Source Paper
Todd W. Vanderah, Luis R. Gardell, Shannon E. Burgess, Mohab Ibrahim, Ahmet Dogrul et al.
Journal of Neuroscience • 2000
The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO), an opioid mu agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion) and a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the mu receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dynorphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine. Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.
Objective: Evaluate dynorphin A(1-17) antiserum effects on tactile allodynia, thermal hyperalgesia, and morphine antinociceptive potency in DAMGO-infused rats to determine if spinal dynorphin mediates abnormal pain and opioid tolerance
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Measure baseline non-noxious and noxious thresholds in rats prior to any infusions
Note: Baseline measurements needed for comparison with treatment groups
“Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds”
Administer DAMGO intrathecally to induce abnormal pain and opioid tolerance
Note: DAMGO-infused rats develop tactile allodynia and thermal hyperalgesia
“Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion)”
Measure tactile allodynia in hindpaws during DAMGO infusion
Note: Tactile allodynia is a sign of abnormal pain induced by DAMGO
“Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws”
Measure thermal hyperalgesia in hindpaws during DAMGO infusion
Note: Thermal hyperalgesia is a sign of abnormal pain induced by DAMGO
“Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion)”
Quantify lumbar dynorphin content in spinal dorsal horn following DAMGO infusion
Note: DAMGO elicits an increase in lumbar dynorphin content
“Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the μ receptor immunoreactivity in the spinal dorsal horn”
Assess μ receptor immunoreactivity in spinal dorsal horn following DAMGO infusion
Note: DAMGO causes a decrease in μ receptor immunoreactivity
“Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the μ receptor immunoreactivity in the spinal dorsal horn”
Evaluate the antinociceptive potency and efficacy of spinal morphine in DAMGO-infused rats
Note: DAMGO-infused rats show decreased antinociceptive potency and efficacy of spinal opioids (tolerance)
“a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury”
Administer dynorphin A(1-17) antiserum intrathecally to block dynorphin effects
Note: Antiserum treatment is applied to DAMGO-infused rats
“Intrathecal administration of dynorphin A(1–17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels”
Measure tactile allodynia following dynorphin antiserum administration
Note: Dynorphin antiserum blocks tactile allodynia induced by DAMGO
“Intrathecal administration of dynorphin A(1–17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels”
Measure thermal hyperalgesia following dynorphin antiserum administration
Note: Dynorphin antiserum reverses thermal hyperalgesia to above baseline levels (antinociception)
“Intrathecal administration of dynorphin A(1–17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception)”
Evaluate the antinociceptive potency and efficacy of spinal morphine following dynorphin antiserum administration
Note: Dynorphin antiserum reestablishes morphine antinociceptive potency and efficacy
“Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine”
Administer control serum intrathecally as a control comparison
Note: Control serum does not affect pain thresholds or morphine response in saline-infused rats
“Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats”
Measure non-noxious and noxious thresholds in saline-infused control rats
Note: Saline-infused rats serve as controls and do not develop abnormal pain
“Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws”
Evaluate intrathecal morphine antinociceptive response in saline-infused rats
Note: Saline-infused rats maintain normal morphine antinociceptive response
“Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats”
Rats infused with DAMGO or saline as control groups