Attacking Pain At Its Source: New Perspectives on Opioids

Christoph Stein, Michael Schäfer, Halina Machelska


Nat Med. 2003;9(8) 

In This Article

Tolerance at Peripheral Opioid Receptors

An important question is whether tolerance -- a loss of analgesic efficacy after recurring application of agonists -- also develops at peripheral opioid receptors. Peripheral tolerance has been observed in animal models using repeated opioid pretreatment in the absence of persistent inflammation[45,46,47,48]. However, because the number, affinity and coupling efficacy of opioid receptors are enhanced under inflammatory conditions, these studies do not permit conclusions regarding tolerance in pathological situations. In other models, peripheral opioid analgesia is resistant to the development of tolerance[49,50], and clinical studies suggest a lack of cross-tolerance between peripheral exogenous and endogenous opioids in synovial inflammation[14]. Clearly, more investigations will be needed to define the differences in peripheral opioid receptor function between noninjured neurons, nerve damage and persistent inflammation, and to elucidate underlying mechanisms such as changes in receptor affinity, phosphorylation, G-protein coupling and internalization[51]. From the clinician's viewpoint, the induction of tolerance by opioid pretreatment in the absence of painful tissue injury is not illustrative because patients usually do not consume opioids when they are not in pain (except in the case of opioid abuse).


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