- Email: [email protected]
Opioid action
28
Abstracts
(675) Anti-hyperalgesic effects of delta opioid receptor agonists in a model of neuropathic pain
(677) Role of central mu opioid receptors in opioid- induced itch in primates
S. Holdridge; Queen’s University, Kingston, ON Pharmacological evidence supports the involvement of the Delta opioid receptor in antinociception. However, its role in the treatment of neuropathic (NP) pain remains largely unknown. In the present study, we examined the role of delta opioid receptors in an animal model of peripheral nerve injury (PNI). Rats (225-250 g) underwent chronic constriction of the sciatic nerve in accordance with the Mosconi/Kruger model. A cold water test was employed to assess cold hyperalgesia prior to and at various intervals following peripheral nerve injury. Neuropathic rats developed cold hyperalgesia as early as two days following surgery and this sensitivity persisted for the two week testing period. Sham animals did not respond in the testing paradigm employed. The effects of a selective delta opioid receptor agonist were assessed on day 14 following PNI. Intrathecal administration of [D-Ala2]-Deltorphin II (30ug), produced a significant increase in the latency to respond to the noxious cold compared to pre-drug values. Western blotting experiments on dorsal spinal cord segments of day 14 NP rats revealed significantly higher total delta opioid receptor protein levels ipsilateral to nerve injury compared to the contralateral side. These data suggest that delta opioid receptor agonists are a potential therapeutic target for drug development in treating neuropathic pain.
M. Ko, H. Lee; University of Michigan Medical School, Department of Pharmacology, Ann Arbor, MI Pruritus (itch sensation) is one of side effects associated with opioid analgesics. The aim of this study was to elucidate the role of opioid receptor types and the site of action in opioid-induced itch in monkeys. Scratching responses after administration of various drugs were counted by observers blinded to conditions. Systemic administration of mu opioid receptor (MOR) agonists (morphine, fentanyl, alfentanil, and remifentanil) evoked scratching dose- and time-dependently. However, a kappa opioid agonist (U-50488H) and a delta opioid agonist (SNC80) did not increase scratching. Intrathecal (i.t.) administration of a peptidic MOR agonist (DAMGO, 0.00032-0.01 mg) potently evoked scratching. However, i.v. administration of DAMGO (0.01-1 mg/kg) did not increase scratching. This large potency difference between i.t. and i.v. routes was also observed with morphine-induced scratching (i.t., 0.0032-0.032 mg; i.v., 0.1-3.2 mg/kg). In addition, systemic administration of an opioid receptor antagonist, naltrexone (0.0032-0.1 mg/kg), dose-dependently attenuated i.v. fentanyl (0.018 mg/kg)- or morphine (1 mg/kg)-induced scratching. However, quaternary naltrexone (0.0032-0.32 mg/kg) did not block either i.v.. fentanyl- or morphine-induced scratching. Moreover, systemic administration of naltrexone (0.0032-0.032 mg/kg) dose-dependently attenuated i.t. morphine (0.032 mg)-induced scratching. In contrast, an antihistamine, diphenhydramine (0.1-10 mg/kg), did not attenuate i.t. morphine-induced scratching. Taken together, these data suggest that MOR, not other opioid receptor types or histamine, mediates scratching evoked by opioid analgesics. More important, this study provides in vivo pharmacological evidence that activation of central MOR plays an important role in opioid-induced itch in primates (Supported by USPHS Grant DA13685).
(676) Enhanced axonal transport of mu and delta opioid receptors in a model of neuropathic pain
B14 - Pain Pathways
N. Kabli, S. Holdridge, C. Cahill; Queen’s University, Kingston, ON Previous studies have demonstrated that ligation of the sciatic nerve increases beta-endorphin binding sites both distal and proximal to the site of nerve injury. Other studies have demonstrated an increase in mu-opioid receptor (MOR) expression levels proximal to the site of nerve constriction in a model of neuropathic pain (Ann Neurol. 53:366, 2003). In the current study, we investigate axonal transport of MOR and deltaopioid receptors (DOR) to the site of nerve injury in a model of neuropathic pain induced by chronic constriction of the sciatic nerve. Immunocytochemical and immunoblotting techniques were utilized to quantify and localize opioid receptors in the dorsal root ganglia (DRG) and sciatic nerve. MOR protein levels were significantly elevated in DRG and sciatic nerve ipsilateral to the peripheral nerve injury compared to the contralateral side. A significant increase in DOR protein was observed in the sciatic nerve ipsilateral to the injury. Overall the results suggest increased MOR and DOR protein synthesis and enhanced axonal transport ipsilateral to the site of injury, in a model of neuropathic pain. Taken together, these findings indicate that peripherally-acting opioid analgesics may have therapeutic potential in the treatment of neuropathic pain.
(678) Comparison of monkey laminae I and V STT cells with human pain sensation A. Craig ; Barrow Neurological Institute, Phoenix, AZ The aim of this study was to compare the responses of monkey laminae I and V STT cells to repeated brief-contact heat pain and the thermal grill illusion of pain with human psychophysics. Single L5-S1 STT units are antidromically identified and characterized in barbiturate-anesthetized macaques. Repeated brief-contact (0.7 s) heat stimuli are applied at 48, 51, 54C and 5, 3, 2 s ISIs. Reset is tested by omitting 1-2 stimuli in a longer series. The thermal grill is applied with a series of parallel 2mm bars at 40/20C. All HPC lamina I STT cells tested showed augmentation, reset, and grill responses corresponding to human sensation. In contrast, NS lamina I and WDR lamina V STT cells showed little or no augmentation, reset, or grill responses. These observations support the concept that HPC lamina I STT cells have a unique role as a virtual labeled line for second pain (Craig, Ann Rev Neurosci 26:1-30, 2003). Dysfunction of HPC cells could be important for neuropathic pain.
Abstracts
(675) Anti-hyperalgesic effects of delta opioid receptor agonists in a model of neuropathic pain
(677) Role of central mu opioid receptors in opioid- induced itch in primates
S. Holdridge; Queen’s University, Kingston, ON Pharmacological evidence supports the involvement of the Delta opioid receptor in antinociception. However, its role in the treatment of neuropathic (NP) pain remains largely unknown. In the present study, we examined the role of delta opioid receptors in an animal model of peripheral nerve injury (PNI). Rats (225-250 g) underwent chronic constriction of the sciatic nerve in accordance with the Mosconi/Kruger model. A cold water test was employed to assess cold hyperalgesia prior to and at various intervals following peripheral nerve injury. Neuropathic rats developed cold hyperalgesia as early as two days following surgery and this sensitivity persisted for the two week testing period. Sham animals did not respond in the testing paradigm employed. The effects of a selective delta opioid receptor agonist were assessed on day 14 following PNI. Intrathecal administration of [D-Ala2]-Deltorphin II (30ug), produced a significant increase in the latency to respond to the noxious cold compared to pre-drug values. Western blotting experiments on dorsal spinal cord segments of day 14 NP rats revealed significantly higher total delta opioid receptor protein levels ipsilateral to nerve injury compared to the contralateral side. These data suggest that delta opioid receptor agonists are a potential therapeutic target for drug development in treating neuropathic pain.
M. Ko, H. Lee; University of Michigan Medical School, Department of Pharmacology, Ann Arbor, MI Pruritus (itch sensation) is one of side effects associated with opioid analgesics. The aim of this study was to elucidate the role of opioid receptor types and the site of action in opioid-induced itch in monkeys. Scratching responses after administration of various drugs were counted by observers blinded to conditions. Systemic administration of mu opioid receptor (MOR) agonists (morphine, fentanyl, alfentanil, and remifentanil) evoked scratching dose- and time-dependently. However, a kappa opioid agonist (U-50488H) and a delta opioid agonist (SNC80) did not increase scratching. Intrathecal (i.t.) administration of a peptidic MOR agonist (DAMGO, 0.00032-0.01 mg) potently evoked scratching. However, i.v. administration of DAMGO (0.01-1 mg/kg) did not increase scratching. This large potency difference between i.t. and i.v. routes was also observed with morphine-induced scratching (i.t., 0.0032-0.032 mg; i.v., 0.1-3.2 mg/kg). In addition, systemic administration of an opioid receptor antagonist, naltrexone (0.0032-0.1 mg/kg), dose-dependently attenuated i.v. fentanyl (0.018 mg/kg)- or morphine (1 mg/kg)-induced scratching. However, quaternary naltrexone (0.0032-0.32 mg/kg) did not block either i.v.. fentanyl- or morphine-induced scratching. Moreover, systemic administration of naltrexone (0.0032-0.032 mg/kg) dose-dependently attenuated i.t. morphine (0.032 mg)-induced scratching. In contrast, an antihistamine, diphenhydramine (0.1-10 mg/kg), did not attenuate i.t. morphine-induced scratching. Taken together, these data suggest that MOR, not other opioid receptor types or histamine, mediates scratching evoked by opioid analgesics. More important, this study provides in vivo pharmacological evidence that activation of central MOR plays an important role in opioid-induced itch in primates (Supported by USPHS Grant DA13685).
(676) Enhanced axonal transport of mu and delta opioid receptors in a model of neuropathic pain
B14 - Pain Pathways
N. Kabli, S. Holdridge, C. Cahill; Queen’s University, Kingston, ON Previous studies have demonstrated that ligation of the sciatic nerve increases beta-endorphin binding sites both distal and proximal to the site of nerve injury. Other studies have demonstrated an increase in mu-opioid receptor (MOR) expression levels proximal to the site of nerve constriction in a model of neuropathic pain (Ann Neurol. 53:366, 2003). In the current study, we investigate axonal transport of MOR and deltaopioid receptors (DOR) to the site of nerve injury in a model of neuropathic pain induced by chronic constriction of the sciatic nerve. Immunocytochemical and immunoblotting techniques were utilized to quantify and localize opioid receptors in the dorsal root ganglia (DRG) and sciatic nerve. MOR protein levels were significantly elevated in DRG and sciatic nerve ipsilateral to the peripheral nerve injury compared to the contralateral side. A significant increase in DOR protein was observed in the sciatic nerve ipsilateral to the injury. Overall the results suggest increased MOR and DOR protein synthesis and enhanced axonal transport ipsilateral to the site of injury, in a model of neuropathic pain. Taken together, these findings indicate that peripherally-acting opioid analgesics may have therapeutic potential in the treatment of neuropathic pain.
(678) Comparison of monkey laminae I and V STT cells with human pain sensation A. Craig ; Barrow Neurological Institute, Phoenix, AZ The aim of this study was to compare the responses of monkey laminae I and V STT cells to repeated brief-contact heat pain and the thermal grill illusion of pain with human psychophysics. Single L5-S1 STT units are antidromically identified and characterized in barbiturate-anesthetized macaques. Repeated brief-contact (0.7 s) heat stimuli are applied at 48, 51, 54C and 5, 3, 2 s ISIs. Reset is tested by omitting 1-2 stimuli in a longer series. The thermal grill is applied with a series of parallel 2mm bars at 40/20C. All HPC lamina I STT cells tested showed augmentation, reset, and grill responses corresponding to human sensation. In contrast, NS lamina I and WDR lamina V STT cells showed little or no augmentation, reset, or grill responses. These observations support the concept that HPC lamina I STT cells have a unique role as a virtual labeled line for second pain (Craig, Ann Rev Neurosci 26:1-30, 2003). Dysfunction of HPC cells could be important for neuropathic pain.