Two of the most commonly used terms in the pain research and medicine world are hyperalgesia and allodynia. The word hyperalgesia means an increased response to a painful stimulus. The word allodynia means a painful response to a normally innocuous stimulus.
Here is an example of hyperalgesia: if your arm was pricked by a pin and you said that it gave you 3 out of 10 pain this would be your baseline response. If an experimenter then gave you some injection (let’s say capsaicin — the pungent ingredient in hot peppers) and then 30 minutes later pricked you with the pin again and you reported 6 out of 10 pain this would be hyperalgesia. For hyperalgesia to occur it is important for the stimulus to be painful to begin with. Remember that hyperalgesia is always an increased pain response to a noxious stimulus.
Here is an example of allodynia: if an experimenter brushed your arm with a cotton bud (like a q-tip) you would almost certainly say that the stimulus was not painful — 0 out of 10. If the experimenter then injected your arm with capsaicin and brushed your arm again 30 minutes later you would likely report that it was painful — let’s say 4 out of 10 pain. This is an allodynia, a painful response to an innocuous stimulus. In order for allodynia to occur the stimulus MUST NOT normally be painful.
So now that we know what these word mean it is time to understand why they occur. First of all, there are a variety of pain conditions where one of these conditions is present but not the other. This is because they are mechanistically different. Sensory neurons that innervate your skin and visceral organs roughly fall into three categories: 1) Rapidly adapting mechanotransducers. These are neurons that respond to touch and non-noxious temperatures, they conduct action potentials (or nerve impulses) rapidly and they make a subset of nerve fibers called A-beta fibers. 2) Proprioceptive neurons. These are neurons that tell you about the position of your muscles, they also conduct action potentials rapidly and they comprise the other subset of nerve fibers called A-beta fibers. 3) Nociceptors. These are pain sensing neurons that respond to painful mechanical or thermal stimulation. They also comprise the class of neurons that respond to chemical irritants (like capsaicin). They are lightly or unmyelinated so they conduct action potentials more slowly than A-beta fibers. They also generally fail to adapt to stimulation so they keep firing until the stimulus is removed or escaped from. These neurons fall into two classes, A-delta (the lightly myelinated ones) or C-fibers (the unmyelinated ones). Neurons of all of these classes send a projection into the dorsal horn of the spinal cord where processing of incoming sensory information first occurs (all you neuroscientists forget about A-betas and the dorsal funiculus, they send a projection to lamina III as well where they synapse on interneurons that send projections back into lamina I/II). This processing center in the dorsal horn of the spinal cord is commonly referred to as “the gate” — a term that was spawned from Melzack and Wall’s famous gate theory of pain control. These signals are then sent onto the brain where sensory perception occurs.
The physiological basis of hyperalgesia and allodynia lies in the distinction between the type of fibers that carry the information evoked by the stimulus in the periphery.
Remember that hyperalgesia always involves a noxious stimulus, it just becomes more painful when hyperalgesia is present. The noxious stimulus activates nociceptors in the periphery that then send the signal onto the spinal cord. Hyperalgesia involves an amplification of the pain signal. This amplification can occur in the periphery (e.g. the nociceptor is sensitized by an irritant, by inflammation or by disease) or in the spinal cord (via an amplification of synaptic transmission between the nociceptor and the dorsal horn neuron that sends the signal to the brain) or in both locations. There are some cases where the amplification is thought to occur in higher brain centers as well. This can happen, for instance, after a stroke. We will talk more about mechanisms of amplification and there promise for therapy in a later post.
Allodynia involves a noxious response to an innocuous stimulus (think putting on a shirt with a severe sunburn). Because the stimulus is innocuous, and generally of the mechanical variety, it could be carried by rapidly adapting mechanotransducers or by sensitized nociceptors. These two possibilities have been the focus of decades of research both in humans and in animals. While there is evidence that the information can be carried by sensitized nociceptors this is quite controversial. Our current understanding of allodynia suggests that nociceptor mechanical thresholds do not change enough for them to carry information concerning light touch, brush or gentle vibration in conditions where allodynia is present. Rather, it appears that rapidly adapting mechanotransducers (or A-beta fibers) continue to be the sole carrier of this information in conditions where allodynia is present. The change that causes allodynia occurs in the spinal cord. Through an unknown process, A-beta-fibers gain access to the nociceptive channel. In normal conditions A-beta-fibers cannot activate dorsal horn neurons that respond only to painful stimulation. In allodynic conditons, these same neurons begin to receive input from A-beta-fibers. This allows for A-beta-mediated information to gain access to the nociceptive channel thereby stimulating the perception of pain in the brain. Because allodynia can occur rapidly it is unlikely that this change is mediated by a physical change in the connections of neurons in the dorsal horn (although this may occur over the longer term). Rather, it appears that there are changes in the neurochemistry of the “gate” such that inhibitory neurotransmission can switch to excitation. Because GABA (the primary inhibitory neurotransmitter in the brain) can switch from inhibition to excitation (or vice-a-versa) in certain conditions (like epilepsy and during early neural development) much current focus is on the role of GABA in allodynia.
In chronic pain conditions both allodynia and hyperalgesia are major problems for these patients. Small movements, putting on or wearing clothes and even sitting or laying down can become very painful due to allodynia. Patients are often able to avoid hyperalgesia but hyperalgesia can be so intense that it causes an aversion to even the most mundane of activities for fear of triggering an attack. In the chronic pain patient both of these conditions are extremely difficult to treat. Allodynia is notoriously resistant to opiate and NSAID analgesics especially in conditions involving a peripheral neuropathy caused by injury or disease (like diabetes).
To wrap up:
Hyperalgesia is an increased response to a noxious stimulus. It is caused by sensitization of peripheral nociceptors and/or by sensitization of central neurons that carry nociceptive information.
Allodynia is a painful response to a non-painful stimuli. It is caused by a change in the dorsal horn of the spinal cord that gives non-noxious sensory information access to the nociceptive system causing innocuous stimuli to be perceived as painful.