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    558—Pain Models: Physiology

    Tuesday, November 12, 2013, 8:00 am - 12:00 noon

    558.05: Bidirectional virally-mediated optogenetic control of pain

    Location: Halls B-H

    Bioengineering, Stanford Univ., Stanford, CA

    Abstract Body: Optogenetic control of primary nociceptors could potentially have great translational and basic research value. Here, we demonstrate bidirectional optogenetic control over pain perception in non-transgenic, virally injected, freely moving mice, through non-invasive illumination of the mouse environment. We use injection of wild-type mice with adeno-associated virus to express opsins in unmyelinated nociceptors. We show that blue light illumination of the feet of mice injected with AAV6-ChR2 (channelrhodopsin-2) is aversive, and appears to result in characteristic pain-like behavior. Interestingly, we also find that low intensities of blue light that are insufficient to induce outward signs of pain can still induce place aversion, and sensitize mice to mechanical and thermal stimuli. We demonstrate that the same viral system can be used to deliver halorhodopsin (NpHR) to unmyelinated nociceptors, and show that yellow light illumination can significantly raise mechanical and thermal withdrawal thresholds in these mice.

    Lay Language Summary: Using light to induce and inhibit acute pain and to treat symptoms of neuropathic pain.
    In this study, we demonstrate the capability to induce and inhibit acute pain through non-invasive illumination of a mouse paw. We also demonstrate that this ability to inhibit pain can be used to reverse sensitivity to heat and mechanical force caused by a model of neuropathic pain.
    Previous research presented by others at SfN 2012 demonstrated optical inductionof acute pain, through the creation and use of a transgenic mouse line. Here, we induce pain with a similar light delivery strategy, but target pain neurons through viral gene delivery. In addition to inducing pain, we then show how such an approach may have clinical utility by inhibiting acute pain, and finally show that it can also be used to optically inhibit chronic neuropathic pain.
    To achieve our results, we used a technique called optogenetics, which has been widely used to study and treat many neural disorders. We introduced light-sensitive ion channels/pumps (opsins) specifically into nociceptive (pain-transducing) neurons, through an injection of adeno-associated virus (AAV) into the sciatic nerve. We chose to use these viruses as they are currently being tested for use in other applications in clinical trials, and therefore have translational relevance. This injection resulted in selective expression of channelrhodopsin-2 (an ion channel that activates neurons, and is sensitive to blue light), or halorhodopsin (a pump that inhibits neurons, and is sensitive to yellow light). These two opsins were trafficked down into the feet of the injected mice, reaching free nerve endings that are immediately superficial. As a result, light shone on the paw of these injected mice either activated or inhibited pain-transducing neurons.
    We showed that mice injected with the activating ion channel now felt pain when lit with blue light. They escaped from blue light, showing classical signs of pain, and avoided relatively dimly blue-lit areas, even when they showed no obvious signs of pain in those areas. Interestingly, dim levels of blue light also made these mice more sensitive to standard measures of heat and mechanical sensitivity. Mice injected with the inhibiting ion channel, on the other hand, were less sensitive to heat and mechanical force when illuminated with yellow light. We induced neuropathic pain in some of these mice, using a commonly used, clinically relevant, model of nerve injury. This injury made these mice very sensitive to mechanical force and heat. However, when we illuminated these injured mice with yellow light, their sensitivity returned to pre-injury levels.
    These techniques are likely to be used by many other scientists who study acute and chronic pain, and can also be readily combined with commonly used genetic techniques to improve our understanding of the mechanisms behind pain. They also serve as a proof-of-concept for a potential therapy for intractable chronic pain.