SPINAL DYNORPHIN AND OPIOID TOLERANCE

Project: Research project

Description

One of the most significant health problems in our country is the inadequate treatment of chronic abnormal pains such as those associated with nerve injury or pathology (neuropathic pain). Inextricably linked to such chronic pains are the difficulties associated with the use of opioids for prolonged periods, where tolerance limits effectiveness. An unexplained clinical and experimental paradox is that the use of spinal opioids for chronic pain results not only in analgesic tolerance, but also in the development of abnormal pain (i.e., hyperesthesias including hyperalgesia and allodynia). Opioid tolerance and the post-nerve injury state have been suggested to be (mechanistically similar, at least at the spinal level. Blockade of the NMDA receptor has been shown to both prevent the development of, and reverse established, opioid tolerance as well as many of the behavioral consequences of experimental neuropathic pain. While such studies underscore the importance of the NMDA receptor in these processes, these pharmacological investigations have not identified the underlying endogenous spinal mechanisms which may promote opioid tolerance and the consequences of nerve injury through direct or indirect actions at the NMDA receptor. Like others, we have noted many similarities between the post-nerve injury state and spinal opioid tolerance and have discovered a multisegmental elevation of spinal dynorphin in both conditions. In both situations, blockade of the actions of elevated spinal dynorphin with antiserum to the peptide reestablishes opioid antinociceptive potency and efficacy and blocks abnormal pain. These observations lead us to hypothesize that (a) spinal opioid antinociceptive tolerance and the abnormal pain seen following spinal opioid administration are due, at least in part, to the non-opioid actions of elevated (i.e., pathological) levels of spinal dynorphin, and (b) prevention of dynorphin action, or expression, will reverse or prevent opioid tolerance and spinal opioid associated pain. This hypothesis will be tested by (i) evaluating intrathecal (i.th.) opioid agonist or antagonist- induced regulation of spinal dynorphin, (ii) pharmacological elevation of spinal dynorphin with i.th. infusion of dynorphin or the non-opioid peptide dynorphin(2-17), and (iii) prevention of the actions, or expression of, elevated levels of spinal dynorphin elicited by i.th. opioid infusion using antiserum to the peptide or antisense oligodeoxynucleotides to prodynorphin. It is hypothesized that enhancing spinal dynorphin levels either physiologically, or pharmacologically, will result in features common to opioid tolerance and to peripheral nerve injury (i.e., reduced antinociceptive actions of spinal opioids and abnormal response to sensory input including hyperalgesia and tactile allodynia), while blockade of endogenous dynorphin action or prevention of dynorphin expression will reverse or prevent opioid tolerance and related pain. Such experiments will establish whether the action or expression of dynorphin is critical for the development or maintenance of opioid antinociceptive tolerance and the abnormal pain produced by sustained spinal administration of opioids. The data from these studies will provide new insight on the possibility that dynorphin may be a crucial link in promoting opioid tolerance, reveal the regulation of spinal dynorphin expression by opioids, and provide a mechanistic basis for the paradoxical pain seen following spinal opioids in animals and in humans.
StatusFinished
Effective start/end date9/30/994/30/13

Funding

  • National Institutes of Health: $276,351.00
  • National Institutes of Health: $268,303.00
  • National Institutes of Health: $312,621.00
  • National Institutes of Health: $304,678.00
  • National Institutes of Health: $305,546.00
  • National Institutes of Health
  • National Institutes of Health: $313,410.00
  • National Institutes of Health: $294,366.00
  • National Institutes of Health: $260,486.00

Fingerprint

Opioid Analgesics
Dynorphins
Hyperalgesia
Opiate Alkaloids
Pain
Central Nervous System Sensitization
Wounds and Injuries
Hyperesthesia
Central Nervous System
Essential Drugs
Nervous System Trauma
Peripheral Nervous System
Dinoprostone
N-Methyl-D-Aspartate Receptors
Nervous System
Chronic Pain
Spinal Cord
Up-Regulation
Neuralgia

ASJC

  • Medicine(all)