Pain is a double-edged sword: an evolutionarily ancient mechanism that is critical for our survival, it also disables hundreds of millions of people worldwide, at a huge cost to society and the economy.
In a lecture at the annual meeting of the Society for Neuroscience, held in New Orleans this past fall, David Julius of the University of California, San Francisco, described progress in our understanding of the molecular mechanisms of nociception, the process sensory nerve endings use to detect noxious stimuli.
“Nociception is the beginning phase of our experience of pain,” said Julius. “It’s the mechanism whereby the somatosensory system detects stimuli that are capable of causing tissue damage. It’s a warning system which can become chronic and debilitating.”
Nociception is the first system that protects us from bodily harm. It consists largely of small diameter sensory neurons that extend from beneath the skin surface into the spinal cord. These specialized cells, called nociceptors, detect mechanical stimuli, hot and cold temperatures, and irritant chemicals released from damaged cells or present in the environment, and send signals about them to the brain so it can respond.
These mechanisms evolved to save us from potentially life-threatening injuries, but when they go awry, the consequences can be severe. For example, in 2006, researchers identified three Pakistani families, whose members carry mutations in gene that encodes a sodium channel called NaV7.1.
NaV7.1, expressed in sensory neurons, is essential to generating the pain-signaling nervous impulses. People who carry mutations in both copies of the gene have an inactive NaV7.1 channel. This leads to a congenital insensitivity to pain, which is extremely dangerous, since it can make them oblivious to life-threatening injuries.
While researchers knew a lot about how the signals are transmitted, they were not as sure how these cells detect noxious hot and cold temperatures in the first place.
Then, in 1997, Julius and his colleagues reported that they had isolated and cloned the gene encoding a heat-sensitive receptor that is expressed in subsets of primary sensory neurons. This receptor, named Transient Receptor Potential (TRP) channel V1, is activated by temperatures higher than 42°C (107.6°F). It also contains a specialized binding site for capsaicin, a component of chili peppers, which is why chili peppers produce a burning sensation when eaten.
Other members of the TRP channel family eventually were identified, too, all of which act as temperature sensors. TRPV2, is sensitive to, and activated by, temperatures above 52°C; TRPV3 by temps above 33°C; TRPV4, between 27°C and 42°C.
Other members of this protein family are sensitive to colder temperatures: TRPM8 by temps below 27°C, and TRPA1 by those under 17°C (62.6°F). TRPM8 also contains binding sites for menthol (found in peppermints) and eucalyptol, both of which produce a cooling sensation.
“Presumably, plants generate these compounds as a mechanism for deterring predators,” said Julius. “There’s a thin line between pleasure and pain, and we’ve learnt to experience these natural products for their culinary delights, but in the laboratory they’ve turned out to be fantastic tools for gaining insights into the processes of nociception and pain transmission.”
Julius described experiments by his group and others analyzing the temperature preferences of genetically engineered mice missing one or another of the TRP genes. Normally, experimental animals prefer standing on a warm plate to a cold or hot one, but those lacking a TRP gene have no such preferences because they cannot properly distinguish between temperatures.
Mice lacking the TRPM8 gene, for example, spend roughly equal amounts of time on warm and cold plates, whereas those lacking TRPV1 take much longer to pull their paws away from a painfully hot plate than normal animals. But neither of these mutants is completely insensitive to temperature, suggesting that there are other, as yet unidentified, sensors that contribute to detecting noxious hot and cold temperatures.
Changing the threshold for pain
When a person is injured, the activity of primary sensory neurons changes, which can result in their developing hypersensitivity to pain. Having sunburn or a swollen ankle, for example, significantly enhances our sensitivity to both pressure and temperature.
Tissue damage activates nociceptors, which then not only generate a nervous impulse that travels into the spinal cord, but also release peptides such as Substance P and CGRP from their nerve terminals in the skin. This “antidromic” signaling causes the release of an inflammatory soup containing peptides, growth factors, and classical neurotransmitters [See "Neurotransmitters – A Primer"], which together act back on the nociceptors, lowering their threshold for generating nervous impulses and thus driving the cycle of pain hypersensitivity.
TRP channels play an important role in these mechanisms. Research suggests that TRPV1 in particular may be the primary mediator in the process by which the inflammatory soup sensitizes the peripheral nerve endings of nociceptors.
Recent studies suggest that some components of the inflammatory soup, such as protons, the positively charged particles found inside the atomic nucleus, and anandamide, an endogenous cannabinoid synthesized by the brain, modulate TRPV1 activity directly, lowering its sensitivity to heat by binding to specialized sites, altering the structure of the protein.
TRP channels also play a role in allodynia, the process by which stimuli that are normally innocuous are perceived as being painful. If researchers can better understand the mechanisms of TRP channel modulation, they might build new and better treatments to manage such pain.
“Understanding the peripheral organization of the nociceptive pathway and how the pain information is transduced to central synapses are major challenges to the field,” said Julius. “With identification of molecular markers for these different subsets of nociceptive cells, we stand a good chance of being able to make serious progress in this area.”