The preceding experiments were conducted with 110 lux GLEDs. However, whether this lux level was sufficient to elicit the antinociceptive behavior is not known. Consequently, we exposed the rats to GLEDs spanning several lux intensities. Exposing rats for 8 hours to 4 lux GLED levels was sufficient for increasing PWLs compared with nonexposed rats (Fig. 3). Similar levels of PWLs were observed with rats exposed to 12, 36, or 110 lux GLED levels (Fig. 3). Exposure of rats to GLED 330 lux level significantly increased PWLs compared with baseline ambient light-exposed rats but resulted in only a half-maximal response when compared with the other lux conditions (Fig. 3). As the 4-lux GLED exposure for 8 hours was sufficient for achieving maximal antinociception, we used this lux level for all subsequent experiments.
We also tested if prolonged exposure to GLEDs could elicit tolerance to the antinociceptive effect. Rats exposed to GLEDs for an additional 7 days past the initial 5 days exposure (4 lux, 8 h/d)—total of 12 days of GLED exposure—did not develop tolerance (Fig. 3B). This is in contrast with published data with morphine where analgesic tolerance can be observed within 3 days67 and causes rats to be hyperalgesic within 5 days.82
We determined whether the mechanism of GLED-induced antinociception requires direct activation of the visual pathway by fashioning dark, opaque, plastic contact lenses that permitted no light penetration (confirmed by measuring light intensity). These were fitted onto the rats' eyes under anesthesia. As a control, transparent clear lenses were also installed onto control rats' eyes. The application of contact lenses did not alter the baseline PWL. Both groups of rats were then exposed to GLEDs for 8 hours daily for 5 days and their PWLs were monitored. Following this exposure paradigm, rats fitted with the dark, opaque, contact lenses failed to develop antinociception, whereas rats fitted with clear, transparent, contact lenses developed antinociception similar to rats with no contacts (Fig. 4A). Consistent with the importance of the visual system in the development of GLED-induced antinociception, rats fitted for 8 hours with “green” contacts that permit light transmission in the green part of the visual spectrum (Fig. 4B), developed antinociception when exposed to room light (Fig. 4C). Importantly, histological analysis of the eyes of the rats at the end of the experiments revealed no damage caused by either contact lens (data not shown). These results support a role for the visual system in mediating the GLED-mediated antinociception.
To test if pigmented skin is involved in the antinociceptive effects of GLEDs, we selected the pigmented LE rats, which are different from the albino SD rats that lack pigmentation. A similar level of antinociception was observed in SD or LE rats exposed to GLEDs for 8 hours daily for 5 days; the PWLs were significantly higher than the respective strains exposed to ambient light (Fig. 5). The antinociception was not restricted to male rats as female SD rats exposed to the same GLED paradigm also exhibited increased PWLs (Fig. 5). Collectively, these results suggest that pigmentation is not important for developing antinociception.
The mechanisms that might underlie the antinociceptive effects of GLEDs were investigated by determining possible contributions of endogenous pain transmitters and circuits as well as mediators of stress. Naive rats exposed to GLEDs for 8 hours daily for 5 days received antagonists immediately after light termination, and then PWLs were measured 20 to 30 minutes later. The GLED-induced antinociception was reversed, to baseline levels, after administration of the mu-opioid receptor (MOR) antagonist naloxone (20 mg/kg intraperitoneally [i.p.]). Twenty microgram, i.t., of naloxone also reversed the antinociception (Fig. 6A). These results suggest that GLED exposure likely elicits antinociception through release of endogenous opioids.
Neurons within the RVM are known to project to the spinal or medullary dorsal horns to directly or indirectly enhance or diminish nociceptive traffic.85 We examined the possible contribution of the RVM in the GLED-induced antinociceptive response by microinjection of 2% lidocaine. Rostral ventromedial medulla lidocaine reversed the development of antinociception when the rats were exposed to GLEDs (Fig. 6B).
Although our data, thus far, suggest a role for the endogenous opioid system, it is possible that the exposure conditions may result in stress-induced analgesia that could involve the sympathetic nervous system with engagement of alpha- and beta-adrenergic receptors by norepinephrine or epinephrine.5,10,45,51,74,78 Thus, to elucidate the role of the adrenergic system, several adrenergic receptors antagonists were tested including phenoxybenzamine (1 mg/kg i.p.), a nonselective irreversible alpha-blocker; phentolamine (3 mg/kg i.p.), a nonselective reversible alpha-blocker; and propranolol (10 mg/kg s.c.), a nonselective beta-blocker. All these drugs given immediately after light termination and tested 15 to 20 minutes afterwards failed to prevent or reverse the antinociceptive effect of GLEDs (Fig. 7A). Additionally, rats exposed to GLEDs or ambient light were observed to have normal ambulation and huddling, as well as maintained regular grooming behaviors (data not shown), which is in contrast with diminished grooming observed in stressed rats.38
To address the possibility of the antinociception being the result of anxiety due to overstimulation of the visual system, we performed EPM experiments. A cohort of rats exposed to GLEDs for 8 hours daily for 5 days developed antinociception as before (Fig. 7B), showed no signs of stress/anxiety as there were no differences in closed- or open-arm entries, or in the anxiety index (Fig. 7C, D); the index combines EPM parameters into one unified ratio with values ranging from 0 to 1, with a higher value indicating increased anxiety.34 In fact, rats exposed to GLEDs spent a significantly higher amount of time in the open arms than rats exposed to ambient room light (Fig. 7E), suggesting that GLED exposure was anxiolytic. Collectively, these results show that GLED-induced antinociception is not due to an anxiety-related response in these rats.
If, after exposure to GLEDs, the rats had a reduced motor activity, then this could contribute to the antinociception. To test this possibility, we investigated if the GLED exposure affected motor performance using the rotarod assay. After verification of antinociceptive behaviors induced by exposure to GLEDs for 8 hours daily for 5 days exhibited antinociception, we observed no change in the ability of the rats to stay on a rotating rod (Fig. 8). Thus, repeated GLED exposure does not affect motor performance or sedation.
A total of 430 nonredundant proteins were identified in dorsal horn tissues, of which 43 were found only in the samples from rats with GLED-induced thermal analgesia (Fig. 9E). We observed a higher number of proteins associated with “metabolic process” and “cellular process” categories in the dorsal horn from GLED-exposed rats compared with the dorsal horn from ambient room light-exposed rats (Fig. 9F). The molecular functions associated with these proteins suggest a decreased “transporter activity” and an increased “binding” functions in the dorsal horn from rats with GLED-induced thermal analgesia compared with controls (Fig. 9G). Finally, more proteins were observed to be in “cytoskeleton” and “intracellular organelles,” whereas fewer proteins noted in “membrane,” “plasma membrane,” and “organelle membrane” in the dorsal horn from GLED-exposed rats compared with the dorsal horn from ambient room light-exposed rats (Fig. 9H). Thus, fewer proteins are localized in membranes in the dorsal horn, which is correlated, with fewer proteins implicated in localization processes in DRG.
Having determined that GLEDs are antinociceptive in naive animals, we next asked if this nonpharmacological paradigm could be effective in reversing allodynia and hyperalgesia associated with the SNL model of experimental neuropathic pain. Probing the plantar surface of the hind paw ipsilateral to the side of nerve injury in SNL rats, 7 days postinjury, revealed thermal hyperalgesia (Fig. 10A) and tactile allodynia (Fig. 10B). Exposing SNL-injured rats for 8 hours daily to 4 lux GLED levels resulted in complete reversal of thermal hyperalgesia; the latencies were significantly higher than baseline so as to be antinociceptive (Fig. 10A). Paw withdrawal thresholds were also maximally reversed by a 3-day exposure to GLEDs (Fig. 10B). To address the duration of the GLED effect in SNL rats, we terminated GLED exposure and continued to measure antihyperalgesic and antiallodynic behaviors. After termination of GLEDs, it took 10 days for the thermal latencies (Fig. 10C) and 4 days for mechanical thresholds to return to postsurgical values (Fig. 10D).
Using quantitative RT-PCR, we determined expression levels of mRNAs for various endogenous opioids in spinal cords of naive rats as well as rats with SNL or sham in the presence of GLED exposure. Expression of the following genes was measured: (1) prepronociceptin (PNOC) coding for nocistatin, nociceptin, and orphanin17; (2) pro-opiomelanocortin (POMC) coding for N-terminal peptide of proopiomelanocortin (NPP), melanotropin gamma, corticotropin, melanotropin alpha, lipotropin beta, lipotropin gamma, melanotropin beta, beta-endorphin, and met-enkephalin11; (3) proenkephalin-A (PENK) coding for synenkephalin, met-enkephalin (4 copies), met-enkephalin-arg-gly-leu, met-enkephalin-arg-phe, and leu-enkephalin18; (4) proenkephalin-B (PDYN) coding for alpha-neoendorphin, beta-neoendorphin, and leu-enkephalin (3 copies), big dynorphin, dynorphin A (1-17), dynorphin A (1-13), dynorphin A (1-8), leumorphin, and rimorphin17; and (5) mu-type opioid receptor (OPRM1) coding for prepronociceptin and pro-opiomelanocortin.61 These analyses demonstrate that expression of PENK gene, but not others, is significantly increased after GLED exposure (Fig. 10E), suggesting that the increased enkephalin levels in the spinal cord of GLED-exposed rats could be one contributing factor for their analgesia.
We characterized the antinociceptive and antihyperalgesic effects of GLED phototherapy. In naive rats, the antinociceptive effect of GLEDs involves (1) visual system, (2) mu-opioid receptor pathways and descending pain inhibitory pathways from the RVM, (3) increased spinal cord expression of enkephalins, and (4) alterations in spinal cord and nociceptor proteomes. We were unable to link GLED-mediated antinociception to stress/anxiety. We demonstrate GLED phototherapy's ability to reverse reduced sensory thresholds in a model of neuropathic pain, supporting its use as a possible novel, nonpharmacological approach in managing chronic pain.
A key issue in interpreting photically induced antinociception is delineating the route of entry of light and its possible relationship with pain modulatory circuits. Here, whole-body illumination with GLEDs for 8 hours resulted in antinociception. By contrast, previous studies reported reversal of pain in mice after 30 to 150 seconds of infrared LED exposure directly touching the skin.15,16 The differences in exposure times (seconds vs hours) and “routes of administration” with either direct skin exposure or whole-body illumination could result in engagement of different mechanisms. Additionally, lower-intensity GLEDs was more antinociceptive. These results are consistent with a recent study,63 which reported that low-intensity green light reduced the intensity of migraines by ∼15% compared with lights of other colors and higher intensities.
Blocking GLED access to the eyes prevented antinociception, arguing for an important role by the visual system in the development of antinociception. Our data point to a role for the visual system in the antinociceptive and antiallodynic effects of GLEDs. However, exactly how this occurs is unknown. Electrical stimulation of the optic nerves in rats has been reported to increase blood pressure and heart rate, and to decrease baroreceptor-mediated vagal bradycardia. This effect was largely attenuated by inactivation of the periaqueductal grey (PAG), an anatomical region known to modulate pain,33,54 suggesting mechanistic neural links between the optic nerve and the PAG.13 Light-sensitive melanopsin-containing ganglion cells in the eyes69 project directly to the circadian rhythm controlling suprachiasmatic nucleus31,80 and PAG30; these structures are connected.41 Importantly, the suprachiasmatic nucleus has been linked with pain as inferred from disruption of the circadian rhythm of thermoregulation in models of chronic inflammatory pain in rats75 and increased c-fos levels in rats with cystitis pain.6 Finally, a retrograde labeling of the PAG demonstrated glutamate-like immunoreactivity in several regions of the brain including the occipital cortices,4 further supporting a link between the visual system and pain response. Martenson et al.52 have recently identified a possible circuitry for photic stimulation that included pain-modulating “ON-cells” and “OFF-cells” in the RVM which project to the dorsal horn of the spinal cord where they are postulated to modulate somatosensory processing. An imbalance of these may lead to enhanced or diminished pain with ON-cells facilitating nociception and OFF-cells inhibiting nociception. Our studies support a role for the RVM as its chemical inactivation prevented GLED-induced antinociception.
We demonstrated that GLED-induced antinociception involves opioid receptors. However, whether this occurs through a peripheral or central mechanism of action is at present unknown. Suppression of GLED-induced antinociception with the opioid receptor antagonist naloxone, administered systemically, may support a role of peripheral opioid receptors, which is consistent with previous reports demonstrating that administration of naloxone prevents infrared spectrum therapy–induced antinociception in models of postoperative16 or inflammatory pain.53 However, the ability of naloxone given i.t. to reverse the antinociception effect argues in favor of a central site of action for the GLEDs since this dose and volume would not be expected to have a significant effect if the site of action was in the periphery. It is conceivable that GLEDs may have both central and peripheral effects. Future studies will explore these possibilities.
Although overstimulation of the visual system could cause stress-induced antinociception, our data suggest that GLED-induced antinociception is not linked to stress/anxiety for several reasons. First, pharmacological antagonism of receptors implicated in stress did not affect antinociception. Second, behavioral studies did not link GLED-induced antinociception to anxiety in the EPM experiments. Finally, grooming behaviors of rats with GLED exposures were unaffected, thus implying no link to stress. Future studies will assess neurochemical correlates of stress (eg, glucocorticoids) in GLED antinociception.
Sensory neuronal adaptations, due to possible changes in activities of voltage-gated calcium and/or sodium channels, may help explain the molecular mechanisms underlying GLED-induced antinociception. N-type voltage-gated calcium channels (CaV2.2) are key for antinociception.73 The overall functional competence of neurons for calcium influx, as assessed by their ability to respond to agonists of various receptors using a high-throughput calcium imaging platform,56 was not different between sensory neurons from rats exposed to ambient light or GLEDs (Supplementary Fig. 1, available online at http://links.lww.com/PAIN/A358). However, we observed a decrease in depolarization-induced Ca2+ influx through CaV2.2 in sensory neurons from GLED-exposed rats (Supplementary Fig. 1E, http://links.lww.com/PAIN/A358). No changes were observed in sodium channels (Supplementary Fig. 2, available online at http://links.lww.com/PAIN/A358) ruling out their involvement in neuronal adaptations and GLED-induced analgesia. It is possible that the prolonged antinociceptive effect of GLEDs may, in part, be attributed to long-term changes in CaV2.2 or other calcium channel subtypes. Further studies will investigate the role of calcium and other channels in mediating the long-lasting effect of GLEDs.
Our findings identify the cellular and molecular basis of GLED-mediated antinociception. From a translational perspective, the discovery that GLED exposure is antinociceptive and antiallodynic, opens up routes for the development of a noninvasive therapeutic approach to pain. Consequently, modulating the duration and intensity of GLEDs may prove useful, clinically, for reducing opioid in pain management. Additionally, the long-lasting and nontolerance-inducing effects of GLEDs may improve patient compliance.
The authors have no conflicts of interest to declare.
The authors thank Dr Chris Atcherley for help with determining the absorbance properties of the fabricated lenses and Molly M. Ryan for assistance with analysis of proteomics data.
M. M. Ibrahim and A. Patwardhan are co-first authors. M. M. Ibrahim and R. Khanna contributed equally. F. Porreca and R. Khanna are co-senior authors.
This work was supported, in part, by a Career Development Award from the University of Arizona Health Sciences (to A. Patwardhan), and a Children's Tumor Foundation NF1 Synodos grant (to R. Khanna), and start-up seed funds (to M. M. Ibrahim and R. Khanna). A. Moutal was partially supported by a Young Investigator Award from the Children's Tumor Foundation.
Supplemental Digital Content associated with this article can be found online at http://links.lww.com/PAIN/A358.
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Video content associated with this article can be found online at http://links.lww.com/PAIN/A385
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