Sci. Aging Knowl. Environ., 2 July 2003
Vol. 2003, Issue 26, p. nw93
[DOI: 10.1126/sageke.2003.26.nw93]

NOTEWORTHY ARTICLES

Ouch!

Glycine puts extra hurt into pain neurons

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/26/nw93

Key Words: glutamatergic • glycinergic • dorsal horn

The neurotransmitter glycine normally quenches pain's fire, but a new study suggests that it also stokes the flames. The work illuminates a mechanism that underlies chronic pain and suggests that blocking release of the neurotransmitter might relieve persistent aches.

Pain is the body's damage alarm, but when pain-transmitting nerves keep firing after an injury heals, trouble results. Chronic pain is especially prevalent in the elderly, and it impedes mobility, which can provoke other health problems. Understanding the circuits that relay pain signals could lead to new ways of combating the problem (see "The Burden of Pain on the Shoulders of Aging").

Sensory nerves detect injury in skin or other tissues and connect with neurons in the spinal cord. Glutamate, a neurotransmitter released at those connections--called synapses--excites nerves and passes the sting to the brain. Chronic pain results when too much glutamate stimulates so-called NMDA receptors on the spinal cord neurons. A compound called glycine, released by inhibitory neurons, as well as other signals soothe pain messages. Glycine also binds to NMDA receptors and increases their firing, but no one knows whether animals aggravate pain sensation by changing glycine quantities.

To investigate this question, the researchers isolated rat spinal cords, electrically stimulated their neurons, and measured the resulting currents. Treating the spinal cord with nocistatin--a protein that quashes glycine release--decreased inhibitory and excitatory signals. Next, the team doused the spinal cords with D-serine, which mimics glycine's effect on NMDA receptors, and with nocistatin. This treatment restored the excitatory signal, suggesting that glycine, traditionally thought to quash nerve firing, also incites it. Further experiments revealed that blocking uptake of glycine by other, non-neuronal cells--which remove glycine that has escaped synapses--restored the stimulatory signal in nocistatin-exposed tissue. This finding suggests that excess glycine travels from inhibitory synapses to excitatory ones, where it augments pain.

Next, the researchers injected nocistatin into rats' spinal cords, then shot up their paws with formalin, which causes pain. At low doses, nocistatin caused the rats to suffer less pain--they flinched less often than did untreated animals. At higher doses, however, the compound heightened the pain response. The authors speculate that in small quantities nocistatin inhibits the excitatory signal, whereas in larger quantities it quenches the inhibitory signal. Supporting that notion, injections of D-serine reversed the pain-killing effect of low-dose nocistatin, but not the pain-promotion of large amounts.

The finding suggests that "the [nervous] system is designed to make pain worse," says neurobiologist Allan Basbaum of the University of California, San Francisco. For acute pain, "that could be valuable," he says but it also primes the body for chronic aches. The study suggests a potential strategy for limiting distress. Impairing glycine release with nocistatin might mollify pain without side effects such as motor or learning problems associated with drugs that tie up NMDA receptors directly, says Basbaum. Future experiments should test whether nocistatin eases pain caused by insults other than formalin, he adds. If successful, the work might provide a new way to extinguish the burn of chronic pain.

--R. John Davenport


July 2, 2003
  1. S. Ahmadi et al., Facilitation of spinal NMDA receptor currents by spillover of synaptically released glycine. Science 300, 2094-2097 (2003). [Abstract/Free Full Text]
Citation: R. J. Davenport, Ouch! Sci. SAGE KE 2003, nw93 (2 July 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/26/nw93








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