pain is caused by constant bombardment of the second order neurons in the
Dorsal Horn of the Spinal Cord. This creates several problems, including sprouting
of Wide Dynamic Range (WDR) neurons and induction of glutamate dependent N-methyl-D-aspartate
(NMDA) receptors. This type of glutamate dependent receptor is extremely fast
and appears to be responsible for not only amplifying pain, but causing opioid
tolerance, as well.
pain signals continue to enter the Dorsal Horn and synapse with the nerve
cell bodies located there, WDR neurons can be found in areas of the Dorsal
Horn, where they were not previously located. Specifically they grow into
the areas where pain receiving nerve cell bodies are located. WDR neurons
can experience a broad range of stimulating signals and pass these on to the
brain or spinal cord. Once C-nociceptive fibers are activated and continue
to bombard the nerve cells in the Dorsal Horn over extended periods of time,
Aß touch sensitive fibers begin to fire and this effects nerve cell
bodies in the Dorsal Root Ganglion (DRG) and the Dorsal Horn. Glutamate, an
extremely fast neurotransmitter, is released at the DRG presynaptic membrane
and attaches to non-NMDA receptors in the nerve cells in the Dorsal Horn.
After continued bombardment by C fibers and Aß fibers the Magnesium,
which normally prevents NMDA post synaptic receptors from receiving Glutamate,
is displaced and wind-up begins. Due to ongoing
pain signals reaching and being amplified at the Dorsal horn, the nerve cells
begin to increase the number of NMDA receptors at the post synaptic membrane.
This further increases Windup and exhibits a nasty side effect of causing
increased tolerance to opioids.