Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions

Pain. 1995 Sep;62(3):259-274. doi: 10.1016/0304-3959(95)00073-2.


Over the last several years, compelling evidence has accumulated indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. Such neuronal plastic changes may involve activation of central nervous system excitatory amino acid (EAA) receptors, subsequent intracellular cascades including protein kinase C translocation and activation as well as nitric oxide production, leading to the functional modulation of receptor-ion channel complexes. Similar EAA receptor-mediated cellular and intracellular mechanisms have now been implicated in the development of tolerance to the analgesic effects of morphine, and a site of action involved in both hyperalgesia and morphine tolerance is likely to be in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, may be interrelated by common neural substrates that interact at the level of EAA receptor activation and related intracellular events. This view is supported by recent observations showing that thermal hyperalgesia develops when animals are made tolerant to morphine antinociception and that both hyperalgesia and reduction of the antinociceptive effects of morphine occur as a consequence of peripheral nerve injury. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Central Nervous System / physiopathology
  • Drug Resistance
  • Drug Tolerance
  • Humans
  • Hyperalgesia / physiopathology*
  • Morphine / therapeutic use*
  • Receptors, Amino Acid / physiology
  • Receptors, N-Methyl-D-Aspartate / physiology


  • Receptors, Amino Acid
  • Receptors, N-Methyl-D-Aspartate
  • Morphine