A detailed review of the role of CNS noradrenaline in pain can be found in html or pdf.

Noradrenaline (NA) is a key neurotransmitter of the endogenous pain inhibitory system. Peripheral nociceptive stimuli activate noradrenergic brainstem projections to the spinal cord, resulting in antinociception and inhibition of spinal nociceptive neurons. Lesion or inhibition of noradrenergic spinal afferents, in contrast, produces a state of acute hyperalgesia and reduced antinociceptive effects of opiates.
These findings have lead to the hypothesis that noradrenergic dysfunction might be a key component of chronic intractable pain disorders. A major caveat to this noradrenergic hypothesis of pain is that most experimental studies on which it is based use acute rather than chronic pain models and therefore do not mimic the major types of pain encountered in humans.

We are currently using several approaches to study the consequences of chronic noradrenaline depletion in nociceptive behavior:

  • Noradrenergic denervation

  • DBH knockout mice: mice missing the gene coding for dopamine beta-hydroxylase (DBH), the enzyme responsible for converting dopamine to NA

The DBH -/- mice also allow us to verify a number of hypotheses on the mechanism of pain in fibromyalgia. Fibromyalgia is common pain disorder that affects approximately 2% of the general population. Fibromyalgia patients have a decreased threshold for pain and decreased response to opiates. There has been a considerable effort through clinical research to find the etiology of this disease, which resulted in the identification of decreased levels of noradrenaline's principal metabolite (3-methoxy-4-hydroxyphenethylene) in fibromyalgia patients.

Research in animal models of decreased endogenous pain inhibition now allow us to test the hypothesis that the pain encountered in fibromyalgia patients is related to the observed decrease in noradrenaline. While we believe that other variables could be involved in the pathogenesis of fibromyalgia, the proposed mouse model will allow us to isolate one variable, the noradrenergic system, and test the impact of its dysfunction on complex pain behaviors and opiate analgesia.

 


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