Biochemistry of pain

Receptor apparatus and excitation mechanisms

The perception of pain signals is carried out through specialized nerve endings — nociceptors. They are widely represented in various body tissues: skin, skeletal muscles, joint capsules, periosteum, and internal organs.

Nociceptors are capable of responding to three main types of stimuli:

• Mechanical (compression, trauma).
• Thermal (extreme temperatures).
• Chemical (change in pH, appearance of specific molecules).

A special role in the biochemical perception of pain is played by vanilloid receptors. Their excitation occurs under the action of a number of chemical activators: bradykinin, ATP molecules, hydrogen protons (H+), as well as exogenous vanilloids (e.g., the alkaloid capsaicin).

Biochemical shifts and the phenomenon of sensitization

Any tissue damage triggers a cascade of biochemical changes that affect extracellular structures, the basement membrane, endothelium, and vascular smooth muscle cells. This inevitably leads to dysregulation of vascular tone.

The key mechanism for the formation of pain in the focus of inflammation is tissue acidosis. A decrease in pH directly irritates nerve endings.

In addition, the phenomenon of sensitization develops — a sharp increase in receptor sensitivity to external influences. This process is caused by the release of endogenous substances (inflammatory mediators):

• Histamine
• Serotonin
• Prostaglandins
• Bradykinin

In pronounced inflammatory processes, these mediators are able not only to lower the excitation threshold, but also to independently generate a pain impulse.

Pathogenesis of pain using osteoarthritis (OA) as an example

Pain syndrome in osteoarthritis has a complex nature, since a healthy articular cartilage itself is aneural (devoid of nerves) and avascular.

Sources of pain during joint degradation:

1. Changes in cartilage: pain occurs only when blood vessels begin to grow into the affected areas of cartilage tissue, and along with them — sensitive nerve fibers.
2. Changes in subchondral bone: pain impulse generation is provoked by the development of osteosclerosis, osteophyte formation, microfractures, local osteitis, and increased intramedullary (intraosseous) pressure.

According to its character, pain in OA is divided into nociceptive (caused by structural and biochemical shifts in the bone, synovium, muscles, and periarticular tissues), as well as neuropathic and/or nociplastic. It is important to remember that pain perception is always subjective and modulated by genetic, psychological, social, and demographic factors.

Visceral pain and associated syndromes

Pain syndrome can be a leading sign of internal organ damage. For example, in acute viral hepatitis in children, a pronounced abdominal pain syndrome develops. It is characterized by pain in the epigastric and umbilical regions, as well as tenderness in the projection of the gallbladder (Murphy's point / Kehr's sign).

Biochemical and inflammatory changes in the liver are accompanied by a number of systemic reactions:

• Intoxication syndrome: acute onset, fever, chills, myalgia, progressive weakness.
• Dyspeptic syndrome: nausea, anorexia, vomiting, loose stools.
• Asthenovegetative syndrome: general weakness, fatigue, sleep disturbance.
• Polylymphadenopathy syndrome: systemic enlargement of lymph nodes.

Class and exam questions

What else to study on this topic

• The role of vanilloid receptors and ATP molecules in pain perception.
• Mechanisms of vascular tone dysregulation during biochemical shifts.
• Differential diagnosis of nociceptive, neuropathic, and nociplastic pain.
• The influence of genetic and psychosocial factors on the subjective perception of pain.
• Pathogenesis of increased intramedullary pressure and osteosclerosis in osteoarthritis.
• Biochemical markers of intoxication and dyspeptic syndromes in liver lesions.

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.