Photomedicine and Laser Surgery

Volume X, Number X, 2011

ª Mary Ann Liebert, Inc.
Pp. 1–17
DOI: 10.1089/pho.2010.2928

Inhibitory Effects of Laser Irradiation on Peripheral

Mammalian Nerves and Relevance to Analgesic Effects:
A Systematic Review

Roberta Chow, M.B., BS(Hons), FRACGP, MApplSci, (Med Acu), Ph.D.,1 Patricia Armati, B.Sc., M.Sc., Ph.D.,1
E-Liisa Laakso, B Phty(Hons1), Ph.D., GCMgmt(QH),2 Jan M. Bjordal, B.Sc.,
Physiotherapy, M.Sc., DPhil,3 and G. David Baxter, TD BSc(Hons), DPhil, M.B.A.4

Abstract

Objective: The objective of this review was to systematically identify experimental studies of non-ablative laser
irradiation (LI) on peripheral nerve morphology, physiology, and function. The findings were then evaluated with
special reference to the neurophysiology of pain and implications for the analgesic effects of low-level laser therapy
(LLLT). Background: LLLT is used in the treatment of pain, and laser-induced neural inhibition has been proposed
as a mechanism. To date, no study has systematically evaluated the effects of LI on peripheral nerve, other than those
related to nerve repair, despite the fact that experimental studies of LI on nerves have been conducted over the past
25 years. Methods: We searched computerized databases and reference lists for studies of LI effects on animal and
human nerves using a priori inclusion and exclusion criteria. Results: We identified 44 studies suitable for inclusion.
In 13 of 18 human studies, pulsed or continuous wave visible and continuous wave infrared (IR) LI slowed
conduction velocity (CV) and/or reduced the amplitude of compound action potentials (CAPs). In 26 animal
experiments, IR LI suppressed electrically and noxiously evoked action potentials including pro-inflammatory
mediators. Disruption of microtubule arrays and fast axonal flow may underpin neural inhibition. Conclusions: This
review has identified a range of laser-induced inhibitory effects in diverse peripheral nerve models, which may
reduce acute pain by direct inhibition of peripheral nociceptors. In chronic pain, spinal cord changes induced by LI
may result in long-term depression of pain. Incomplete reporting of parameters limited aggregation of data.

Introduction Several reviews have demonstrated the effectiveness of

LLLT in numerous common, chronic conditions such as neck
pain,9,10 osteoarthritis,11 tendinitis,12 and lateral epicondyli-
T he rising incidence of chronic pain, which is pre-
dicted to reach epidemic proportions in the developed
world over the next 30 years, is a major medical and economic
tis.13 Responding to the increasing levels of evidence, the
World Health Organization’s Committee of the Decade of the
challenge for clinicians and researchers.1 The cost of chronic Bone and Joint has also recently incorporated LLLT into
musculoskeletal pain in European countries is estimated to be guidelines for treatment of neck pain.14 Mechanisms for pain-
e240 million per year,2 and in the United States, lost produc- relieving effects are, however, not clearly understood al-
tivity from chronic musculoskeletal pain was $61.2 billion in though several have been proposed,15 including the gate
2003,3 and from arthritis alone, $7.11 billion.4 Drugs are widely theory,16 modulation of ß-endorphin production,17–19 and
used for pain management, however they are expensive to anti-inflammatory effects,.20,21 Direct inhibition of neural ac-
individuals and health budgets, have limited efficacy5,6 and tivity has also been identified as a plausible mechanism, based
potentially serious adverse effects, especially when taken long- on human and animal studies in which laser irradiation (LI)
term7. There is, therefore, an imperative to develop safe non- slowed conduction velocity (CV) in peripheral nerves.22–26
drug options for the treatment of pain, and low-level laser The only other review of the effects of LI on mammalian
therapy (LLLT) is increasingly recognized as one such option.8 nerves focused on LI-stimulated repair in experimentally

1
Nerve Research Foundation, Brain and Mind Research Institute, The University of Sydney, Camperdown, New South Wales, Australia.
2
Convenor Physiotherapy Programs, School of Physiotherapy and Exercise Science, Griffith Health Institute, Gold Coast Campus, Griffith
University, Queensland, Australia.
3
Faculty of Health and Social Science, Centre for Evidence-Based Practice, Bergen University College, Mollendalsvn, Bergen, Norway.
4
School of Physiotherapy, University of Otago, Dunedin, New Zealand.

1
2 CHOW ET AL.

injured nerves.27 Our review, however, systematically eval- Human studies

uated effects of LI on peripheral mammalian nerve function
Eighteen human studies included a total of 630 partici-
including electrophysiology and morphology, outside the
pants, with the number in individual trials ranging from 9 to
context of nerve repair. In particular, we sought to identify
90 22,28–44 (Table 1).
such laser-induced effects directly relevant to pain physi-
ology and clinical pain relief.
Participant selection
Methods Five studies reported recruitment of ‘‘healthy’’ or ‘‘nor-
Search strategy mal’’ participants,28,30–32,44 and 12 studies excluded par-
ticipants with underlying neurological problems.22,29,33–42
We searched the following computerized databases from Both male and female participants were selected in seven
their inception to May 2010: Medline, Cochrane Database of studies;22,29,37–41 one study recruited only female subjects,36
Systematic Reviews, Allied and Complementary Medicine and another only males.43
(AMED), Cinahl, Biological Abstracts, and Biosis, using the
following key words: neuron/neural effects/peripheral Neurophysiological methodologies
nerve/nerve conduction/compound action potential/CAP/
electrophysiology, combined with a broad range of synonyms Nine studies22,29,36,39–42,44,45 used standardized protocols
to capture the diversity of terms for LI used clinically and for assessment of electrophysiology.46–55
experimentally (laser therapy; low-level/low power/low Ten studies used maximal or supramaximal electrical
intensity/low reactive level laser therapy; LI/inhibition/ stimuli, to ensure all axons were stimulated prior to LI and
stimulation/ effects; photoradiation; phototherapy; photo- to establish consistent baseline responses for each partici-
biostimulation; photobiomodulation; LILT/LLLT/LTLT/ pant.22,29,33–39,42 CAP response to LI was recorded in six
LPLI; 632.8 nm; 670 nm; 830 nm; 904 nm; GaAs; GaAlAs; studies,29–31,40,43,44 of which four studies recorded CV and
HeNe; infrared (IR)/visible laser). We also hand-searched CAP simultaneously.29,40,43,44 Cambier used ‘‘mild discom-
reference lists of retrieved articles and textbooks. The search fort’’ as the upper limit of intensity of electrical stimulation
strategy was limited to English. (ES).41

Inclusion criteria LI application

We included studies in which LI of any wavelength, in LI was applied transcutaneously in all human studies,
pulsed or continuous wave (cw) mode, was applied transcu- to between four and ten points to the arm or leg, at 1-cm
taneously or directly to exposed peripheral mammalian nerves intervals along or medial to the course of the median nerve
or neurons, in vivo or in vitro, in animals or human subjects. in seven studies;30,33–35,37–39 of the superficial radial nerve in
Studies were included if there were a control group or set of six studies;22,28,29,31,36,42 and of the sural nerve in two stud-
observations with which to compare pre and post-LI effects. ies.41,43 In three studies, LI was applied to a single point
We evaluated functional responses, spontaneous or evoked or or area of skin overlying a nerve, specifically: the median
morphological changes in peripheral nerves or neurons. nerve at the wrist or forearm;40 one point on the skin of
the palm, supplied by the median nerve;32 and the apex of
Exclusion criteria a tooth, supplied by the trigeminal nerve.44 Electro-
We excluded studies of non-mammalian nerves, studies physiological responses were recorded for up to 30 min,
evaluating nerve repair in experimentally injured nerves, 1–5 min intervals.
those that used wavelengths and power densities with abla-
tive potential, and studies in which LI was used as a noxious Laser parameters
or sensory stimulus. We also excluded studies where non- Wavelength (l) and beam mode of LI, either cw or pulsed,
laser light sources were used. were reported in all studies. Output power ranging from 1 to
400 mW was reported in all but two studies.29,32 Pulsed laser
Responses evaluated parameters, such as duration of pulse, and pulsation fre-
We evaluated pre- and post-LI effects in nerves or neurons, quency (Hz) were not consistently reported. Duration of LI at
specifically (a) morphological changes, (b) effects on enzymes each point ranged from 10 sec to 30 min; energy densities
or neurotransmitters, (c) electrophysiology, including CV, (ED) ranged from 0.019 to 138.4 J/cm2; and power densities
latency, compound action potentials (CAP), somatosensory (PD) ranged from 300 to 1,730 mW/cm2 but were inconsis-
evoked potentials (SSEP), and/or noxiously evoked poten- tently reported. Beam spot size was reported in 10 human
tials. Where studies reported only changes in latency, we studies22,28,30,32,36–38,40,41,44 and in 14 animal studies.23,25,56–67
reported change in CV, as latency is inversely proportional to Only parameters that were reported in each study were lis-
CV. Where individual studies included two or more separate ted in the tables. In general however, in most studies pa-
experiments using different parameters, doses or wave- rameters were not fully reported, limiting aggregation of
lengths, each experiment was evaluated separately. data (Table 1).

Results Human studies

Forty-four of 381 studies initially identified by our search, Fifteen studies reported CV response to LI22,28,29,33–44 and
of which 18 were human studies and 26 were animal studies, six studies reported CAP response,29–31,40,43,44, four of which
fit our inclusion criteria. recorded CV and CAP simultaneously.29,40,43,44
REVIEW OF LASER IRRADIATION ON PERIPHERAL NERVES 3

LI effects on CV Noxiously evoked potentials were elicited by mechanical,

Visible LI. Continuous 632.8–633 nm (1 mW) and 670 nm thermal, or chemical stimulation,45,60,65,71,72 or by formalin,
(cw,3 mW) LI slowed CV in four studies.22,28,36,43 However, turpentine, or bradykinin injection25,62,64–66 (Table 3).
pulsed 632.8 nm (1.7mW, 50 Hz) LI (for 120 sec) to the apex of LI-induced morphological and other functional changes
a tooth did not.44 related to nerve impairment were assessed by electron
microscopy,23 immunohistochemistry,67,73–75 biochemical
IR LI. Continuous wave 820–830 nm (30 or 40 mW), ap- assay,73 patch clamping,63 confocal microscopy, or live im-
plied from 4 to 24 sec and 780 nm (cw, 3 or12 mW) applied from aging.67
25 to 835 sec, slowed CV in seven studies when applied trans-
cutaneously overlying the course of median, sural, or radial LI application
nerves.33–37,39,43 Continuous wave 830 nm (90 mW) LI did not Visible or IR LI in pulsed or cw mode was applied
slow CV when applied for 33 sec in four cycles to a single area of transcutaneously, or to exposed nerves in situ, to isolated
median nerve,40 nor did 830 nm (40 mW) applied for 30 sec, nerves, or to nerve cell cultures, for 5 sec to 30 min. One
when applied 4 cm medial to the course of the median nerve.39 study assessed repeated LI, applied twice daily for 7 days, to
Pulsed, 830 nm LI, 140 mW (1,500 Hz; ED: 5.1 J/cm2) bradykinin-injected rat facial skin.23
slowed CV in the sural nerve; however 30 mW (1,500 Hz; ED: Reporting of output power, beam mode, ED, PD, total
2.55 J/ cm2) or 400 mW (1,500 Hz; ED: 7.65 J/ cm2) did not.41 energy, duration of exposure, and site of exposure of LI
Pulsed 820–830 nm (12Hz, 73Hz, 5kHz; 9 or 73 Hz) LI at any parameters was inconsistent, with only Chow et al. reporting
ED did not slow CV in median or sural nerves.38,42 Pulsed all relevant parameters.67
904 nm, (73 Hz) LI slowed CV of the superficial radial nerve
with 120 sec irradiation per point but not with 20 sec.29 Studies of CV and CAP recorded simultaneously

LI effects on CAP amplitude Visible LI. Continuous wave 632.8 nm (5.5 mW) LI for 3,
5, or 10 min decreased CAP amplitude, but did not slow CV,
Visible LI. Continuous wave LI, 670 nm (3 mW), at three at all exposures, for up to 150 min in excised preparations of
different EDs, decreased the sural nerve CAP amplitude.43 rat cervical sympathetic ganglion neurons, and the pre- and
Pulsed 632.8 nm (1 mW, 3.1 Hz) LI, delivered continuously post-ganglionic fibers.61 This outcome followed supramax-
for 20 min to the superficial radial nerve, decreased CAP imal stimuli to the pre-ganglionic fibers for 30 min recorded
amplitude by 90%,30 although Wu et al. could not replicate the at the post-ganglionic fibers. Continuous wave 632.8 nm (1 or
findings of Walker et al. (1985)30 using apparently identical 4 mW) LI to exposed dog sciatic nerve did not slow CV or
experimental methodology.31 Pulsed, 632.8nm LI (1.75 mW, alter CAP amplitude of SSEPs recorded at the scalp,59 nor in
50 Hz) for 120 sec, delivered fiberoptically to the apex of the Ad and C fibers of excised rabbit cornea.60 Importantly, the
third molar, decreased SSEP amplitude by 72%44 (Table 1). study by Kao et al. did not report the power output or other
parameters,59 and the study by Jarvis60 has been challenged
IR LI. Continuous wave 780 nm LI (3 mW), at three dif-
as an inappropriate model.76
ferent EDs, decreased CAP amplitude.43 However, 830 nm
(CW, 90 mW) LI applied to a single area of the median nerve
IR LI. Continuous wave 830 nm (40 mW) LI to exposed
at the wrist or forearm,40 or when applied 4 cm medial to the
rat saphenous nerve reduced CV in the slow component of
course of the median nerve,39 did not change CAP ampli-
CAPs at exposures of 180 and 60 sec, but not at 30 sec.69 The
tude. Pulsed 904 nm (73 Hz) LI applied transcutaneously
fast component, representing the large-diameter myelinated
over the superficial radial nerve, decreased CAP amplitude
fibres, remained unchanged. LI for 60 and 180 sec also re-
after 120 sec, but not after 20 sec.29
duced CAP amplitude with the effect lasting up to 4 h but 30-
sec irradiation had no effect on CAP amplitude.
LI can initiate SSEPs de novo
Following electrical stimulation of exposed dog sciatic
Visible, pulsed 632.8 nm (1 mW, 3.1 Hz) LI evoked SSEPs at nerve, Gallium diode-based LI (8 mW, l not reported) did not
Erb’s point when applied over the median nerve at the wrist,30 change CV of SSEPs.59 However, the amplitude of the SSEPs
however, Wu et al. could not replicate this study.31 Pulsed was reduced, which later returned to normal after cessation of
332.2 nm LI (power or pulse rate not reported) elicited SSEPs LI, although duration of stimulation was not reported.
at the scalp when applied to the palm, also innervated by the
median nerve.32 Six of the 11 subjects reported awareness of LI effects on CV and CAP amplitude
the stimulus but the recorded response was identical whether Visible LI. CW, 632.8 nm LI did not slow CV in excised
or not the subject perceived any stimulation.31 rat sciatic nerve at five EDs ranging from 0.1 to 1 J/cm2.68
Parameters, including output power, were not reported.
Animal studies Pulsed, 632.8 nm (1 mW, 100 Hz) LI to exposed rabbit sural
Twenty-six studies of LI on guinea pig, rat, mouse, cat, nerve in the popliteal fossa slowed CV by 9–19%, persisting
ferret, rabbit, or dog nerve met our inclusion criteria. for 20 min.70
Continuous wave 632.8 nm (16 mW) LI to rat sciatic nerve
Methodology. Electrophysiological studies assessed elec- delivered transcutaneously and continuously for 30 min, did
trically evoked CAPs, SSEPs or noxiously evoked potentials. not alter CAP amplitude with a cumulative dose of 3 J at
CAPs26,56–58,60,61,63,68–70 and SSEPs59 were measured follow- 6 min. However, CAP amplitude increased during the period
ing supramaximal stimuli after baseline potentials had been 6–15 min as the dose increased to 8 J, with the increase lasting
established (Table 2). *7 min.57 When total cumulative dose of 8–15 J was reached
 Table 1. Human Studies of Transcutaneous or Dental Laser Irradiation on Conduction Velocity (CV)
and Compound Action Potential (CAP) Amplitude

l (nm) & beam Power and Rx Effect on Effect on compound

Author and year Nerve mode parameters Sites treated conduction velocity action potential

Greathouse Superficial radial 904, 73 Hz exp: 1 20 sec 5 points at 1 mm exp 1: no change exp 1: no change
et al.29 n ¼ 20 exp: 2 120 sec above skin surface; exp 2: decreased exp 2: no change
(power not reported) observed at 1, 3, 5, p < 0.05
10, and 15 min
post-LI
Snyder-Mackler et Superficial radial 632.8, cw 1 mW 6"1 cm2 points along Decreased NR
al.28 n ¼ 20 course of nerve; p < 0.05
0.5 mm from skin
surface
Walker & Akhanjee30 Superficial 632.5, 3.1 Hz 1 mW 4 mm2 area at each NR exp 1: decreased
radial & exp 1: 800 pulses nerve exp 2: decreased
median n ¼ 10 exp 2: 4,800 pulses spot size: 4 mm2 (more prolonged
duration of exposure: exposure dec. by
20 min 20–90%)
Wu et al.31 Median 632.5, 3.1 Hz 1 mW; fiberoptic probe 4 mm2 area; NR No light-evoked

4
n¼9 2 mm above skin response
Snyder-Mackler & Superficial radial 632.8, cw 1 mW, 20 sec 6"1 cm2 points over Decreased by 14.2% NR
Bork22 n ¼ 40 0.02 J nerve; p < 0.001
ED: 19 mJ/cm2 0.5 mm from skin
Czopf et al.32 Median 337.1, pulsed 300 mJ per pulse Palm of hand Not applicable Evoked potential
n ¼ 20 (power NR) pulse duration: 1.0 nsec (acupuncture measured at the
(power not reported) points: PC6 and scalp
LI10)
beam area:
0.3 mm2
Baxter et al.33 Median 830, cw 40 mW, 10 points over nerve Decreased NR
n ¼ 27 ED: 1.2 J/cm2 in contact with p < 0.05
30s per pt skin
Baxter et al.34 Median 830, cw 40 mW, 10 points over Decreased (>1 h NR
n ¼ 48 ED: 1.2 J/cm2 nerve post-LI)
30 sec/pt p < 0.05
Baxter et al.35 Median 830, cw 40 mW, 10 points over nerve Decreased NR
n ¼ 24 ED: 1.2 J/cm2, 0, 1, 2, and 5 min
30 sec per pt post-LI
Kramer & Sandrin36 Radial exp 1: 780, cw exp 1:12 mW, 15sec 6"1 cm2; 1 mm from Exp 1: no change NR
n ¼ 40 exp 2: 632.8, 0.18 J surface; exp 2: decreased
cw exp 2: 10 mW, 18 sec spot size diam: p < 0.03
0.10 J 0.15 cm
ED: 10 J/cm2 0 and 1 min post-LI
 Baxter et al.39 Median 830, cw 40 mW, exp 1: 30 sec, 10 exp 1: decreased obs 1 h NR
n ¼ 51 30 sec per pt, points along at 5 min intervals; p
1.2J per pt course of nerve 0.05
ED: 9.6J/cm2 exp 2: as above but exp 2: no change
4 cm medial to exp 3: decreased p
nerve 0.05
exp 3: 4 points
along palm
Lowe et al.37 Median 830, cw 30 mW, 10 points over nerve exp 1–3: decreased NR
n ¼ 80 PD: 300 mW/cm2 20 min obs at 2 min p < 0.05
exp 1: 1.5 J, 5 sec intervals
exp 2: 3 J, 10 sec spot size: 0.1 cm2, exp 4 and 5 no effect
exp 3: 6 J, 20 sec
exp 4: 9 J, 30 sec
exp 5: 12 J, 40 sc
Lowe et al.38 Median 820, pulsed, 46 mW (av power) 10 points over nerve exp 1–6: no significant NR
n ¼ 90 12 Hz and ED 1.5 J/cm2 in contact with change at any pulse
73 Hz and or ED 9.0 J/ cm2 skin rate or ED
5 kHz Spot size: 0.125 cm2,
368 mW/cm2
Exp 1: 0.18 J, 4 sec
Exp 2: 0.18 J, 4 sec
Exp 3: 0.18 J, 4 sec
Exp 4: 1.1 J, 24 sec

5
Exp 5: 1.1 J, 24 sec
Exp 6: 1.1 J, 24 sec
Bartlett et al.40 Median 830, cw 90 mW, X 3 multi-head; spot exp 1: LI at wrist–no No change 0 and
n ¼ 42 ED: 33 J/cm2 size: 0.09 cm2 change 10 min
(4 groups) PD: 1 W/cm2 single area; 2 areas exp 2: LI at forearm–
33 sec x 4, 12 J treated separately no change
exp 1: LI at wrist
exp 2: LI at fore-
arm
Cambier et al.41 Sural 830, pulsed exp 1: 400 mW; 3.8 sec per 6 points over nerve exp 1: no change NR
n ¼ 15 1-500 mW pt, 1.5 J spot size: exp 2: decreased
freq: ED: 7.65 J/ cm2 0.196 cm2 p < 0.05
0-1500 Hz; exp 2: 140 mW; 5 sec, exp 3: no change
pw: 500 ms 1 J per pt,
ED: 5.1 J/ cm2
exp 3: 30 mW; 16.6 sec
per pt;
ED: 2.55 J/cm2; 0.5 J

(continued)
 Table 1. (Continued)

l (nm) and Power and Rx Effect on Effect on compound

Author and year Nerve beam mode parameters Sites treated conduction velocity action potential

Walsh et al.42 Superficial radial 820, 46 mW, 0.125 cm2, 3 points over nerve; exp 1: no change NR
n ¼ 32 pulsed, ED: 9.55 J/cm2 5, 10, and 15 min exp 2: no change
9.12 Hz 368 mW/cm2
&73 Hz 1. J per pt,
exp 1: 24 sec
exp 2: 24 sec
Nelson and Trigem. nerve, 632.5, 1.7mW, spot size: 1 point at left maxil- No change Decreased to 65% at
Friedman44 maxil. branch pulsed 0.001 cm2, PD:1.73 W/ lary 3rd molar 10 min and 72% at
n ¼ 24 50 Hz cm2,ED:138.4 J/cm2 apical area 20 min p < 0.001
120s/pt, 0.2 J
Hadian and Sural exp 1–3: 670, 3 mW Along course of exp 1–6 all decreased exp 1–6 all decreased
Moghada43 n ¼ 38 cw exp 1: ED:0.5J/cm2 5 J, nerve p < 0.01 p < 0.01
exp 4–6: 780, 167 sec (number of points p < 0.001 p < 0.001
cw exp 2: ED:1.5J/cm2 15 J, unspecified)
501 sec
exp 3: ED: 2.5 J/cm2 25 J,
835 sec
exp 4: ED: 0.5 J/cm2
0.075 J, 25 sec
exp 5: ED:1.5 J/cm2

6
0.150 J, 75 sec
exp 6: ED: 2.5 J/cm2
0.325 J, 125 sec

exp, experiment; pt, point; l, wavelength; PD, power density; ED, energy density; cw, continuous wave; NR, not reported.
REVIEW OF LASER IRRADIATION ON PERIPHERAL NERVES 7

after 15 min, the CAP amplitude decreased to baseline levels. mitochondrial membrane potential (MMP) in 67% of neu-
With continuing LI, CAP amplitude was decreased to below rons, measured by patch clamping, in rat sensory nodose
baseline levels after *30 min. A similar biphasic response was ganglion neurons.63 Depolarization persisted for 3–8 min;
reported by Nissan et al. using the same model and parame- however, in 35% of these neurons remained depolarised for a
ters.56 In contrast, in a third study using the same model and further 40 min. Tetrodotoxin (TTX, 7.5 mM), a sodium chan-
LI parameters, CAP amplitude increased by 43% after 20 min nel blocker, abolished the LI-induced depolarization, sug-
with no decline.58 Shimoyama et al. also demonstrated an gesting LI-
increase in CAP amplitude following 632.8 nm (5.5 mW) LI to induced inhibition of voltage-gated sodium channels. As
rat superior cervical ganglion neurons.61 Pulsed, 632.8 nm reported earlier, the diameters of these neurons were con-
(1 mW) LI to exposed cat sural nerve decreased CAP ampli- sistent with their being nociceptors.
tude by 25%.26
There were no studies of IR LI on electrically evoked Visible LI hyperpolarizes sympathetic neurons
CAPs.
Intracellular recording of individual fibers of superior rat
cervical sympathetic ganglionic nerve following 632.8 nm
LI reduces noxiously evoked SSEPS
(cw, 5.5 mW), LI for 3, 5, or 10 min, showed hyperpo-
LI applied before, during, or after noxious stimuli de- larization with an increase in CAP amplitude.61 However,
creased amplitudes of noxiously evoked SSEPs (Table 3). decreased CAP amplitudes recorded extracellularly in the
post-ganglionic nerve were observed, indicating that LI-
Visible LI. Continuous wave, 632.8 nm (8.5 mW) LI for induced hyperpolarization reduced the number of neurons
30 min prior to formalin injection to rat hind paw, innervated capable of responding to ES.
by peroneal nerve, inhibited SSEPs measured at the ipsilat-
eral, lumbosacral dorsal horn neurons.62 Pulsed, 632.8 nm IR LI induces neuronal morphological
(1 mW, 100 Hz) LI for 10 min to exposed sural nerve inhibited and functional changes
SSEPs elicited by pinch of skin of rabbit hind paws.72
Continuous wave, 830 nm (20 mW) LI induced varicosity
However 632.8 nm (cw, *1 mW), LI used as an aiming
formation and inhibited outgrowth of the nociceptive neu-
beam for Nd:YAG laser, did not inhibit SSEPs when ferret
ropeptide substance P and CRGP-stained positive neurites
tooth pulp was mechanically stimulated.45 Similarly, pulsed
by 30% in cultured murine neurons.74 The effect was re-
632.8 nm (5 mW, pulse rate not reported) LI for 5 min failed
versed after 5 h. LI of 830 nm (cw, 300 mW) at 5, 30, 60, or
to inhibit the nociceptor Ad and C fiber response in excised
120 sec was also found to induce varicosity formation in
rabbit cornea following mechanical, thermal, or chemical
cultured, rat DRG neurons, indicating microtubule disrup-
noxious stimuli.60
tion.67 Varicosities were b-tubulin positive and contained
clusters of mitochondria. Real-time confocal microscopy with
IR LI. Laser irradiation at 830 nm (cw, 350 mW) for 2 min
JC-1, a radiometric dye, showed statistically significant de-
to the surface of rat incisor, inhibited SSEPs evoked by nox-
creased axonal and cell body MMP, and blocked fast axonal
ious ES, in the ipsilateral trigeminal subnuclear caudal neu-
flow, which was reversed within 24 h.
rons;25 and 830 nm (40 mW) LI for 3 min to exposed rat
Bradykinin injected into rat facial skin, innervated by the
saphenous nerve, inhibited noxiously induced SSEPs in the
maxillary branch of the trigeminal nerve, showed increased
ipsilateral L4 dorsal root following turpentine injection to the
mitochondrial density in the related trigeminal nucleus.23 LI
paw,64,65 and heat, pinch, and cold to the paw, but did not
of 830 nm (cw, 60 mW) for 15 sec per point, to 12 points over
inhibit response to brush stimulation,65 indicating the speci-
the dermatome twice daily for 7 days, reduced the mito-
ficity of the effect on the nociceptive Ad and C fibers but not
chondrial density to control levels at day 12.
the Ab fibres. In a parallel experiment, neonatal rats treated
LI of 830 nm (cw, 60 mW) for 1 min to exposed, electrically
with capsaicin at birth, thereby specifically destroying the
stimulated, rat sciatic nerve inhibited production of sub-
nociceptor Ad and C fibers, showed no response to noxious
stance P in the ipsilateral lumbar DRG.75
stimuli or LI. As in the previous experiment, these rats con-
Pulsed, ruby LI (l ¼ 694 nm, power or pulse frequency not
tinued to respond normally to light touch.
reported) for 10 min increased acetylcholine release from the
LI of 830 nm (cw, 16.2 mW) applied to axons in the outer
Auerbach plexus of isolated guinea pig ileum, after 3 min,
chamber of a two-chamber culture preparation of murine
lasting up to 30 min.77
dorsal root ganglion (DRG) neurons <25 mm diameter, char-
acteristically nociceptors, inhibited bradykinin-evoked po-
IR LI affects enzyme activity
tentials in cell bodies in the inner chamber as demonstrated by
patch clamping techniques.66 LI of 830 nm (cw, 60 mW) applied transcutaneously over rat
Another study showing nociceptor specificity was seen in saphenous nerve for 6–15 sec (0.9 J) increased activity of Naþ
a study of pulsed, 904 nm (2 W, 3040 Hz) LI to cat tongue, in K þ -ATPase, essential for maintenance and restoration of
which LI for 1 min inhibited noxious heat stimulation in 60% resting membrane potential. The enzyme activity levels then
of nociceptors.71 Further LI for 3–10 min inhibited firing declined with a further 30 sec of LI, decreasing to below-normal
frequency in 100% of cases. levels following 60 and 120 sec.73 LI for <6 sec had no effect.

IR LI depolarizes sensory neurons Discussion

Continuous wave, 830 nm (2.5–150 mW) LI at ED between This review demonstrates a range of LI-induced functional
2.5 and 30 J/cm2, caused a dose-dependent reduction in neural impairment in human and animal peripheral nerve,
 Table 2. Animal Studies of Laser Irradiation on Conduction Velocity, Electrically Evoked Compound Action Potentials, Somatosensory
Evoked Potentials, Morphology, or Enzyme Activity

Animal and l (nm), beam Site treated and Conduction Electrically evoked Morphological
Study nerve irradiated mode, power, duration of LI velocity CAP or SSEP or functional change

Vizi et al.77 Guinea pig 694, P Isolated NR NR Increased production of

Auerbach’s (Hz and power NR) Auerbach’s plexus acetylcholine-commenced
plexus after 3–10 min and lasted
(in vitro) 25–30 min
Rochkind et al.57 Rat sciatic 632.8, cw Cumulative NR Phase 1: <3 J: NR
(in vivo) 16 mW exposure: 30 min no change
n¼4 4 mm diameter transcutaneous Phase 2: >3J <8 J
increased
Phase 3: >8J decreased
Nissan et al.56 Rat sciatic 632.8, cw Cumulative exposure; NR Phase1: increased after NR
(in vivo) 16 mW 30 min 6 min (<3 J)
n¼4 4 mm diameter Transcutaneous Phase 2: high/stable for
7 min; (>3.5–7.5J J)
Phase 3: decreased next
7 min

8
(8–15 J)
Rochkind et al.58 Rat sciatic 632.8, cw Cumulative NR Increased by 43% 20 min NR
(in vivo) 16 mW exposure; 30 min after LI
n ¼ 13 4 mm diameter, transcutaneous
TE ¼ 5 J
ED *10 J/cm2
Kao et al.59 Dog 632.8 P and cw Exposed 632.8 exp 1: no change NR
sciatic 100-1000Hz nerve; exp 1 no change exp 2: no change
(in vivo) exp 1: 1 mW 10 min exp 2: exp 3 decreased
exp 2: 4 mW cortical SSEP mea- no change (reversible)
beam diameter: 1.47mm sured at scalp IR laser
Ga IR exp 3 no change
exp 3: 8 mW
Kudoh et al.73 Rat saphenous 830, cw Isolated nerve NR NR Naþ Kþ-ATPase activity
nerve 60 mW 6–120 sec exposure $ 6–15 sec increased ac-
tivity
$ 30 sec declined
$ 60 and 120 sec decreas-
ing below normal levels
 Maeda23 Rat 830, cw Skin of face innervated NR NR Inhibition of increased mi-
trigeminal 60 mW by maxillary branch tochondrial density in
nerve PD: 1.9 W/cm2 of trigeminal nerve trigeminal nucleus after
(in vivo) 12 pts 15 sec per pt bradykinin stimulation
2"/day for 7 days; (12th day after LI)
spot size 2 mm p < 0.001
Arber et al.68 Rat 633, (?cw and Isolated segment exp 1–5 NR NR
sciatic power NR) exp 1 10 sec no change
(in vitro) ED: 0.1–1 J/cm2 exp 2 1 min
PD: 0.6–10 W/cm2 exp 3 5 min
exp 4 10 min
exp 5 20 min
Jarvis et al.60 Rabbit 632.5, cw (a) Spontaneous spike No change after No change after 120 min NR
n ¼ 20 4 mW activity Ad and 120 min
corneal noci- beam diameter 4 mm C fibers;
ceptors in ex- 0–1,800 sec (b) electrically evoked
cised cornea single fiber dis-
charges;
5 min
Shimoyama Rat 632.8, cw Intra- and extracellular exp 1 (3 min): no exp 1 (3 min) : decreased NR
et al.61 superior cervi- 5.5 mW recordings from iso- change p < 0.05
cal sympathetic spot size 1.4 mm, lated nerves; exp 2 (5 min): exp 2 (5 min): decreased
ganglia PD: 350 mW/cm2 3, 5, or 10 min no change p < 0.01
(in vitro) exp 3 (10 min): exp 3 (10 min):

9
no change decreased
p < 0.05
Chen et al.74 Murine 830, cw DRG neurons in culture; NR NR Varicosity formation
nerve cultures 20 mW 5 or 15 min and suppression of
growth of
nociceptors at
0 and 5 h post-LI –
p < 0.001
Kono et al.26 Cat sural 632.8, cw Exposed nerve in popli- NR Decreased NR
n¼3 power NR teal fossa, by an average of 25.6%
(in vivo) 1 mW, measuring evoked p < 0.01
100 Hz dorsal horn re-
fiberoptic delivery 20– sponses;
25 mm above nerve 10 min
Tsuchiya et al.69 Rat 830, cw Exposed nerve; exp 1 (30 sec): no exp 1 (30 sec): no change NR
saphenous 40 mW response to LI mea- change (fast exp 2 (60 sec): decreased
nerve PD 1 W/cm2 sured in L5 dorsal component) p < 0.01
n ¼ 25 exposed nerve; 0.5– roots exp 2 (60 sec): exp 3 (180 sec): de-
(in vivo) 1.5 mm from nerve 30, 60, and 180 sec decreased creased 12-67% p < 0.01
spot size: 2 mm (slow effects lasted up to 4 h
component)

(continued)
 Table 2. (Continued)

Animal and l (nm), beam Site treated and Conduction Electrically evoked Morphological
Study nerve irradiated mode, power, duration of LI velocity CAP or SSEP or functional change

Kasai et al.70 Rabbit 632.8, P Exposed in popliteal Ad fiber CV de- NR NR

sural 1 mW fossa; creased by 9–
n¼7 100 Hz 10 min 19%; persisted
(in vivo) fiberoptic delivery 20 min p < 0.05
20–25 mm above nerve
Miura and Rat cultured no- 830, cw Direct LI to cultures NR (a) depolarization of neu- NR
Kawatani63 dose ganglion 2.5–150 mW rons
cells beam diameter: 0.4 mm (b) increase in Naþ cur-
ED: 5–20 J/cm2 rent
(c) TTX abolished laser-
induced depolarization
Ohno75 Rat sciatic nerve 830, cw LI to exposed nerve Substance P syn- Suppression of substance P NR
n ¼ 41 60 mW thesis L4-6 at DRGs
(in vivo) DRGs p < 0.05
Chow et al.78 Rat DRG cultures 830, cw Direct LI to cultures; NR NR Exp 1–5:
(n ¼ 10) 400 mW 5–30 sec varicosity formation;
PD: 300 mW/cm2 decreased MMP
ED: 1.4 J/cm2–33.3 J/cm2 disrupted FAF;
spot size: 1.4 cm2 p < 0.05
p < 0.01

10
l, wavelength; cw, continuous wave; DRG, dorsal root ganglion neurons; ES, electrical stimulation; FAF, fast axonal flow; MMP, mitochondrial membrane potential; P, pulsed; NR, not reported; PD,
power density; ED, energy density; CAP, compound action potential; SSEP, somatosensory evoked potential.
REVIEW OF LASER IRRADIATION ON PERIPHERAL NERVES 11

isolated nerve, and primary nerve cell cultures. This is the inhibition of nerve activity at lower energy outputs with
first review to examine such a range of neurological effects. visible LI.
Neural impairment included CV slowing, decreased CAP Although transcutaneous LI can slow CV in human
and SSEP amplitudes, suppression of response to noxious nerves, these studies do not provide evidence that LI-
stimuli, suppression of pain-related neurotransmitters re- induced neural inhibition is causal in the pain-relieving ef-
lease, inhibition of enzyme activity, and morphological fects of LLLT. The animal studies, however, evaluated a
changes related to nerve conduction. diverse range of effects, which have particular relevance to
The human studies were methodologically uniform with the analgesic effects of LI. In particular, specific inhibition of
transcutaneous visible and IR LI, applied at several points Ad and C fibers, which transmit nociceptive stimuli, provide
along the course of peripheral nerves, causing CV slowing the strongest evidence that functional impairment of these
and decreased amplitudes of CAPs or SSEPs. What is im- fibers mediates clinical pain relief. In these experiments,
portant is that these findings establish the principle that pulsed and cw, visible and IR LI, reduced response in noci-
photons delivered transcutaneously can inhibit or at least ceptors to a variety of noxious stimuli, including proin-
slow or partially block nerve conduction. Furthermore, these flammatory substances.64,65 What is important is that in rats
studies demonstrate that LI is most effective when applied at in which nociceptors were ablated by capsaicin application at
several points over the nerve causing an additive effect, rather birth, there was no response to noxious stimuli or to LI, al-
than to a single point. These findings are of direct relevance to though non-noxious stimuli were transmitted normally and
the clinical application of LLLT showing its effectiveness in were not inhibited by LI.
painful conditions such as neck or back pain. Clinically, LI is LI-suppression of bradykinin activity, a pro-inflammatory
applied transcutaneously to multiple points, such as tender neuropeptide that sensitiszes nociceptors and is a key ele-
points,78 trigger points,79 or acupuncture points,80 in the re- ment in clinical pain and the associated inflammation,23,66,88
gion of injury or pathology. The neural network of nociceptor is directly relevant to pain relief. Continuous wave, 830 nm,
fibers within the epidermis would be most affected by the (16.2 mW) LI to isolated neurons blocked the stimulatory
transmitted photons, as photon density is maximal in the effects of bradykinin activity on nociceptors,66 and in the
epidermis and decreases exponentially. trigeminal nucleus of rats, induced by bradykinin injection to
The human studies also point to an important difference in facial skin, following 830 nm, (cw, 60 mW) LI over the in-
the clinical effects of pulsed, IR LI compared with cw mode. jection site.23 The latter study is consistent with 830 nm, (cw,
In the majority of studies, pulsed 820–830-nm LI had no ef- 350 mW) LI-induced inhibition of SSEPs in the trigeminal
fect on CV, although CW LI of the same wavelengths did. nucleus of rats induced by noxious electrical stimulation of
Pulsed LI (either ‘‘chopped’’ or intrinsically pulsed) delivers the related tooth pulp.25 Further evidence for neurally-me-
lower total energy ( Joules) to the nerve than does cw mode, diated suppression of bradykinin, was the downregulation
supporting the hypothesis that CV slowing requires ‘‘high’’ of B1 and B 2 kinin receptors,89 which are expressed on no-
dose LI. A study showing that 904-nm LI slowed CV with ciceptors,88 by visible LI (l ¼ 660 or 684 nm), following in-
120 sec exposure but not with 20 sec exposure, which dem- jection of the pro-inflammatory polysaccharide, carrageenan,
onstrates a dose-dependent response,29 adds weight to the into rat paw. As bradykinin is associated with neural in-
proposition that inhibition of nerve conduction requires flammation and peripheral sensitisation of nerves, which
comparatively higher doses of LI. occur at an injury site, these studies also provide evidence for
Visible LI in pulsed or cw modes did slow CV, which oc- a direct link between local LI and reduced inflammation,
curred at a lower output power range (1–10 mW) compared again by direct suppression of nociceptor response.
with IR LI (30–400 mW). However, direct comparisons be- Substance P, another neuropeptide associated with noci-
tween visible and IR studies were not possible as many ception, was decreased in lumbar DRG neurons when the
studies did not report all relevant parameters, such as power electrically-stimulated ipsilateral rat sciatic nerve was irra-
density (irradiance) and energy density (radiant exposure). diated with 830 nm (cw, 60 mW) LI.75 Such suppression
We propose that intrinsic differences between visible and IR distally demonstrated that visible or IR LI to peripheral
LI may account for the apparent effectiveness of visible LI nerve, conveying nociceptive stimuli, could cause upstream
occurring at much lower output powers than IR. Red photons inhibition of synaptic activity, via synaptic plasticity, in
have greater electron voltage than IR, and visible LI has second-order neurons, in the dorsal horn and to the
greater coherence than IR, with the possibility of more intense pain matrix, with potential importance in long-term pain
intra-tissue ‘‘speckle’’ formation, with the ‘‘speckles’’ being modulation.90
points of higher intensity caused by interference effects. 81,82 How LI causes functional neural impairment remains
Countering this rationale is the lower penetration depth of unclear. Changes in neuronal morphology, in particular ax-
visible LI (2–5 mm for visible LI compared with 3–5 cm for IR onal varicosity formation, seen after LI, are an example of a
LI ), although epidermal nociceptor terminals will be well specific structural change, which is a likely substrate for
within the depth of penetration in the first 2 mm of skin.83 electrophysiological changes. Axonal varicosities are identi-
Differences in mechanisms of action between visible and IR LI fied as multiple swellings or ‘‘beading’’ occurring at regular
have been described,84 which include the formation of greater intervals along an affected axon. Confocal microscopy of
levels of reactive oxygen species (ROS) with visible LI85–87 varicosities shows disruption of the cytoskeleton with clus-
than with IR LI. Such differences may also account for the tering of mitochondria, blockade of fast axonal flow (FAF),
variation in biological responses between wavelengths, al- and decreased MMP, which have been described.67,74 Var-
though not all authorities agree with this assertion and icosity formation occurs following various stimuli to nerves
therefore it remains an area for debate and further resolution. including mechanical stress, hypoxia, and, most relevant to
We propose that all of these factors may be relevant to the LI, application of reactive oxygen species such as hydrogen
 Table 3. Animal Studies of Effects of All Wavelengths of Laser Irradiation on Noxiously Evoked Stimuli

l (nm), beam mode,

Study Animal and nerve power, LI duration Noxious stimulus Site of measurement CAP/SSEP response
71
Mezawa et al. Cat 904, P Heat 30 sec to tongue Single fiber discharge in Exp 1: minimal change
lingual nerve 2W exp 1: 1 min nociceptors in tongue exp 2: inhibition

12
(in vivo) 3040 Hz; pulse width exp 2: 3 min exp 3: inhibition
n ¼ 11 200 ns exp 3: 5 min exp 4: inhibition
exp 4: 10 min
Jarvis et al.60 Rabbit 632.5, P Mechanical, Single fiber discharge in No change after 120 min
corneal nociceptors 5 mW; chemical excised cornea Ad fi-
n ¼ 20 5 min heat bers and mechano-re-
pulse width ceptors
0–1,800 sec
4 mm diam.
Shimoyama et al.62 Rat dorsal horn neurons 632.8, cw Subcutaneous injection Extra-cellularly re- Inhibition
n ¼ 14 8.5 mW of formalin to skin of corded single fiber
(in vivo) 30 min transcutane- hind paw discharge in neurons
ous LI - innervated by pero- of the associated
neal nerve lumbosacral spinal
cord, recorded
Wakabayashi et al.25 Rat 830, cw Electrical stimulation of Ipsilateral trigeminal Inhibition of C fiber EP
mandibular branch of 350 mW tooth pulp nucleus caudal neu- spike activity; no change
trigeminal nerve 2 min LI, to lower in- of incisor rons, recorded extra- in Ad fibre (persisted for
n ¼ 12 cisor cellularly 15 min after LI) p < 0.005
(in vivo) 10 mm above surface
beam diam: 3 mm
Kasai et al.72 Rabbit 632.8, P Pinch to hind paw Exposed Inhibition of evoked and
sural nerve 1 mW nerve sural nerve proximal spontaneous neural dis-
n¼7 100 Hz to LI charge
(in vivo) p < 0.01
 Sato et al.64 Rat 830, cw Turpentine injection to L4 nerve root Exp 1: 30 sec no change
saphenous nerve 40 mW paw exp 2: 60 sec no change
(in vivo) LI to exposed nerve exp 3: 180 sec inhibition
or skin overlying slow component,
nerve p < 0.05;
no change in Ab fibers
inhibition
Tsuchiya et al.65 Rat 830, cw Pinch Neuronal discharge in Decreased discharge of
saphenous nerve 40 mW heat ipsilateral dorsal horn nociceptors (by *30%)
(in vivo) LI to exposed cold exp 1: pinch; p < 0.01
n ¼ 12 saphenous nerve turpentine injection exp 2: heat; p < 0.01
n ¼ 7 (Rx’d with cap- PD: 1 W/cm2 to paw exp 3: cold; p < 0.01
saicin) 3 min exp 4: inj. turpentine
beam diam: 2 mm p < 0.01
exp 5: brush; no change
exp 6. In capsaicin Rx’d
rats – no change
Jimbo et al.66 Mouse 830, cw Bradykinin – topical Cell body of neuron Inhibition 2 min after LI
DRG neurons 16.2 mW application to axon
ED: 1 J/cm2
1 min LI to
cultured DRG to cell
process before BK
application
area irrad: 75 mm

13
Orchardson Ferret 632.8 Mechanical Intradental nerve re- No inhibition
et al.45 lingual nerve *1 mW sponses
(in vivo) 60 s LI to exposed
dentine in canine
teeth

cw, continuous wave; ED, energy density; EPs, evoked potentials; P, pulsed; PD, power density; BK, bradykinin.
14 CHOW ET AL.

peroxide. Such changes would have a profound effect on number of animal studies using visible LI, which demon-
nerve conduction and, because they appear to be specific for strated increased CAP amplitude.57,58,61 In two studies, LI
small diameter fibers, Ad and C nociceptors, are directly was applied transcutaneously to rat sciatic nerve in vivo and
relevant to pain relief. in the third, to rat sympathetic ganglion neurons in vitro. The
Support for the relationship between varicosity formation authors postulated that LI caused an increase in ATP with
and functional neural impairment and establishing a model subsequent hyperpolarization of the nerve, which in turn
for LI effects, is provided by the study by Tanelian and led to increased amplitude of the action potential. In light
Markin, in which application of substance P induced vari- of the remainder of the literature, the effects noted by
cosity formation in DRG neurons.91 The authors proposed a Nissan et al.,56 Rochkind et al.,57 and Shimoyama et al. 61
biomathematical model of conduction block in the presence need to be reconciled, but may be the result of parameters
of varicosity formation to explain the biophysical conse- or methodologies not originally reported, including a bi-
quences of such morphological changes in DRG neurons. phasic response, not yet identified in peripheral nerve
They also proposed that varicosity formation was important models.98
in physiological nociceptive signalling and in the develop- The inhibitory findings in this review represent an alternate
ment of pain ‘‘memory’’. Similar neuritic varicosities in cen- perspective on the effects of LI in biological systems. Previous
tral nervous system (CNS) neurons following H2O2 exposure research has been oriented to laser-induced stimulation, ra-
have been demonstrated in an ‘‘oxidative stress’’ model.92 As ther than inhibition, as the intended and desirable outcome,
LI-induced ROS formation in mitochondria is postulated to and the biphasic response of biological systems to LI is widely
be a mechanism of laser energy transduction in cells,93 which recognized.98 Although inhibitory effects in compact cells
would have a similar effect as H2O2 did in the Roediger and such as fibroblasts are well documented,99,100 these are un-
Armati study,92 this provides a mechanism by which LI re- desirable, especially in wound healing, which dominated
sults in conduction block. Varicosity formation also occurs early laser research.101 In the context of pain relief, we propose
following local anaesthetic application to DRG neurons,94,95 a causal relationship between LI-induced impairment of
and may have relevance in understanding LI-induced pain neural function and pain relief, suggesting a positive aspect to
relief. inhibition.15,26,74,102
It is significant that varicosities result from blockade of Poor reporting of parameters and the small number of
FAF, which is associated with disruption of microtubules studies using different experimental models makes pooling
and the resulting block of anterograde transport of ATP-rich of data to guide clinical application unhelpful and potentially
mitochondria. Interruption of FAF reduces the availability of misleading. Although this limits extrapolation of the data to
ATP necessary for microtubule polymerization and mainte- clinical settings, this review does establish potential lines
nance, and maintenance of the resting potential. The ATPase, of investigation to further explore the role of laser therapy in
Naþ-Kþ-ATPase, the enzyme responsible for the generation neural inhibition and pain relief.
of action potentials, which requires ATP for function, is in-
hibited by high-dose LI.73 Hence reduced availability of ATP Conclusion
following LI would result in failure of generation of action
potentials and disruption of nerve conduction. The report by This systematic review provides evidence that visible and
Miura and Kawatani, showing that 83-nm LI causes depo- IR LI cause neural impairment, in particular in small diam-
larization of rat nodose ganglion neurons by disruption of eter Ad and C fibers, which convey nociceptive stimuli, so
sodium channels, in a dose-dependent manner,63 provides relevant to pain. Disruption of the cytoskeleton, decreased
additional evidence of the importance of Naþ-Kþ-ATPase in ATP availability, and impaired conduction in nociceptors,
nerve function and its potential role in LI-induced inhibition may therefore underpin the pleiomorphic inhibitory effects
of nerve conduction. In addition, as peripheral nervous of LI in a diverse range of nerve functions. Lack of complete
system neurons have axons up to one meter in length in reporting of the parameters limited comparison of studies
humans, they may be uniquely vulnerable to disruption of and aggregation of data. Nevertheless, the evidence supports
FAF compared with compact cells, such as fibroblasts, as the view that neural inhibition is a plausible mechanism for
their function relies on FAF along the cytoskeleton for the relief of acute and chronic pain with LLLT.
transport of ATP-rich mitochondria from the neuronal cell
body where synthesis of ATP activity occurs. Therefore, re- Acknowledgments
duced axonal ATP provides a mechanism for LI-induced
We acknowledge the contribution of Brigid Ryan, the
pleiomorphic, inhibitory effects, particularly on nociceptor
Centre for Physiotherapy Research, School of Physiotherapy,
responses.
University of Otago, for assistance with research and
Release of serotonin in the CNS is also postulated as a
proofreading the manuscript.
mechanism for pain relief. This was demonstrated by in-
creased levels of urinary excretion of the serotonin by-
product, 5 hydroxyindoleacetic acid (5HIAA), following LI Author Disclosure Statement
to peripheral nerves.96 As low serotonin levels are associated No competing financial interests exist
with chronic pain,97 increase in excretion of 5HIAA, follow-
ing LLLT for chronic pain, suggests a significant CNS re-
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