Pain: From genes and proteins to cells in the living organism
The earliest theories of pain arguably came from ancient Greece. Philosophers such as Aristotle and Plato proposed that pain is “a matter of the heart.” Just prior to the scientific renaissance, scholars even believed that pain existed outside of the body as a trial sent from God. The age of experimental sciences ushered in a new framework for understanding pain, with scholars shedding the belief that pain is a spiritual and mystical experience, and embracing instead the concept that pain is a biological phenomenon arising from the brain and not the heart. Descartes in 1664 famously proposed that the body was similar to a machine, and pain was a signal passed down along nerve fibers until it reached the brain.
Following on from Descartes's theory, our knowledge of pain biology continued to evolve. It is now known that modality‐specific sensory receptors (nociceptors) and pain fibers (primary afferents) functionally connect the periphery to the central nervous system (CNS). Primary afferents carrying sensory information enter the spinal cord dorsal horn, where pain signals are processed within a complex network of circuits and then relayed to the brain. In 1965, Melzack and Wall introduced the “gate control” theory (Melzack and Wall, 1996), which proposed that both thin (pain) and large‐diameter (touch, pressure, vibration) nerve fibers carry information from the site of injury to the spinal dorsal horn. The large afferent fibers can excite inhibitory interneurons, which, in turn, inhibit the activity of thin fibers; it is through this mechanism that nonpainful input can suppress pain by closing the “gates” to painful input, halting the transmission of pain signals to the rest of the CNS. To date, the spinal dorsal horn is regarded as the “hub” of pain processing, where the first pain synapse is found, and also the final relay for descending signals from the brain. Spinal mechanisms of pain remain an active area of research. In this issue, Bonin and colleagues (Perez‐Sanchez et al., 2017) further expand our knowledge by presenting novel findings on the mechanisms underlying GABA‐mediated tonic inhibition in the dorsal horn, and its role in suppressing nociceptive signals.
Importantly, the “gate control” theory proved that the CNS has an intrinsic network (i.e., pain pathways), which not only receive but can also modulate pain signals. Following this important discovery, numerous studies were dedicated to the better understanding of the pain pathways. From the late 60s onwards it was discovered that in mammals, exogenous electrical or pharmacological stimulation of several brain sites elicits profound analgesia.