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(664)
Abstracts
S17
(664) Oxidative stress and sensitivity to pain and opioids in rats
(666) Anabolic-androgenic steroid effects on pain and opioid analgesia
A Ratka, A Raut; Texas A&M Health Science Center College of Pharmacy, Kingsville, TX Oxidative stress plays an important role in aging and development of neurodegeneration. Aberrant pain associated with oxidative stress-induced neurodegenerative disorders is inadequately managed because the neurodegeneration-related changes in sensitivity to pain and opioids are poorly understood. The knowledge about effects of oxidative stress on the opioid system is very limited. We have demonstrated significant decrease in opioid receptor function in neuronal cell cultures exposed to oxidative stress. The goal of this project was to study the relationship between oxidative damage and sensitivity to pain and opioids in rats. Three age groups (3-6, 9-12, and 21-24 months) of male Fisher 344 rats were tested for pain threshold and responses to three doses of morphine or fentanyl using the hot plate method. Various brain regions were used to measure oxidative stress markers and opioid receptors protein levels. The baseline sensitivity to thermal nociceptive stimulus increased significantly with age. There was a significant agedependent and dose-dependent decrease in the antinociceptive effects of morphine and fentanyl. Levels of oxidative stress markers were the highest in brain regions from the oldest group of rats. There was a significant negative correlation between morphine antinociception and protein oxidation in cortex, striatum, and midbrain (r ⫽ 0.73, 0.87, and 0.77, respectively), and lipid peroxidation in cerebral cortex and striatum (r ⫽ 0.73 and 0.71, respectively). The mu opioid receptor protein level in cerebral cortex was significantly lower in the oldest rats. The results from this research show that (1) at the advanced age, the sensitivity to pain is significantly increased and the antonociceptive effect of opioids significantly decreased, (2) oxidative stress is negatively correlated with the opioid-induced antinocoception, and (3) age-related changes in pain and analgesia may be due to oxidative stress-induced reduction in opioid receptors protein level. Supported by NIH-NIA AG022550.
R Craft, L Sternod, R Wood; Washington State University, Pullman, WA It has been suggested that anabolic-androgenic steroids such as testosterone promote body building in part because they reduce pain sensitivity. The present study was designed to determine whether male rats’ nociceptive and opioid antinociceptive sensitivity changed after chronic exposure to high-dose testosterone. Adult, gonadally intact SpragueDawley male rats were given once-daily injections of testosterone propionate (TP, 5 mg/kg s.c.) or safflower oil vehicle for 28 days. Beginning 3 hr after the vehicle or TP injection on day 28, latency to respond on two tests of acute thermal nociception (hotplate and tail withdrawal) and a test of acute mechanical nociception (paw pressure) was recorded, or behavior on a test of inflammatory nociception (formalin test) was recorded; in the latter group of rats, the development of thermal hyperalgesia and mechanical allodynia was also evaluated periodically for a month after formalin injection, during which daily vehicle or TP injections were continued. Morphine antinociceptive sensitivity was also determined in each test. Preliminary data indicate that chronic TP-treated males gained significantly less weight, had significantly smaller epididymal fat pads and larger seminal vesicles (per kg body weight) than vehicle-treated controls. Hotplate, tail withdrawal and paw pressure latencies did not differ significantly between TP- and vehicle-treated rats. Morphine antinociceptive sensitivity was similar between TP- and vehicle-treated rats on the tests of acute thermal nociception, whereas a subset (approximately 35%) of TP-treated rats were substantially more sensitive than vehicle-treated rats to morphine on the paw pressure test. TP treatment blocked the development of thermal hyperalgesia but enhanced the development of mechanical allodynia during the month following formalin injection. These data suggest that chronic anabolicandrogenic steroid use does not consistently reduce pain or enhance opioid analgesia.
(665) Thermal nociception of NK-1 receptor knockout mice in an operant escape assay
B14 - Pain Pathways
F. Wong; University of Florida Health Science Center, Gainesville, FL Society for Neuroscience abstract
(667) Noradrenergic neurons of the locus coeruleus contribute to the development and maintenance of neuropathic pain J Brightwell, B Taylor; Tulane University Health Sciences Center, New Orleans, LA The locus coeruleus (LC), a primary source of noradrenergic (NE) input to the spinal cord, is usually associated with descending pain inhibition, but recent studies have suggested the LC contributes to pain facilitation. To test hypotheses that the LC contributes to allodynia and hyperalgesia in a rodent model of peripheral neuropathic pain, we examined the effect of reversible inactivation of the LC using a local anesthetic (Expt 1) and noradrenergic lesions of the LC using anti-DBH-saporin (Expt 2). In Expt 1, male rats were implanted with bilateral guide cannulae aimed above the LC. Rats were tested for hypersensitivity to mechanical stimuli prior to both SNI and drug administration. 14 d following transection of the tibial and common peroneal nerves leaving the sural branch intact (SNI), 4% lidocaine or saline was bilaterally injected in the LC followed by tests for mechanical allodynia [using von Frey hairs and a machine mounted probe (Ugo Basile)] cold allodynia (plantar application of acetone), and mechanical hyperalgesia (plantar pin prick). Lidocaine reduced allodynia and hyperalgesia at 15 and 45 min (p’s ⬍ .05); hypersensitivity returned to pre-drug values within 90 min. These results indicate that the LC contributes to the maintenance of neuropathic pain. In Expt 2, antidopamine-beta-hydroxylase-saporin or IgG-saporin (control) was administered intracerebroventricularly, prior to nerve injury. After two wk, SNI surgery was performed, and then behavior was re-assessed at 7, 14, 21, and 28 d. Dopamine-beta-hydroxylase immunohistochemistry confirmed LC lesions in all but one animal, which was removed from the analysis. LC lesions did not change responses at the contralateral paw (p’s ⬎ .05), but reduced allodynia and hyperalgesia at every time point. We conclude that the LC contributes to the development and maintenance of neuropathic pain.
S17
(664) Oxidative stress and sensitivity to pain and opioids in rats
(666) Anabolic-androgenic steroid effects on pain and opioid analgesia
A Ratka, A Raut; Texas A&M Health Science Center College of Pharmacy, Kingsville, TX Oxidative stress plays an important role in aging and development of neurodegeneration. Aberrant pain associated with oxidative stress-induced neurodegenerative disorders is inadequately managed because the neurodegeneration-related changes in sensitivity to pain and opioids are poorly understood. The knowledge about effects of oxidative stress on the opioid system is very limited. We have demonstrated significant decrease in opioid receptor function in neuronal cell cultures exposed to oxidative stress. The goal of this project was to study the relationship between oxidative damage and sensitivity to pain and opioids in rats. Three age groups (3-6, 9-12, and 21-24 months) of male Fisher 344 rats were tested for pain threshold and responses to three doses of morphine or fentanyl using the hot plate method. Various brain regions were used to measure oxidative stress markers and opioid receptors protein levels. The baseline sensitivity to thermal nociceptive stimulus increased significantly with age. There was a significant agedependent and dose-dependent decrease in the antinociceptive effects of morphine and fentanyl. Levels of oxidative stress markers were the highest in brain regions from the oldest group of rats. There was a significant negative correlation between morphine antinociception and protein oxidation in cortex, striatum, and midbrain (r ⫽ 0.73, 0.87, and 0.77, respectively), and lipid peroxidation in cerebral cortex and striatum (r ⫽ 0.73 and 0.71, respectively). The mu opioid receptor protein level in cerebral cortex was significantly lower in the oldest rats. The results from this research show that (1) at the advanced age, the sensitivity to pain is significantly increased and the antonociceptive effect of opioids significantly decreased, (2) oxidative stress is negatively correlated with the opioid-induced antinocoception, and (3) age-related changes in pain and analgesia may be due to oxidative stress-induced reduction in opioid receptors protein level. Supported by NIH-NIA AG022550.
R Craft, L Sternod, R Wood; Washington State University, Pullman, WA It has been suggested that anabolic-androgenic steroids such as testosterone promote body building in part because they reduce pain sensitivity. The present study was designed to determine whether male rats’ nociceptive and opioid antinociceptive sensitivity changed after chronic exposure to high-dose testosterone. Adult, gonadally intact SpragueDawley male rats were given once-daily injections of testosterone propionate (TP, 5 mg/kg s.c.) or safflower oil vehicle for 28 days. Beginning 3 hr after the vehicle or TP injection on day 28, latency to respond on two tests of acute thermal nociception (hotplate and tail withdrawal) and a test of acute mechanical nociception (paw pressure) was recorded, or behavior on a test of inflammatory nociception (formalin test) was recorded; in the latter group of rats, the development of thermal hyperalgesia and mechanical allodynia was also evaluated periodically for a month after formalin injection, during which daily vehicle or TP injections were continued. Morphine antinociceptive sensitivity was also determined in each test. Preliminary data indicate that chronic TP-treated males gained significantly less weight, had significantly smaller epididymal fat pads and larger seminal vesicles (per kg body weight) than vehicle-treated controls. Hotplate, tail withdrawal and paw pressure latencies did not differ significantly between TP- and vehicle-treated rats. Morphine antinociceptive sensitivity was similar between TP- and vehicle-treated rats on the tests of acute thermal nociception, whereas a subset (approximately 35%) of TP-treated rats were substantially more sensitive than vehicle-treated rats to morphine on the paw pressure test. TP treatment blocked the development of thermal hyperalgesia but enhanced the development of mechanical allodynia during the month following formalin injection. These data suggest that chronic anabolicandrogenic steroid use does not consistently reduce pain or enhance opioid analgesia.
(665) Thermal nociception of NK-1 receptor knockout mice in an operant escape assay
B14 - Pain Pathways
F. Wong; University of Florida Health Science Center, Gainesville, FL Society for Neuroscience abstract
(667) Noradrenergic neurons of the locus coeruleus contribute to the development and maintenance of neuropathic pain J Brightwell, B Taylor; Tulane University Health Sciences Center, New Orleans, LA The locus coeruleus (LC), a primary source of noradrenergic (NE) input to the spinal cord, is usually associated with descending pain inhibition, but recent studies have suggested the LC contributes to pain facilitation. To test hypotheses that the LC contributes to allodynia and hyperalgesia in a rodent model of peripheral neuropathic pain, we examined the effect of reversible inactivation of the LC using a local anesthetic (Expt 1) and noradrenergic lesions of the LC using anti-DBH-saporin (Expt 2). In Expt 1, male rats were implanted with bilateral guide cannulae aimed above the LC. Rats were tested for hypersensitivity to mechanical stimuli prior to both SNI and drug administration. 14 d following transection of the tibial and common peroneal nerves leaving the sural branch intact (SNI), 4% lidocaine or saline was bilaterally injected in the LC followed by tests for mechanical allodynia [using von Frey hairs and a machine mounted probe (Ugo Basile)] cold allodynia (plantar application of acetone), and mechanical hyperalgesia (plantar pin prick). Lidocaine reduced allodynia and hyperalgesia at 15 and 45 min (p’s ⬍ .05); hypersensitivity returned to pre-drug values within 90 min. These results indicate that the LC contributes to the maintenance of neuropathic pain. In Expt 2, antidopamine-beta-hydroxylase-saporin or IgG-saporin (control) was administered intracerebroventricularly, prior to nerve injury. After two wk, SNI surgery was performed, and then behavior was re-assessed at 7, 14, 21, and 28 d. Dopamine-beta-hydroxylase immunohistochemistry confirmed LC lesions in all but one animal, which was removed from the analysis. LC lesions did not change responses at the contralateral paw (p’s ⬎ .05), but reduced allodynia and hyperalgesia at every time point. We conclude that the LC contributes to the development and maintenance of neuropathic pain.