Optochemical genetics to turn pain off, sight on

Ashley N. Paddock, ashley.paddock@photonics.com

Optogenetic tools that use light to control neurons could lead to highly targeted pain relief and might even restore sight to the blind, say biologists at the University of California, Berkeley (UCB) and Ludwig Maximilian University (LMU) of Munich.

UCB's Richard H. Kramer and Dirk Trauner of LMU sought to develop a molecule that can block the activity of pain-sensing neurons in a controlled and reversible way. Local anesthetics suppress pain by blocking the activity of pain-sensing neurons, but most act nonselectively on all nervous system cells.

Optical control of pain-sensing neurons. QAQ selectively enters pain-sensing neurons and silences their activity (top, green light). Illumination with violet light (bottom) quickly restores signal conduction. Courtesy of Alexandre Mourot.

The researchers synthesized the molecule quaternary ammonium-azobenzene-quaternary ammonium, or QAQ, which is structurally similar to a lidocaine derivate they had used in the past. While the two molecules use the same mechanism to selectively enter pain-sensing neurons, QAQ features an important difference: Its activity can be controlled by light. Specifically, ultraviolet light turns it on, and green light turns it off.

They demonstrated the capacity of QAQ as a light-sensitive analgesic in the retina of living rats in a paper published online Feb. 19 in Nature Methods (doi: 10.1038/ NMETH.1897).

Unblinded by the light

Another collaborative venture between chemists at the two universities successfully converted an intrinsically "blind" receptor molecule into a photoreceptor, a feat that one day might allow use of such synthetic photoreceptors to restore sight to those with certain types of blindness, said Trauner, a professor of chemical biology and genetics at LMU and one of the project's leaders.

Communication between nerve cells relies on specialized receptor molecules on the surfaces of the neurons to relay signals back and forth. But the investigators found that they could use molecular genetic techniques to attach what amounts to a light-controlled chemical "switch" to a receptor that normally is activated by the endogenous neurotransmitter acetylcholine.

These molecular machines transmit nerve impulses by converting an incoming chemical signal into an electrical response, which is then propagated along the length of the nerve fiber. Binding acetylcholine to the external surface of the receptor acts as a switch — a research method known as "optochemical genetics."

As with the light-sensitive pain relief applied to rat eyes, the synthetic photoreceptors can be switched on using UV light and switched off using green light.

The project was carried out under the auspices of the Collaborative Research Center on Formation and Function of Neuronal Circuits in Sensory Systems, which is funded by the German Research Foundation.

Trauner received a European Research Council grant in 2010 for a project that is also based on a "photopharmacological" approach. The long-term goal of this ongoing research is to find ways of compensating for the loss of dedicated photoreceptors in the eye, the most common cause of blindness. He is working to develop hybrid photoreceptors.

"The basic idea, which has in principle been shown to work in animal models, is to confer light sensitivity on surviving neurons in the eye that do not normally respond to light," Trauner said.

The work was published online Jan. 8 in Nature Chemistry (doi: 10.1038/NCHEM. 1234).