General anaesthetics activate a heat-sensitive protein found in pain pathways and may exacerbate post-operative pain, according to a new study published online yesterday in the Proceedings of the National Academy of Sciences.
Anaesthetics suppress activity of the central nervous system, leading to a reversible loss of consciousness. The suppression of neural activity is thought to occur by the actions of the anaesthetic on the GABA receptor, which is normally activated by gamma-aminobutyric acid, the principal inhibitory neurotransmitter in the brain.
Every year, more than 100 million patients are given a general anaesthetic prior to undergoing surgery, and a significant proportion of them experience a burning sensation at the injection site, or in the lungs and airways following inhalation of a gaseous anaesthetic. However, the exact mechanism underlying this was unknown.
The new study, led by Gerard Ahern, an associate professor of pharmacology at Georgetown University in Washington DC, elucidates the molecular mechanism by which anaesthetics induce the burning sensation. It shows that some anaesthetics activate a heat-sensitive ion channel called TRPA1, and further, suggests that they may sensitize sensory neurons in the pain pathway, and so exacerbate the painful inflammation that occurs following surgery.
The transient receptor potential (TRP) channels are a family of membrane proteins that are expressed in the primary sensory neurons which detect noxious stimuli and transmit them to the central nervous system. Most of the TRP channels identified to date have a special role in thermosensation. TRPV1, the first family member to be identified, is activated by temperatures of 43 degrees Celcius and above. It also contains a binding site for capsaicin, the active ingredient in chili peppers, and TRPV1 activation by this compound is what induces the burning sensation experienced when eating spicy food. On the other hand, TRPM8 is a cold receptor: it is activated by low temperatures, and contains bindings sites for cooling compounds such as menthol.
Ahern and his colleagues first examined the effects of anaesthetic compounds on cultured human embryonic kidney cells expressing TRPA1, TRPV1, or TRPM8. The cells were impaled with microelectrodes, and the gaseous anaesthetic isoflurane was introduced into the growth medium. As a result, inward currents were generated in cells expressing TRPA1, but not in those expressing TRPV1 or TRPM8.
Next, the researchers sought to determine whether anaesthetics have the same effect on TRPA1 channels in sensory neurons. Using calcium imaging, they found that the anaesthetics desflurane and propofol induced elevations in calcium ion concentration, which is indicative of neuronal activity. That this was due to activation of TRPA1 was confirmed by the observation that the anaesthetics did not evoke increases in calcium ion concentration in cells isolated from mutant mice in which the TRPA1 gene has been deleted.
A series of behaviourla tests were then performed. When propofol was applied to the nasal epithelium of mice, they repeatedly wiped their noses in the sawdust bedding of their cages. This characteristic pain-related behaviour was also observed in mice lacking the gene encoding TRPV1, but not in mice lacking the TRPA1 gene. Finally, isoflurane was found to increase the inflammation induced by injection of allyl isothiocyanate, the compound which gives mustard its pungent taste, into the animals’ ears.
Significantly, these effects were only observed with the so-called volatile anaesthetics. These findings therefore have important implications, as the volatile aneasthetics are the most commonly used ones.
Matta, J.A. et al. (2008). General anesthetics activate a nociceptive ion channel to enhance pain and inflammation. Proc. Nat. Acad. Sci. 105 (25), 8784-8789. DOI: 10.1073/pnas.0711038105