Pathogenesis of Postoperative Oral Surgical Pain: Neuropharmacology of Postoperative Pain

In: Anesthesia

1 Oct 2009

A surgical procedure activates the inflammatory process, which is a complex series of biochemical and cellular events involving a variety of inflammatory mediators and algogenic substances. These have vascular and neural effects. The vascular effects are vasodilatation and an increased vascular permeability causing edema/ swelling. The neural effects involve either activating or sensitizing nociceptors and thus relate to pain. Sensitized nociceptors have spontaneous activity, a decreased threshold, and prolonged responses to suprathreshold stimuli. Some of these mediators are listed in the Table. Hyperalgesia due to sensitization of the afferent nerves is an important factor in the continued sensation of pain after tissue damage. This is in part due to the sustained actions of inflammatory mediators, which were thought to interact in the development of a local positive feedback cycle, and is also the result of plasticity changes in the CNS. The continued synthesis or release of these inflammatory mediators contributes to the prolonged duration of inflammatory pain in oral surgery. There are at least 3 sources of algogenic substances: the damaged cells themselves, secondary to plasma extravasation and lymphocyte migration, or the nociceptor itself.

Potassium and Adenosine Triphosphate.

Damage of tissue cells produces leakage of intracellular contents. Algogenic substances that act immediately in response to tissue injury should be immediately available for rapid release. This requires that the substance be at low external concentrations relative to the internal concentrations of a damaged cell. Furthermore, the substance must have targets on the nerve endings of sufficient density to increase action potential firing. Potassium and adenosine triphosphate (ATP) are the most common agents implicated in the immediate response to tissue damage and pain. Cialis Jelly

Probably the most common substance implicated in the

Table 1. Effect of Inflammatory Mediators on Nociceptors and Pain

Mediator*

Effect on Nociceptors

Pain Effect

Potassium

Activate

+ +
ATP

Activate

+ +
Serotonin

Activate

+ +
Bradykinin

Activate

+ + +
Histamine

Activate

+
Prostaglandins

Sensitize

Leukotrienes

Sensitize

Substance P

Sensitize

CGRP

Sensitize

±
* ATP indicates adenosine triphosphate; CGRP, calcitonin gene-related peptide.

immediate response to tissue damage is potassium. Within the cytosol, potassium is between 100 and 150 mM, whereas plasma concentration is 5 mM. Elevated extracellular potassium caused by its release from cytosol depolarizes neurons by changing the potassium electrochemical driving force for current through potassium channels open at the resting potential. Because potassium channels provide the major resting permeability in all sensory neurons, an increase in potassium will excite all neurons as well as nociceptors. Regardless of its nonselective actions, when potassium is injected into the skin, it causes pain. However, it is unknown whether tissue injury can increase extracellular potassium to the concentrations necessary to elicit pain. At least 100 mM is needed to produce even moderate pain when injected into human skin. As a direct test of the potassium hypothesis, human erythrocyte lysates were applied to a skin blister. As expected, the lysates caused pain, but the pain was greater than that produced by an equivalent amount of potassium. This was an indication that potassium was not the only substance in the erthrocyte lysates that can cause pain.

It was identified that ATP within the erythrocyte lysates also produced pain. ATP was shown to open nonspecific cation channels (P2X receptors) on sensory neurons, thus forming a direct connection between ATP release during tissue damage and excitation of sensory neurons. The work of several laboratories showed that >90% of sensory neurons express P2X receptors. cheap female viagra

Other algogenic substances must be synthesized or cells that contain them must be recruited before they can accumulate or be released at sites of tissue injury. For example, bradykinin is made from circulating plasma kininogen, and serotonin is released by activated platelets and mast cells.
Bradykinin and Serotonin. Bradykinin and serotonin are 2 endogenous substances released after tissue injury that are capable of evoking pain when applied to a blister base preparation even at very low concentrations. Bradykinin is synthesized in plasma whenever blood vessels are damaged because it is a by-product of the cascade triggered by activation of the coagulation system. The enzyme prekallikrein is converted to kalli-krien, which then acts on the bradykinin precursor kininogen, resulting in the release of bradykinin into the tissues. Bradykinin has a wide range of proinflammatory actions: it is a potent activator of nociceptors, increases vascular permeability, promotes vasodilatation, and induces chemotaxis of leucocytes. Bradykinin is present in inflammatory exudates and produces pain in man when given intradermally, intra-arterially, or intraperi-toneally. Serotonin can be released from activated platelets and from mast cells and is found in high concentrations in inflammatory exudates. Serotonin is able to activate nociceptors and potentiate the effect of other inflammatory mediators such as bradykinin.

Prostaglandins, Leukotrienes, Prostacyclin.
Prostaglandins, leukotrienes, and thromboxanes, collectively known as eicosanoids, are an important group of algogenic substances that promote inflammation. They are metabolized from arachidonic acid from damaged cell walls. The events following tissue damage involve breakdown of the phospholipids of the cell wall to arachidonic acid mediated by the enzyme phospholipase A2. Arachidonic acid is further converted to prostaglandins, prostacyclins, and thromboxanes by the enzyme cyclo-oxygenase (COX) and to leukotrienes and hydro-peroxy acids derivatives by lipooxygenase. There are 2 forms of the COX enzyme. COX-1 is the constitutive form and is associated with the physiological protective role of prostaglandins. COX-2 is the inducible form and is associated mainly with inflammation and pain.
Evidence clearly indicates that stable prostaglandins of the E series are involved in the hyperalgesia seen in acute inflammation. PGE2 is the predominant eicosa-noid in such inflammatory conditions, acting synergis-tically with other mediators to produce inflammatory pain. PGE2 has no direct pain-producing activity, but it does sensitize receptors on afferent nerve endings to the actions of bradykinin and histamine. Bradykinin in turn stimulates the release of prostaglandins. The two are therefore mutually potentiating.
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Many other COX products have been detected in inflammatory lesions, but usually they are present at only a fraction of the concentration of PGE2. Prostacyclin is the most important of these in terms of inflammatory signs and may even be present in concentrations comparable with that of PGE2. It has been proposed that prostacyclin is a more potent vasodilator than PGE2 by several orders of magnitude. More recently, Vane and Botting have suggested that their potency is similar. Nevertheless, prostacyclin is a more potent hyperalgesic agent in both rats and dogs. In both these animal models the hyperalgesia produced by prostacyclin is immediate and of short duration, disappearing in less than 1 hour. That produced by PGE2 is slow in onset and of long duration and lasts more than 3 hours. Leu-kotriene B4 is a potent chemotactic factor for polymorphs, which in turn lowers the firing threshold of pain fibers and thus stimulates nociceptors directly. Leukotrienes produce hyperalgesia in animal and human models. The hyperalgesia produced by leokotriene B4 is blocked not by COX inhibitors but by depletion of polymorphonuclear leucocytes. This may suggest that leukocytes contribute to nociceptor activation, but this is yet to be substantiated.

Substance P and CGRP. In addition to the chemical mediators that are released from damaged cells or synthesized in the region of damage, the nociceptors themselves also can release substances that enhance nociception. Both the primary afferent neuron and the sympathetic postganglionic neuron contribute to the inflammatory reaction. The synthesis and release of neuropeptides from these nerves is known as neurogenic inflammation, and their effects include vasodilatation, increased vascular permeability, hyperalgesia, and histamine release from mast cells. The neuropeptides that have been described best are substance P and CGRP, which are synthesized in the body of the nerve cell of the A-delta and C-fibers, both bipolar neurons with the cell body situated in the spinal ganglion of the dorsal root. These neuropeptides are highly concentrated in peripheral tissue such as dental pulp and periapical tissue. These neuropeptides may modulate inflammation by altering the release of histamine and prostaglandin PGE2. The role of these peripheral nerve terminals of unmyelinated afferents in disease has been supported by experiments with capsaicin, which, when given neo-natally, destroys primary afferents. For example, in the disease model of experimental arthritis in rats, capsaicin significantly attenuated the inflammatory response. Interestingly, neurogenic inflammation can be influenced by nicotine, and these effects may explain the aggravated inflammatory disease in people who smoke.
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However, most of these studies merely document the ability of mediators and neuropeptides, usually administered at supraphysiological doses, to stimulate processes related to nociception. Recently, Hargreaves and his research team conducted a breakthrough study. A microdialysis technique was developed that permits collection of inflammatory mediators in conscious dental surgical patients, who can report pain scores simultaneously. These clinical studies used the microdialysis probes to collect tissue levels of immuno-reactive bradykinin, prostaglandin PGE2, leukotriene B4, substance P, and other inflammatory mediators. It indicates that all the aforementioned mediators are detectable in tissue dialysates collected from the extraction site of conscious patients after surgical removal of third molars. Data for the time of peak levels and peak concentrations of the mediators were determined. Pharmacological studies have evaluated the effects of NSAIDs and steroid treatment on tissue levels of inflammatory mediators in this model. As compared with placebo treatment, administration of NSAIDs and steriod significantly reduces the tissue levels of these mediators. Hence, these provide an excellent model of a biochemically based approach for
• identifying the inflammatory mediators released after surgery;
• determining the pharmacological regulation;
• evaluating their interactions and contributions to the development of pain and inflammation.


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