transcription factor nuclear factor kappa B (NF kB) EMF devices could help clinicians who seek an alternative or complementary treatment for relief of patients chronic pain and disability. Objective The research team intended to review the literature on the effects of EMFs on inflammatory pain mechanisms. Design We used a literature search of articles published in PubMed using the following key words: low frequency electromagnetic field therapy, inflammatory pain markers, cyclic adenosine monophosphate (cAMP) cyclic guanosine monophosphate cGMP) opioid receptors, G protein coupling receptors, and enzymes. Setting The study took place at the Wake Forest School of Medicine in Winston Salem, NC, USA. Results The mechanistic pathway most often considered for the biological effects of EMF is the plasma membrane, across which the EMF signal induces a voltage change. Oscillating EMF exerts forces on free ions that are present on both sides of the plasma membrane and that move across the cell surface through transmembrane proteins. The ions create a forced intracellular vibration that is responsible for phenomena such as the influx of extracellular calcium (Ca2+ and the binding affinity of calmodulin (CaM) which is the primary transduction pathway to the secondary messengers, cAMP and cGMP, which have been found to influence inflammatory pain. Conclusions An emerging body of evidence indicates the existence of a frequency dependent interaction between the mechanical interventions of EMF and cell signaling along the peripheral inflammatory pain pathway. (Altern Ther Health Med. 2016;22(3) Christina L. Ross, PhD, is a research fellow at the Wake Forest Institute for Regenerative Medicine (WFIRM) and a research fellow at Wake Forest Center for Integrative Medicine, Wake Forest School of Medicine, in Winston Salem, North Carolina. Thaleia Teli, PhD, is a research fellow at WFIRM. Benjamin S. Harrison, PhD, is an associate professor at WFIRM. Corresponding author: Christina L. Ross, PhD E mail address: chrross@wakehealth.edu In humans, electromagnetic field (EMF) therapy has proven to be a safe, noninvasive, easy to use method to treat the site of pain and inflammation.1 Research has shown that therapeutic applications at extra low frequency (ELF) levels (ie, 1 100 Hz) of EMF stimulate the immune system by suppressing inflammatory responses at the cell membrane level.2 Double blind, placebo controlled clinical trials have reported that EMF passes through the skin into the body's conductive tissue,3 5 reducing pain and delaying the onset of edema shortly after trauma.6,7 In a randomized, double blind, sham controlled clinical study, low frequency (LF) pulsed EMF (PEMF) at 0.1 to 64 Hz was reported to improve mobility and decrease pain and fatigue in patients with fibromyalgia (FM).8 Both clinical and in vitro studies have reported that EMF is effective in the treatment of osteoarthritis (OA).9,10 Although many drugs have been used recently for the treatment of OA, the majority of them relieve pain and increase function but do not modify the complex mechanisms that occur in the pathology.11 PEMF has a number of welldocumented physiological effects on cells and tissues, including the expression of the transforming growth factor beta (TGF b) super family, an increase in the levels of glycosaminoglycan, and an anti inflammatory action.12 Due 34 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 Ross Effects of EMF on Inflammatory Pain Mechanisms to those discoveries, a strong rationale exists for supporting the use of biophysical stimulation with PEMF for the treatment of inflammatory pain that is related to diseases such as OA, FM, and migraine headache. Although the treatment may be a promising therapy, investigators have reported conflicting outcomes, with obvious differences in their measuring techniques. Some studies do not report the frequency and intensity (ie, the field strength) of their treatment device; therefore, it is difficult to compare the parameters being used toward specific outcomes. For this review, the authors performed a literature search of articles published in PubMed using the following key words: low frequency electromagnetic field therapy, inflammatory pain markers, cyclic adenosine monophosphate (cAMP) cyclic guanosine monophosphate (cGMP) opioid receptors, G protein coupling receptors, and enzymes. The literature search was conducted from October of 2014 to May of 2015. EMF NOMENCLATURE When discussing cellular influences by either endogenous or exogenous fields, it is important to define the nomenclature. The term EMF is used to summarize the whole field, which includes electric, magnetic, and combined electromagnetic effects. An electric field (EF) involves a current that can be either direct (DC) or alternating (AC) Units of electrical current are measured in amperes (A) and differences in electrical potential are measured in volts (V) Units of magnetic flux density (ie, intensity) are measured in either Gauss (G) or Tesla (T) which is 10 000 Gauss. Faraday's Law of Induction and Maxwell's equations explain how an EMF is generated. A static electric field is generated by a static charged particle (q) The electric field or "E" component of an EMF exists whenever a charge (Q) is present. Its strength is measured in volts per meter (V/m) and is expressed as intensity for field strength. An electric field of 1 V/m is represented by a potential difference of 1 volt existing between 2 points that are 1 m apart. A magnetic field (MF) or the "M" component of an EMF, arises from current flow. The Tesla or Gauss is used mainly to express the flux density or field strength produced by the MF. Both EFs and MFs are generated if a charged particle moves at a constant velocity. Combined, they generate an EMF when the charged particle is accelerated. Most often, the acceleration takes place in the form of an oscillation; therefore, electric and magnetic fields often oscillate. A change in the EF creates an MF, and any change in the MF creates an EF. That interaction suggests that the higher the frequency of the oscillation is, the more the electric and magnetic fields are mutually coupled. EMFs can affect biochemical reactions and the behavior of charged molecules near cell membranes. The magnetic aspect can influence cell behavior by (1) exerting a force on moving charge carriers, such as ions; (2) generating electric fields in conductive substances; (3) changing the rate of diffusion across membranes13; and (4) distorting bond angles, which affects protein structure binding and, therefore, macromolecule synthesis.14 Unlike EFs, which are shielded by the highly dielectric properties of the cell membrane, magnetic gradients penetrate deeper through layers of living tissue,15 acting directly on cell organelles. Pulsing the EMF causes a rise and fall in ion fluxes, whereby changes in the membrane potential cause an inward current flow, resulting in hyperpolarization of its potential.16 Depending on the parameters involved in the EMF treatment and the biological process in question, either stimulation or inhibition can occur. In contrast to the membrane, the cytoplasm or fluids in extracellular spaces contain no free electrons to carry a charge; the current is carried by charged ions, such as sodium (Na+ potassium (K+ chloride (Cl and extracellular calcium (Ca2+ TYPES OF EMF DEVICES EMF devices exhibit varying parameters that include (1) frequency the number of cycles per time unit (Hz) (2) amplitude the intensity or magnetic field strength; and (3) exposure the time duration.17,18 The objective of the devices is the production of a uniform EMF to expose cells or tissue to a consistent set of dosing parameters. For therapeutic purposes, the devices include the transcutaneous electrical nerve stimulation (TENS) and transcranial direct current stimulation (tDCS) devices, the solenoid, and the Helmholtz coil (Figure 1) Figure 1. EMF Devices (A) TENS (B) SolenoidMagnetic Field