Last updated: Tue, Mar 11, 2025
Earlier in this work (see Injury, Inflammation, and Healing), the inflammatory cascade that follows tissue injury was described as a local phenomenon. Tissue damage leads to release of pro-inflammatory chemicals which in turn leads to more chemical release and to increased sensitivity of nociceptors or to direct triggering of signals in nociceptive neurons. An important class of chemical in this signaling system is the cytokines.
All cells are capable of releasing cytokines when subjected to stressors that endanger the integrity of tissues. Cytokines are released not only in response to mechanical, thermal, or chemical cell damage, but also in response to bacterial or viral infection. When tissue is exposed to the outer shells of bacteria or viruses it releases cytokines, which results in sickness behavior or the sickness response. The components of the sickness response include
You may recognize a number of these as symptoms of your own chronic pain condition. This is not a coincidence.
This set of responses can be seen as a protective response, since each of its components tends to promote the organism's recovery by conserving energy. (The immune system burns a lot of energy to fight infections.) The sickness response is orchestrated by an ensemble of the body's regulatory systems, including the autonomic and central nervous systems, the endocrine system, and the immune system. The role of the CNS in this system is not merely to adjust the body's physiology in response to stress, but also to adjust behavior to promote recovery. It is suspected that when these systems become disregulated, the effects may contribute to what we have been discussing as "pain" phenomena: chronic inflammatory pain, neuropathic pain, generalized pain syndromes, and illness symtpoms.1
Cytokines (and possibly other chemical markers of inflammation) are detected by the central nervous system. This happens through two pathways. The first is by binding to specific receptors on sensory neurons. This pathway results in rapid neural transmission into the spinal cord and thence upward. Receptors in the abdominal viscera (stomach and intestines) that communicate through the vagus nerve of the autonomic nervous system are believed to be active in this function, and somatic sensory nerves may also have this capability. The second pathway is transport through the blood, past the barrier that separates the central nervous system from the rest of the body, and into the cerebrospinal fluid that bathes the brain and spinal cord. Once in the cerebrospinal fluid, the cytokines circulate into brain areas such as the hypothalamus that contain receptors for them. This second path of course is much slower than the first.
Microglia and astrocytes of the central nervous system become activated upon the receipt of the inflammatory message and begin to secrete additional excitatory chemicals, thereby exciting the central nervous system. This activates the pathways involved in generating sickness behaviors.2
The development of sickness behavior in response to the presence of pathogens differs in important ways from the development of hyperalgesia in response to tissue damage. For example, it appears to use a pathway through the vagus nerve that isn't available for damage outside of the abdomen. This line of research is just beginning to be followed. It is known, however, that the sickness process and nociceptive hyperalgesia have these commonalities:
This connection between pain and sickness systems also suggests a view of pain reactions as having two phases. The first phase is concerned with responding to the immediate circumstances of injury and may include escaping from or avoiding further injury. The first phase is characterized by activation of energy, analgesia, and alertness. The second phase begins after a delay of hours or days and is concerned with promoting recuperation for perhaps an open-ended period of time using both physiologic and behavioral mechanisms.3
Illness is the doctor to whom we pay most heed: to kindness, to knowledge we make promises only: pain we obey.4