Animal studies 

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Early animal studies published by Jens Schouenborg and Bengt Sjölund showed nerves of the lower spinal cord in anesthetized rats could be stimulated to cause a muscle twitch in response to pain.  There are several types of nerve fibers involved in sensing painful and non-painful stimuli including Aβ (A-beta), Aδ (A-delta), and C-fibers.  Depending on the type of nerve stimulated, different responses were observed and appeared to modify the others’ ability to increase or reduce pain signals entering the dorsal horn of the spinal cord.  In some cases this interaction suppressed the twitch response to pain.(1)  When a stimulus occurs in the brain that would normally be perceived as painful, the interaction of the different nerve fibers may increase or decrease the actual experience of pain. 

 

In 1984, J. M. Chung et al. studied factors that reduce the strength of nerve signals involved in the transmission of pain to the thalamus of the brain.  They observed signals initiated by stimulating a nerve in the leg of anesthetized monkeys and found that Aδ fibers are the most important for suppressing transmission of pain, concluding that prior stimulation of those Aδ fibers could reduce the perception of pain.(2) 

 

In 1985, Lee et al. conducted a study in monkeys that examined the inhibitory effects of transcutaneous nerve stimulation (TENS) on the portion of the spinal cord that connects peripheral nerve sensors to the thalamus. It was shown that an opioid release was not induced and that the pain reducing impact of TENS was localized to the part(s) of the body to which it was applied.  It was also found that inhibiting a pain response with TENS at the Aδ  level required the intensity to exceed the sensitivity threshold of the nerve fiber.(3) 

Also in 1985, B.H. Sjölund published part one of a two-part report studying the characteristics of peripheral nerve stimulation and showed that the C-fiber-evoked flexion reflex in rats could be successfully suppressed.  A higher stimulation intensity triggering both Aβ and Aδ fibers was found to be more effective in depressing the reflex than activating only Aβ fibers.(4)  The second part of the report found that levels of stimulation sufficient to activate Aδ fibers were more effective in depressing C-fiber-evoked activity than lower levels that recruited only Aβ and C-fibers.(5)

 

In 1995, D. J. Linden and J. A. Connor wrote a review on the different forms of long-term synaptic depression (LTD).  LTD, the weakening of nerve connections, is the opposite of hippocampal long-term synaptic potentiation (LTP), the strengthening of nerve connections.  The various types of LTD were summarized (e.g. homosynaptic , heterosynaptic, associative, cerebellar) and the potential benefits for pain reduction were reported, the overall benefit being the ability to interfere with transmission of pain signals to the brain. (6)

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In 2005, J. Wallengren et al. conducted a study in 30 rats to determine if treatment with cutaneous field stimulation (CFS) induced neurochemical changes in the dorsal root ganglia. Dorsal root ganglia are nodules along the spinal cord that control signals coming into the spinal cord and sent to the brain for further processing (e.g. responsible for forwarding pain signals to the brain).  Wallengren et al. reported that CFS with moderate intensity resulted in sensory nerve proliferation in rat skin but had no effect on dorsal root ganglia (DRG).  The resulting proliferation suggested that, with regards to the pain experience, the effects of CFS are local to the region where pain is experienced.  It was anticipated that a course of repeated CFS treatments would be unlikely to activate dorsal root ganglia in humans.  This suggests that pain reduction benefits of CFS are local to the region where the pain is sensed and treatment is applied, rather than operating on the central nervous system in the spinal cord and brain.(7)

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Human pre-clinical studies

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In a study of healthy volunteers to examine the receptive properties of Aδ fibers in human skin nerves, H. Adriaenssen et al. found that human Aδ fibers were similar in function to those already studied in other mammalian species and noted that the firing frequency from painful stimulation is often higher in Aδ fibers than in C-fibers.  It was speculated that the information content transferred from Aδ fibers to the central nervous system may be greater than in C-fibers because Aδ fibers play a greater role in identifying the pain stimulus.(8)

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In 1997, H.J. Nilsson, A. Levinsson, and J. Schouenborg studied a powerful method for combating itch.  While scratching relieves itch, it often aggravates the underlying cause.  In this study of 21 subjects, it was found that CFS could stimulate nerve fibers in the superficial skin and that such conditioning blocked over 80% of the itch sensation within 10 cm of the stimulating electrodes. Related benefit was found to decrease over the house following this conditioning stimulation.(9)  In 1999 Nilsson and Schouenborg conducted a study in 20 healthy subjects to compare CFS to TENS.  They applied CFS or TENS conditioning either to the skin where the chemically-induced itch would be applied (the “direct” site) or to skin far from the location of the itch (the “distant” site).  The right forearm was chosen for the direct site conditioning and the right lower leg was chosen for the distant site conditioning.  Of the four combinations of stimulus and location (CFS or TENS coupled with either direct or distant site conditioning), suppression of pain was only noted when CFS conditioning was applied to the direct site (arm).  None of the four conditioning arrangements reduced non-painful tactile sensation, thus it was concluded that only painful sensation was reduced by CFS.(10)

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In 2002, H.J. Nilsson, E. Psouni, and J. Schouenborg conducted a study in 20 healthy subjects to examine the inhibitory effects of CFS on various types of pain (itch, mechanical, and thermal). It was determined that CFS conditioning between one and ten minutes is required for effective suppression of painful stimuli and that conditioning in excess of ten minutes did not increase the benefit.  It was also observed that stimulation frequencies between 1-10 Hz had similar effects.  These long-term synaptic depression effects were noted to be consistent with those effects observed in previously conducted animal experiments.(11)  In 2004, H.J. Nilsson et al. conducted a study with 35 patients suffering from atopic dermatitis, comparing TENS to CFS.  A significant depression of chronic itch was reported for up to seven hours while no such benefit was derived from TENS.(12)  This showed that CFS is dramatically superior to TENS in reducing particularly unpleasant sensations and should be further studied to treat other noxious stimuli.

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References

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1. Schouenborg J, Sjolund BH.  Activity evoked by A- and C-afferent fibers in rat dorsal horn neurons and its relation to a flexion reflex. J Neurophysiol. 1983 Nov;50(5):1108-21. PMID: 6644362
    

2. Chung JM, Lee KH, Hori Y, Endo K, Willis WD.  Factors influencing peripheral nerve stimulation produced inhibition of primate spinothalamic tract cells. Pain. 1984 Jul;19(3):277-93. PMID: 6472874
    

3. Lee KH, Chung JM, Willis WD Jr.  Inhibition of primate spinothalamic tract cells by TENS. J Neurosurg. 1985 Feb;62(2):276-87. PMID: 3871474
    

4. Sjolund BH.  Peripheral nerve stimulation suppression of C-fiber-evoked flexion reflex in rats. Part 1: Parameters of continuous stimulation. J Neurosurg. 1985 Oct;63(4):612-6. PMID: 3875698
    

5. Sjolund BH.  Peripheral nerve stimulation suppression of C-fiber-evoked flexion reflex in rats. Part 2: Parameters of low-rate train stimulation of skin and muscle afferent nerves. J Neurosurg. 1988 Feb;68(2):279-83. PMID: 3257521
    

6. Linden DJ, Connor JA.  Long-term synaptic depression. Annu Rev Neurosci. 1995;18:319-57. Review. PMID: 7605065
    

7. Wallengren J, Moller K, Sundler F.  Cutaneous field stimulation with moderate intensity current induces nerve proliferation in rat skin but has no effect on dorsal root ganglia. Acta Derm Venereol. 2005;85(4):324-8. PMID: 16191853
    

8. Adriaensen H, Gybels J, Handwerker HO, Van Hees J.  Response properties of thin myelinated (A-delta) fibers in human skin nerves. J Neurophysiol. 1983 Jan;49(1):111-22. PMID: 6298373
    

9. Nilsson HJ, Levinsson A, Schouenborg J.  Cutaneous field stimulation (CFS): a new powerful method to combat itch. Pain. 1997 May;71(1):49-55. PMID: 9200173
    

10. Nilsson HJ, Schouenborg J.  Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers. Pain. 1999 Mar;80(1-2):103-12. PMID: 10204722
     

11. Nilsson HJ, Psouni E, Schouenborg J.  Long term depression of human nociceptive skin senses induced by thin fibre stimulation. Eur J Pain. 2003;7(3):225-33. PMID: 12725845
     

12. Nilsson HJ, Psouni E, Carstam R, Schouenborg J.  Profound inhibition of chronic itch induced by stimulation of thin cutaneous nerve fibres. J Eur Acad Dermatol Venereol. 2004 Jan;18(1):37-43. PMID: 14678529