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Local production of immunoreactive bradykinin in two models of inflammation
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PERIPHERAL ACTIONS OF OPIATES IN THE BLOCKADE OF CARRAGEENAN INDUCED CUTANEOUS HYPERALGESIA. K. Hargreaves, J. Joris* and R. Dubner, Neurobiology & Anesthesiology Branch, NIDR, NIH, Bethesda, MD 20892, USA. Numerous studies have demonstrated that opiates can produce analgesia by acting at multiple sites in the CNS. The present study provides evidence for an additional peripheral antinociceptive effect of opiate agonists. Rats in a chamber with a glass floor had their paws exposed to a beam of radiant heat from beneath; paw withdrawal latency (PWL) was measured as an index of the nociceptive threshold. Both hindpaws were injected with 2 mg carrageenan (C). At 1.5 hrs, one paw was reinjected with either ethylketocyclazocine 10 pg (C/EKC) or fentanyl 0.3 pg (C/FEN); the other paw received saline (C/S). Three other carrageenan groups then received saline into both paws and a systemic subcutaneous (SC) injection of EKC 10 pg or FEN 0.3 pg or saline. Each group had 7-10 rats with data analyzed by ANOVA and Duncan's multiple range test. At 3 hrs, the PWI of C/EKC treated paws (5.5tO.6 set) was significantly longer than contralateral paws given C/S (2.9kO.9 set; pcO.01). Similarly, C/FEN treated paws had a significantly greater PWL as compared to contralateral C/S paws (5.4tO.5 set vs 2.520.2 set; pcO.01). The PWLs of animals given systemic SC EKC (3.2tO.3 set), FEN (2.920.1 set) or saline (2.6tO.2 set) were similar. All PWLS were significantly less than a control group receiving neither C nor opiates (lO.OtO.2 set; ~~0.01 for all). We have demonstrated that the thermal hyperalgesia induced by carrageenan can be unilaterally blocked by hindpaw injection of EKC or FEN. These low doses of EKC and FEN have no effect when administered systemically, suggesting that opiates have a peripheral site of action in inflamed tissue. (J.J. is supported by an FNRS Belgium Fellowship and is on leave from the Dept. Anesth. Univ. Liege, Belgium.)
LOCAL PRODUCTION OF IMMUNOREACTIVE BRADYKININ IN TWO MODELS J. Jorisk, T. McGinn*, A. Zimmerman* and OF INFLAMMATION. pi K. Hargreaves (SPON: R. Dionne), Neurobiology & Anesthesiology Branch, NIDR, NIH, Bethesda, MD 20892, USA. Understanding the action of bradykinin (BK), a major mediator of inflammation, has relied primarily upon drugs affecting its synthesis and The present study describes a subcutaneous paw perfusion degradation. method that directly measures the time course of iBK released during inflammation. Anesthetized rats (7-8/group) had both paws perfused simultaneously; one paw was injected with 3 mg carrageenan (CARRA) or 20 mg yeast 90 mins before anesthesia; the other paw was injected with saline (SAL). A coaxial perfusion system was used; the internal catheter subcutaneously perfused the paw (0.1 ml/min) while the external tubing aspirated the perfusate. After leaving the paw, the perfusate was mixed with peptidase inhibitors After centrifugation,, and collected into 100 mM phenanthroline in ethanol. the supernatant was dried and assayed for immunoreactive bradykinin (iBK). Data were analyzed by ANOVA and Duncan's multiple range test. The iBK level in the CARRA perfusate was 2 to 3 fold higher (F(1,7)= 34.22; p
PERIPHERAL ACTIONS OF OPIATES IN THE BLOCKADE OF CARRAGEENAN INDUCED CUTANEOUS HYPERALGESIA. K. Hargreaves, J. Joris* and R. Dubner, Neurobiology & Anesthesiology Branch, NIDR, NIH, Bethesda, MD 20892, USA. Numerous studies have demonstrated that opiates can produce analgesia by acting at multiple sites in the CNS. The present study provides evidence for an additional peripheral antinociceptive effect of opiate agonists. Rats in a chamber with a glass floor had their paws exposed to a beam of radiant heat from beneath; paw withdrawal latency (PWL) was measured as an index of the nociceptive threshold. Both hindpaws were injected with 2 mg carrageenan (C). At 1.5 hrs, one paw was reinjected with either ethylketocyclazocine 10 pg (C/EKC) or fentanyl 0.3 pg (C/FEN); the other paw received saline (C/S). Three other carrageenan groups then received saline into both paws and a systemic subcutaneous (SC) injection of EKC 10 pg or FEN 0.3 pg or saline. Each group had 7-10 rats with data analyzed by ANOVA and Duncan's multiple range test. At 3 hrs, the PWI of C/EKC treated paws (5.5tO.6 set) was significantly longer than contralateral paws given C/S (2.9kO.9 set; pcO.01). Similarly, C/FEN treated paws had a significantly greater PWL as compared to contralateral C/S paws (5.4tO.5 set vs 2.520.2 set; pcO.01). The PWLs of animals given systemic SC EKC (3.2tO.3 set), FEN (2.920.1 set) or saline (2.6tO.2 set) were similar. All PWLS were significantly less than a control group receiving neither C nor opiates (lO.OtO.2 set; ~~0.01 for all). We have demonstrated that the thermal hyperalgesia induced by carrageenan can be unilaterally blocked by hindpaw injection of EKC or FEN. These low doses of EKC and FEN have no effect when administered systemically, suggesting that opiates have a peripheral site of action in inflamed tissue. (J.J. is supported by an FNRS Belgium Fellowship and is on leave from the Dept. Anesth. Univ. Liege, Belgium.)
LOCAL PRODUCTION OF IMMUNOREACTIVE BRADYKININ IN TWO MODELS J. Jorisk, T. McGinn*, A. Zimmerman* and OF INFLAMMATION. pi K. Hargreaves (SPON: R. Dionne), Neurobiology & Anesthesiology Branch, NIDR, NIH, Bethesda, MD 20892, USA. Understanding the action of bradykinin (BK), a major mediator of inflammation, has relied primarily upon drugs affecting its synthesis and The present study describes a subcutaneous paw perfusion degradation. method that directly measures the time course of iBK released during inflammation. Anesthetized rats (7-8/group) had both paws perfused simultaneously; one paw was injected with 3 mg carrageenan (CARRA) or 20 mg yeast 90 mins before anesthesia; the other paw was injected with saline (SAL). A coaxial perfusion system was used; the internal catheter subcutaneously perfused the paw (0.1 ml/min) while the external tubing aspirated the perfusate. After leaving the paw, the perfusate was mixed with peptidase inhibitors After centrifugation,, and collected into 100 mM phenanthroline in ethanol. the supernatant was dried and assayed for immunoreactive bradykinin (iBK). Data were analyzed by ANOVA and Duncan's multiple range test. The iBK level in the CARRA perfusate was 2 to 3 fold higher (F(1,7)= 34.22; p