Skin, muscle, bone and other tissues have thousands of nerve endings within a single millimetre. When stimulated these nerves generate electrical signals [action potentials], which travel at various speeds along (afferent) nerve fibres to the spinal cord and brain. It can take from a few milliseconds [0.001s] to a few seconds [1.0s] for these signals to generate an experience of ‘pain’ or to produce an appropriate physiological and/or behavioural response e.g. a ‘cry’ and / or withdrawal of the affected limb.
Two quantitatively different types of tissue stimulation are important: Non-Noxious and Noxious.
Non-Noxious stimulation is generally used by the animal to make it aware of the state of its body and of its immediate environment e.g. by touch. Such stimuli travel along thick, myelinated, Aß nerve fibres and rarely produce pain unless the fibres are sensitised e.g. by inflammation.
Noxious stimulation is used by the animal to make it aware of stimuli of an intensity that could or actually do damage body tissues.
Noxious stimulation is detected by nociceptors, which are ‘free’ nerve endings of thin, myelinated, (Aδ) and unmyelinated, (C) nerve fibres, in the tissues.
Studies in humans have shown that thin (Aδ) nerve fibres are necessary for pain:
Nerve compression, blocks thick nerve fibres first and leaves pain sensation intact; it may even increase the pain.
Local anaesthetics block thin fibres first and remove the pain sensation.
Electrical stimulation of nerves only provokes pain when thin fibres are recruited.
Signals from non-Noxious stimulation in thick nerve fibres are necessary for the normal quality of pain.
Nociceptors respond to high intensity mechanical (pricking, stretching), high intensity thermal (heat, cold) and intense chemical stimuli (K+, H+, prostaglandins, cytokines). These chemicals may be released as a result of damage to tissues including that produced by failure of the blood supply (ischaemia). Nociceptors are also stimulated and/or sensitised by chemicals released during (inflammatory) responses to infectious, toxic or allergenic agents. The release or action of some of these chemicals can be reduced or stopped by common analgesic and anti-inflammatory treatments (e.g. NSAIDS, Steroids); Opioids, have a more limited effect.
Abnormal pain responses
Pain from stimulation which is not normally painful e.g. pain from light touch or stroking after sunburn.
Increased pain when the same noxious stimulus is repeated. This can occur when thick nerve fibres (A-β) are blocked or damaged. Changes can occur peripherally (Primary hyperalgesia) or centrally (Secondary hyperalgesia).
Occurs after tissue injury, when nociceptors are sensitised by inflammatory mediators such as prostaglandins produced from Arachidonic acid. The process involves a steroid sensitive enzyme (Phospholipase C) and cyclo-oxygenase enzymes (COX-1 and COX-2).
Conversion of arachidonic acid to prostaglandins can be significantly reduced:
COX-1 is inhibited by drugs such as Aspirin
COX-2 is inhibited by drugs such as Celecoxib and Rofecoxib
COX-2 inhibitors generally have fewer unwanted effects.
Nerves from nociceptors use this peptide to activate relay neurons in the spinal cord. It is also released from the peripheral endings of C-nociceptor fibres when signals are sent out to sensory endings instead of travelling to the spinal cord and contributes to local (neurogenic) inflammatory responses as seen in the surrounding inflammatory ‘flare’ produced by a scratch.
Inflammatory responses to tissue damage
Increased blood flow with Redness (rubor)
Warmth from the increased blood flow (calor)
Swelling as fluid leaks out of blood vessels (tumor)
C-nerve fibres can have widespread branching towards their endings. If the endings of some of these branches are stimulated by a noxious stimulus, signals pass along the branches until they reach branching points and then travel out to the endings of the other branches where Substance P is released into the tissue.
Capsaicin (an irritant found in red peppers)
This is a specific activator for a membrane receptor (VR1) found at the endings of C-nerve fibres from nociceptors. The VR1 receptor may be activated by noxious heat (>42ºC) and/or by acids (H+) produced when tissues are short of oxygen (ischaemia).
Animations of the response to non-noxious and noxious stimulation
This series of animations shows a simplified version of how specialised endings of nerves (receptors) may or may not be activated by non-painful (brushing) and painful (crushing) in normal and in damaged, infected and inflamed tissue.
Animation 1: Gentle brushing of normal skin or underlying tissues. Note: This may be a slow page (36 Kb)
Animation 2: Intense crushing of normal tissues by application of a tight rubber ring. Note: This may be a slow page (76 Kb)
Animation 3: Gentle brushing or stroking of inflamed tissues. Note: This may be a slow page (115 Kb)
Animation 4: Intense squeezing/crushing of inflamed tissues by application of a tight rubber ring. Note: This may be a slow page (134 Kb)
- Now follow this link to see how signals
from these nociceptors can be relayed through the spinal cord.
Note: This may be a slow page (412 Kb)