Pain receptors are found on free nerve endings located in many tissues throughout the body. This includes skin, muscles, joints, connective tissues, and internal organs. Pain receptors are activated in response to a painful stimulus, usually involving tissue damage. Once activated, pain receptors release chemicals called neurotransmitters that send information about the painful stimulus along nerves to the spinal cord and the brain. This entire process of pain transmission is called nociception, and the pain receptors found in tissues are called nociceptors.

The substances that are released from damaged tissues and activate nociceptors are called second messengers. Important second messengers include bradykinin, prostaglandins, histamine, serotonin, leukotrienes, and potassium. Some of these second messengers are inhibited by pain medications. If a drug inhibits the release of second messengers, then the pain receptors will not be activated, the pain impulse will not reach the brain, and the person will not perceive pain from the damaged tissue.

The peripheral nerve fibers that contain pain receptors are afferent nerves. This means that they send nerve impulses towards the brain and spinal cord. There are two main types of afferent nociceptors in the tissues: A-delta and C-sensory fibers.

The A-delta fibers are myelinated nerves. Myelinated nerves transmit pain impulses very quickly. Pain receptors on A-delta fibers are activated in response to sharp, well-localized pain that requires an immediate reaction. This type of painful stimulus is sometimes referred to as somatic pain, and it usually involves damage to skin or muscle.

In contrast, the C-sensory pain fibers have receptors that are activated in response to dull, aching, poorly localized pain stimuli. These pain fibers are unmyelinated, and therefore nerve impulses are transmitted more slowly. C-sensory nerve fibers respond to so-called visceral pain, which is caused by damage to or impingement on internal organs.

Once second messengers activate pain receptors and the painful stimulus is transmitted along afferent nerves, it must go through the dorsal horn of the spinal cord. This is called the relay station for pain signals and is where the painful stimuli are transmitted to different parts of the brain. Some pain impulses are transmitted directly to the thalamus and brain stem for a quick response. Others are sent to the frontal cortex of the brain for further processing. It is in the frontal cortex that the conscious realization of pain takes place.

The final step in the pain transmission process is a response from the brain to tell the body how to react. These instructions are carried as impulses along efferent nerves, away from the brain. During pain transmission, many substances may be released in the brain and spinal cord that either increase or decrease the perception of the painful stimulus. These are called neurochemical mediators, and include endorphins, which are natural analgesics, as well as serotonin and norepinephrine, which enhance the perception of pain. As with second messengers, many of these neurochemical mediators are targets for pain medications.