The stimuli that activate pain receptors vary from one tissue to another. The adequate stimulus for skin is one that has the potential to injure tissue, that is, pricking, cutting, crushing, burning, and freezing. These stimuli are ineffective when applied to the stomach and intestine, where pain is produced by an engorged or inflamed mucosa, distention or spasm of smooth muscle, and traction on the mesenteric attachment. In skeletal muscle, pain is caused by ischemia (the basis of intermittent claudication), necrosis, hemorrhage, injection of irritating substances, and by injuries of connective tissue sheaths. Prolonged contraction of skeletal muscle evokes an aching type of pain. Ischemia is also the most important cause of pain in cardiac muscle. Joints are insensitive to pricking, cutting, and cautery, but pain can be produced in the synovial membrane by inflammation and by exposure to hypertonic saline. The stretching and tearing of ligaments around a joint can evoke severe pain. Injuries to the periosteum give rise to pain but probably not to other sensations. Blood vessels are a source of pain when pierced by a needle or involved in an inflammatory process. Distention of arteries or veins, as occurs with thrombotic or embolic occlusion, may be sources of pain; other mechanisms, operative mainly in headache, relate to traction on arteries or inflammation of the meningeal structures by which they are supported. Pain from intraneural lesions probably arises from the sheaths of the nerves. Nerve root(s) and sensory ganglia, when compressed (e.g., by a ruptured disc), give rise to pain. The special subject of headache and its origins is taken up in Chap. 9.
With damage to tissue, there is a release of proteolytic enzymes, which act locally on tissue proteins to liberate substances that excite peripheral nociceptors. These pain-producing substances—which include histamine, prostaglandins, serotonin, and similar polypeptides, as well as potassium ions—elicit pain when they are injected intraarterially or intradermally. Other pain-producing substances such as kinins are released from sensory nerve endings or are carried there by the circulation. Local vascular permeability is also increased by these substances.
In addition, direct stimulation of nociceptors releases polypeptide mediators that enhance pain perception. The best studied of these is substance P, which is released from the nerve endings of C fibers in the skin during peripheral nerve stimulation. It causes erythema by dilating cutaneous vessels and edema by releasing histamine from mast cells; it also acts as a chemoattractant for leukocytes. This reaction, called neurogenic inflammation by White and Helme, is mediated by antidromic action potentials from the small nerve cells in the spinal ganglia and is the basis of the axon reflex of Lewis; the reflex is abolished in peripheral nerve diseases and can be studied electrophysiologically as an aid to clinical localization. The final pathway of activation of sensory nerves consists of opening of the various channels that are expressed on the surface of sensory endings and axons, as detailed in an earlier section.
Perception of Pain