The Pathophysiology of Pain

Kevin L. Zacharoff, MD, FACPE, FACIP, FAAP, Director of Medical Affairs, PainEDU


In the past, it was thought that a sensory input, such as a pinprick, would simply cause a pain “signal” to be sent directly to the brain via a single nerve. Although still not completely understood today, the science of pain reveals a much more complex process, and theories are still continuing to evolve. New receptors, pathways, and hypotheses are being investigated every day. In addition to identifying new pathways, genetic variations have been discovered at the receptor level that can further complicate treatment.  It is important to have a basic knowledge of the physiology to treat pain effectively.

The following is a brief review of the four basic concepts that are important to begin to understand the physiology of pain. The concepts are transduction, transmission, modulation, and perception.

Transduction is the process by which afferent nerve endings participate in translating noxious stimuli (e.g., a pinprick) into nociceptive impulses.


Noxious stimulation is first carried by the faster A-delta fibers, and then by the slower C fibers. “Silent nociceptors,” also involved in transduction, are afferent nerves that do not respond to external stimulation unless inflammatory mediators are present. The peripheral nervous system contains primary sensory afferent neurons that have an important role in pain signaling. The axons of these afferents diverge from the cell body in the dorsal root ganglion near the spinal cord and send a short fiber centrally into the cord and a long fiber down the peripheral nerve into the tissues. Their receptors detect mechanical, thermal, proprioceptive, and chemical stimuli.

Transmission is the process by which impulses are sent to the dorsal horn of the spinal cord, and then along the sensory tracts to the brain.

The primary afferent neurons are active senders and receivers of chemical and electrical signals. Their axons terminate in the dorsal horn of the spinal cord, where they have connections with many spinal neurons. In turn, spinal neurons have input from many primary afferents. These spinal neurons project axons to the contralateral thalamus, which in turn projects to the somatosensory pathway, frontal cortex, and other areas. The somatosensory cortex is thought to be involved in the sensory aspects of pain, such as the intensity and quality of pain, whereas the frontal cortex and limbic system are thought to be involved with the emotional responses to it.

Modulation is the process of dampening or amplifying these pain-related neural signals. Modulation takes place primarily in the dorsal horn of the spinal cord, but also elsewhere, with input from ascending and descending pathways.

The gate control theory is a popular model of pain modulation proposed by Melzack and Wall in 1965, later revised by Melzack and Casey in 1968. These investigators proposed the existence of an endogenous ability to reduce or increase the degree of perceived pain through modulation of incoming impulses at a gate located in the dorsal horn of the spinal cord. The gate acts on signals from the ascending and descending systems and weighs all of the inputs. The integration of these inputs from sensory neurons, the segmental spinal cord level, and the brain, determines whether the gate will be opened or closed, either increasing or decreasing the intensity of the ascending pain signal.   The role of psychological variables in the perception of pain, including motivation to escape pain, and the role of thoughts, emotions, and stress reactions in increasing or decreasing painful sensations, is evident in the gate control theory. An example is when patients report more pain at night, when they are isolated and less distracted from their pain than they might be during the day. The proposed gate can be opened or closed by pharmacologic manipulation, transduction, transmission and modulation, and psychological intervention.

Perception refers to the subjective experience of pain that results from the interaction of transduction, transmission, modulation, and the psychological aspects of the individual.


As research continues furthering the understanding of this complex process, there is hope that pain treatments can be developed to target specific parts of the physiologic pathway and become more effective than current treatments.