Wind-up 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.

As 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.