Substance P and opioid mechanisms in antinociception produced by noxious cutaneous stimulation in the rat — A physiological and receptor binding study
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Nociceptin receptor
NOP
Nociceptin receptor
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We have examined the effects of several ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and Rg3) adminstered intracerebroventricularly (i. c. v.) or intrathecally (i. t.) on the nociceptive behavior induced by substance P (0.7 μg) injected i. t. Among the several ginsenosides studied, Rb2, Rc, Rd, and Re, but not Rb1, Rf, Rg1 and Rg3, treated i. c. v. (50 μg) attenuated the nociceptive behavior induced by substance P injected i. t. On the other hand, we found that i. t. treatment with 50 μg of Rb1, Rb2, Rd, or Rf effectively attenuated the nociceptive behavior induced by i. t. injected substance P. However, the i. t. treatment with the same doses of Rc, Re, Rg1 or Rg3 was not effective for antagonizing i. t. injected substance P-induced nociceptive behavior. Our results show that ginsenosides Rb2, Rc, Rd, or Re injected supraspinally exert a antinociceptive effect in the substance P-induced pain model. Furthermore, Rb1, Rb2, Rd, or Rf treated spinally produce antinociception in the substance P-induced pain model.
Intrathecal
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Studies have shown that noxious cutaneous stimulation engages physiologically different antinociceptive systems to inhibit a spinal reflex, tail withdrawal from radiant heat. Two experiments are reported that examine the relationship between the inhibition of the tail-flick response and brain-mediated responses to nociception. The induction of a spinally mediated antinociception was accompanied by an increase in latency to vocalize to a noxious thermal stimulus, suggesting pain inhibition. Physiological manipulations that eliminated the inhibition of the tail-flick reflex restored vocalization to thermal stimulation and revealed a concurrent sensitization that generally heightened behavioral reactivity. The results suggest that net pain is regulated by 2 opposing processes, a selective inhibition of nociceptive signals within the spinal cord and a general sensitization that heightens stimulus processing.
Stimulus (psychology)
Tail flick test
Radiant heat
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Nociceptin receptor
NOP
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Background : The heptadecapeptide nociceptin, also known as Orphanin FQ, is a recently discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL 1 . Methods and Results: In the present study, responses to nociceptin, [Tyr 1 ]-nociceptin, noci ceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) were compared in the systemic vascu lar bed of the rabbit. Nociceptin and [Tyr 1 ]-nociceptin induced dose related decreases in systemic arterial pressure (SAP) when injected in doses of 1-30 nmol/kg intravenous (IV); in terms of relative vasodepressor activity, [Tyr 1 ]-nociceptin and nociceptin were similar in potency. However, nociceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) had no effect on SAP when injected in doses up to 30 nmol/kg IV. The decreases in SAP in response to nociceptin and [Tyr 1 ]-nociceptin were not altered by the opioid receptor antagonist naloxone at a time when depressor responses to methionine-enkephalin were reduced significantly. Conclusions: The results of the present study show that vasodepressor responses to noci ceptin and [Tyr 1 ]-nociceptin arc mediated by the activation of a naloxone-insensitive opioid receptor and arc not dependent on the presence of Phc at the N-terminus of the nociceptin sequence. Moreover, the present results show that nociceptin-(2-17). nociceptin-(1-11), and nociccptin-(1-7) do not after SAP in the rabbit, indicating that peptide chain length is important for the expression of vasodepressor activity.
Nociceptin receptor
NOP
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In the present study, we show that hypersensitivity to noxious thermal stimulation can be seen clearly in developing rats. Rats, at postnatal days 3, 6, 9, 12, 15, 21 and 90 were tested for reflex responsiveness to noxious heat, using tail withdrawal from hot water as the assay. Thermal nociceptive thresholds are considerably lowered, relative to adults, up to postnatal day 12. Thresholds were 39, 37.5, 40.8, 43.3, 46.5, 45.2 and 47.2°C for the respective age groups. Enhanced sensitivity to suprathreshold noxious stimuli is seen in neonates up to postnatal day 15 (but not on day 9). Starting on day 21, sensitivity to noxious stimuli decreases with increasing age, as can be seen by the decrease in the slope of the temperature-response curve (system gain). Spinal transections at postnatal days 13, 17, 20, 60, or 100 did not produce a change in nociceptive thresholds in any of the age groups. In contrast, sensitivity to noxious stimulation (system gain) was enhanced by spinalization in rats 20 days of age or older. Based on these results we suggest that threshold elevation with increasing age most probably reflects changes in local spinal properties, while changes in responsiveness to suprathreshold noxious stimuli involves maturation of both spinal and descending supraspinal structures.
Nociceptor
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The spinal cord plays a key role in pain processing, but it remains unexplored in large animal models. We have developed a methodology to record from spinal neurons using three pigs. Here we aim to determine (1) at which rostro-caudal level ulnar nerve evoked responses can be recorded and (2) at which depth distinctly different responses can be recorded after noxious and non-noxious stimulation. Neural signals were evoked by ulnar nerve stimulation and recorded at different levels of the spinal cord in anesthetized pigs. Event-related potentials and peri-stimulus histograms showed that most activity was recorded at the C7 level, which diminished when the electrodes were moved towards C6 or C8. At 1 mm depth, spinal neurons responded primarily to noxious stimulation, which is typical for nociceptive specific neurons. While at 2 mm depth, neurons showed responses typical for wide dynamic range neurons by responding differently to noxious and non-noxious stimulation. Histological analysis showed that these signals may indeed have been recorded from lamina I/II and IV/V, respectively. This method opens new possibilities for studying pain and other spinal mechanisms in large animals and can be combined with peripheral and brain recordings to provide a more integrated picture of (chronic) pain mechanisms.
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Neurophysiology
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It is unclear how neonates respond to noxious stimuli. This study examined the role of neurokinin peptides in 3- and 21-day-old rat pups using the preprotachykinin-A (PPTA) knockout mouse, lacking neurokinin A and substance P. We assessed pain behaviors of these mice before the neurokinin system is putatively active, 3 days after birth, and after this system is active, 21 days after birth. The lack of these peptides failed to alter behavioral responses to nociceptive stimulation in the 3-day-old mice. The 21-day-old mice lacking these peptides were less responsive to 5 microl 2% formalin and to high intensity thermal and mechanical stimuli. Thus, the neurokinins appear not to be an important mechanism in the processing of nociceptive information in the infant.
Neurokinin A
Tachykinin receptor 1
Neurokinin B
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