Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure

Michael H. Ossipov, Josephine Lai, Tamara King, Todd W Vanderah, Frank Porreca

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

The opioid analgesics, commonly exemplified by morphine, represent the best option for the treatment of severe pain and for the management of chronic pain states, of both malignant and nonmalignant origin. It is well recognized that the prolonged use of opioids is associated with a requirement for ever-increasing doses in order to maintain pain relief at an acceptable and consistent level. This phenomenon is termed analgesic tolerance. While the concept that tolerance can develop as a result of cellular adaptations to the presence of the opioid has been proposed, it is now becoming abundantly clear that tolerance may also be related to a state of hyperalgesia that results from exposure to the opioid itself. Patients who receive long-term opioid therapy sometimes develop unexpected, abnormal pain. Similar paradoxical opioid-induced pain has been confirmed in a number of animal studies, even during the period of continuous opioid delivery. A number of recent studies have demonstrated that such pain may be secondary to neuroplastic changes that occur in the brain and spinal cord. One such change may be the activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM) elicited in part by increased activity of cholecystokinin (CCK) in the RVM. A cascade of pronociceptive events may follow, such as opioid-induced upregulation of spinal dynorphin levels that promotes enhanced input from primary afferent nociceptors. This mechanism appears to depend on intact descending pathways from the RVM, since interrupting this pathway abolishes enhanced abnormal pain. Furthermore, extended opioid exposure also can elicit increased calcitonin gene related peptide (CGRP) and substance P expression in the dorsal root ganglia. It is probable that increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance because the same manipulations that block abnormal pain also block antinociceptive tolerance. Taken together, such studies show that opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin, and enhanced, evoked release of excitatory transmitters from primary afferents. These adaptive changes in response to sustained exposure to opioids indicate the need for the evaluation of the clinical consequences of long-term opioid administration. Additionally, these findings suggest a need for novel chemistry involving design of agents that may counteract opiate-induced neuroplastic adaptations resulting in pain relief without analgesic tolerance.

Original languageEnglish (US)
Pages (from-to)319-324
Number of pages6
JournalBiopolymers - Peptide Science Section
Volume80
Issue number2-3
DOIs
StatePublished - 2005

Fingerprint

Morphine
Opioid Analgesics
Pain
Dynorphins
Transmitters
Brain
Animals
Analgesics
Chemical activation
Opiate Alkaloids
Up-Regulation
Nociceptors
Calcitonin Gene-Related Peptide
Cholecystokinin
Hyperalgesia
Spinal Ganglia
Pain Management
Substance P
Chronic Pain
Spinal Cord

Keywords

  • Dynorphin
  • Facilitation
  • Pain
  • Sensitization
  • Tolerance

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics

Cite this

Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. / Ossipov, Michael H.; Lai, Josephine; King, Tamara; Vanderah, Todd W; Porreca, Frank.

In: Biopolymers - Peptide Science Section, Vol. 80, No. 2-3, 2005, p. 319-324.

Research output: Contribution to journalArticle

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