Fundamentals+of+Pain+Mechanisms

=**Fundamentals of Pain Mechanisms**=


 * 1. Describe pathways for //normal pain// feelings, and distinguish these pathways from pathways for nonpainful feelings.**

In normal pain, exposure of free nerve endings to noxious stimuli causes activation of pain pathways to the cortex through the anterolateral or trigeminothalamic pathways. Patterns of cortical activity produced by activation of these pathways cause normal pain sensations. In the generation of pain, the activation of small diameter C and A-delta peripheral neurons and central pain pathways always have a cause and effect association to real noxious stimuli in the body.

In contract, normal non-painful feelings are triggered by non-noxious, low intensity stimuli. These stimuli activate large diameter A-fiber peripheral sensory axons and cortical activity produced by activation of the dorsal column/medial lemniscal or trigeminal lemniscal pathways. Pain pathways are mostly, but not completely, different from those which generate non-painful sensations (some convergence/divergence across pathways).


 * 2. Distinguish how //normal pain// differs from //pathological pain//.**

Normal pain is triggered by noxious stimuli and signals imminent or actually body damage. This elicits a response to minimize further damage and promote healing. It is unpleasant but adaptive and an important part in maintaining health and normal body function.

Pathological pain can be triggered by noxious stimuli (producing abnormal pain), non-noxious stimuli, or can occur spontaneously without stimuli. It is usually not related to actually body damage and is maladaptive to healing. Its effects can be crippling and unremitting, leading to depression, substance abuse, suicide, etc. It can occur in patients suffering a wide range of injuries (inflammation, peripheral nerve problems, limb amputation, demyelination, etc.).


 * 3. Describe how //pathological pain// results from abnormal activation of pain pathways which, in turn, is caused by //sensitization// mechanisms that operate at peripheral and/or central levels.**

Painful stimuli must travel along pain pathways and reach the appropriate pain areas of the brain in order to generate the sensation of pain. Therefore, if abnormal pain is felt in response to painful stimulus, non-painful stimulus, or no stimulus at all, then that pain must result from abnormal activation of pain pathways that have become sensitized to stimuli that they shouldn’t be sensitive to. Sensitization of pain fibers can occur peripherally or centrally in the nervous system and pain pathway levels above the level of the trauma is subject to pain sensitization.


 * 4. Describe mechanisms that cause //peripheral sensitization//.**

Peripheral sensitization mechanisms change peripheral sensory neurons, leading to abnormal activation or synaptic release in response to inappropriate stimuli. Sensitization can be caused by alteration in pain fiber properties such as raising the receptor potential or lowering the threshold potential such that previously sub-threshold depolarizations can evoke an abnormal action potential.

Sensitization can also occur from abnormal, injury-induced expression of receptors that allow pain fiber activation to previously unresponsive synaptic inputs. For example, post-injury pain fibers can abnormally express NE receptors which can get activated by NE release from post-ganglionic sympathetic neurons to cause abnormal reaction in a spympathetically maintained pain condition.

Lastly, sensitization can occur due to phenotypic changes in non-pain fibers that alter its synaptic transmission to mimic that of pain fibers. For example, increased nerve growth factor can activate TrkA receptors that result in intracellular signaling and changes in gene expression. These changes can result in a non-pain fiber to begin substance P synthesis and release, mimicking the chemical transmission properties normally produced by pain fibers.


 * 5. Describe mechanism that cause //central sensitization//.**

Central sensitization mechanisms act on central somatosensory neurons. Central pathways for pain are largely, but not completely different from non-pain pathways and some spinothalamic neurons in the spinal cord receive both pain and non-pain inputs. Normally, these neurons are dominated by pain inputs but, following injury, the activities of these neurons can be increased by phosphorylation of both excitatory and inhibitory receptors. For example, high levels of pain inputs caused by injury can cause release of substance P and glutamate on the spinothalamic neuron. This causes intracellular signally that activates PKC to phosphorylate NMDA receptors for excitation, and GABA receptors for inihibition, resulting in hypersensitivity and disinhibition and, ultimately, abnormal activation of central pain pathways to painful and non-painful stimuli.

Also, sensitization can occur from sprouting new non-pain fiber terminations in the spinal cord. After peripheral nerve damage, pain fibers and their axon terminations in the superficial layers of the dorsal horn can degenerate, leading to freed synaptic space. Non-pain axons can sprout to fill up the vacated space and form synapses with spinothalamic and other neurons that normally receive inputs form the now degenerated pain inputs. This sprouting causes central pain pathways to become abnormally activated by pain inputs.
 * 6. Discuss emerging thinking about brain structures that produce different dimensions of pain.**

Feelings of pain are produced by patterns of brain activity including the primary and secondary somatosensory cortex, posterior parietal area 7, and insular, anterior cingulate, and frontal cortical areas. Other areas appear to be involved also, such as the frontal lobe orbital gyrus cortex, anterior cingulate cortex gyrus, nucleus accumbens, and the sublenticular extended amygdala. fMRI studies are leading to ideas that these structures contribute to different dimensions of pain as different cortical areas contribute to pain feelings.

For example, some structures appear to be involved in producing sensory/discriminative dimensions of pain such as the production of a sensory feeling that is recognized as pain. Other structures are involved in producing affective/emotional aspects of pain such as aversive or distressing emotional weighting to the sensory feeling. These aversion circuit structures likely get somatosensory input from cortical areas and from the anteriolateral tract neurons with synaptic relays in the pons, thalamus, and hypothalamus.

An emerging view is that pain feelings have both sensory and affective/emotional dimensions that appear to be produced by structures in the somatosensory and aversion circuits.


 * 7. Discuss thinking behind mechanism-based pain treatment strategies.**

An emerging mechanism-based pain strategy is being developed which focuses on identify and controlling the specific peripheral and/or central sensitization mechanisms at work in an individual patient. The thinking here is that particular sensitization mechanisms, instead of the disease or injury, are the actual cause of pain symptoms, and it is the mechanisms specific to each particular patient that must be treated.

That is, rather than thinking that a particular disease/injury causes pain symptoms by the same mechanism in most patients, we are thinking that a particular disease/injury causes pain symptoms by different mechanisms in different patients. It would also follow that individual patients with different disease/injury may have pain symptoms caused by the same mechanisms.


 * 8. Point out how pharmacological fMRI (phMRI) is being developed as part of mechanism-based pain treatment.**

Research is being done to understand how analgesic agents affect activity in specific brain structures using fMRI imaging of brain responses to painful stimuli combined with analgesic treatment. This technique is called pharmacological fMRI or phMRI. The ability to analgesics to block activity in specific pain structures may prove useful for blocking pathological pain in individuals with sensitization involving particular structures and types of receptors.