1) Painful Stimuli is sensed in skin or muscle tissue, by a sensory pain receptor.
2) The signal is transmitted from the affected area in the periphery, traveling up the spinal cord through sensory fibers (delta A and C fibers) which are located mainly in the superficial layers of the dorsal (posterior) area of the spinal cord and intersecting at the substantia gelatinosa and the nucleus proprius, to synapse pathways of the spinothalamic tract.
As described in a previous entry (see 'pain perception' entry) two key 'pain' neurotransmitters are glutamate and substance P. - both work synaptically (between nerve endings) to carry signals from one nerve (A and C pain fibers) to the next (spinothalamic tract).
3) At this point, once relayed from A and C fibers to the next pathway, signals travel up the spinothalamic tract to connect with the thalamus.
4) Signals continue from the spinothalamic tract and the thalumus, to areas such as the cingulate cortex, somatosensory cortex, the periaqueductal grey area, and various limbic structures.
Certain medications such as NMDA receptor antagonists work by blocking (or antagonizing) glutamate receptors; heavily within the spinal cord dorsal area. These agents include ketamine, PCP, and dextromethorphan. Other medications which work differently but have additional activity as NMDA antagonists are the opioid agonists methadone and levorphanol. Anti epileptic medications such as gabapentin and pregabalin work by inhibiting the release of glutamate from peripheral nerve endings in the spinal cord.
Inbound pain signalling to the brain is additionally affected (inhibited or enhanced) by descending signals originating from the brain (PAG). SSRI or Tricyclic antidepressant medications including amitriptyline and duloxetine may reduce pain by increasing the inhibitory affect of this descending pathway on ascending pain stimuli.
The amount of pain felt by an individual is not experienced on a linear level with the degree of pain stimuli; i.e what may be experienced as little to no pain for one person, may be experienced as severe or debilitating pain for another.
Chronic periods of pain from the periphery (peripheral nervous system) such as that experienced with arthritis, spinal stenosis, musculoskeletal injury and rheumatic degenerative conditions is likely to lead to increased central sensitivity - the descending pain modulatory system adapts to long term pain. To put simply, during long periods of pain transmission up the spinal cord, it is able to memorize and perpetuate this state, through positive feedback, leading to excessive pain-flow, even in the absence of any actual injury or illness.
A large part of pain sensitivity is modulated by the transmission of glutamate and substance P, at synaptic sites throughout the spinal cord. There are multiple points between the sensory receptor (origin of the signal) and the brain (interpretation of the signal) that a signal may be amplified by increased neuronal excitability and excess release of glutamate/substance P.
In addition, sensory (pain) receptors have their own individual threshhold; where any stimuli exceeding this threshhold will trigger the receptor to send a pain signal - Some individuals will have a lower threshhold for these receptors than others.
Those with fibromyalgia for instance, typically experience spinal (or central) sensitization through both of these phenomena - increased neuronal excitability and low threshhold for pain stimuli.
The latter often manifests in an increased tenderness to a given pressure; which is the origin of the 'tender point test' which serves as a diagnostic tool for the condition of fibromyalgia.