Methods of postoperative pain control.
Explore the source record for details and available documents.
Bupivacaine↗
Biomedical subjects
T J Coderre
Publications and source records attributed to T J Coderre.
Central neural mediators of secondary hyperalgesia following heat injury in rats: neuropeptides and excitatory amino acids.
The contribution of C-fiber neuropeptides and excitatory amino acids (EAAs) as central mediators of secondary hyperalgesia was assessed by examining the effects of intrathecal (i.t.) administration of receptor-selective agonists and antagonists on foot-withdrawal latencies (from 48 degrees C water), both before and after heat injury of the contralateral hindpaw. The hyperalgesia which develops in the hindpaw contralateral to a heat injury, could be reproduced in uninjured rats following i.t. injection of substance P, neurokinin A and N-methyl-D-aspartate (NMDA) but not following calcitonin gene related peptide (CGRP), neurokinin B, kainate or (R,S)-alpha-amino-3-hydroxy-5-methylisozazole-4-propionic acid hydrobromide (AMPA). Contralateral hyperalgesia was reversed by the substance P antagonist Arg1,D-Pro2,D-Phe2-D-His9-substance P, and the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (APV), but not by the non-NMDA EAA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). When the limb of the injured hindpaw was pretreated with the C-fiber neurotoxin capsaicin, hyperalgesia in the contralateral hindpaw was unaffected. Furthermore, prior to injury, the capsaicin pretreatment itself produced hyperalgesia in the contralateral hindpaw. The results give support for a contribution of both C-fiber neuropeptides and EAAs to central nervous system plasticity and secondary hyperalgesia following heat injury.
2-Amino-5-phosphonovalerate↗
Sympathetic neuron factors involved in bradykinin-induced plasma extravasation in the rat.
Previous studies have demonstrated that bradykinin (BK) produces a sympathetically dependent plasma extravasation into the rat knee joint which is, in part, dependent upon the production of a prostaglandin. In the present study, co-administration of the specific prostaglandin, PGE2, markedly enhanced the BK-induced plasma extravasation. In this study we also report that after chemically induced sympathectomy, by chronic pretreatment with 6-hydroxydopamine (6-OHDA), both the plasma extravasation produced by BK and the enhancing effect of PGE2 are markedly attenuated. Plasma extravasation induced by PGE2 alone was small and was not significantly attenuated by sympathectomy. We conclude that BK-induced extravasation involves production of at least two sympathetic postganglionic neuron (SPGN) terminal-dependent factors, one of which is a cyclo-oxygenase product of arachidonic acid metabolism, probably PGE2, (Coderre et al., J. Neurophysiol., 62 (1989) 45-58) and another that is unidentified.
Animals↗
Postnatal development of neurogenic inflammation in the rat.
We have studied the development in the rat of neurogenic inflammatory mechanisms that mediate cutaneous plasma extravasation. At birth and at postnatal day 10, intradermal injection of substance P, histamine, and bradykinin produced no significant plasma extravasation. At day 13 through adulthood (days 42-49), all test agents produced significant plasma extravasation which increased with increasing age. In the adult rat, pretreatment with 6-hydroxydopamine, to eliminate sympathetic postganglionic nerve terminals, attenuated the plasma extravasation elicited by substance P, histamine and bradykinin. The possible role of the sympathetic postganglionic neuron in the age-dependent changes in neurogenic inflammation is discussed.
Aging↗
High-dose epinephrine acts at alpha 2-adrenoceptors to suppress experimental arthritis.
This study assessed the receptor site at which high systemic doses of epinephrine act to reduce the severity of adjuvant-induced arthritis in the rat. To this end we examined the effect of selective adrenergic antagonists on the reduction of arthritis by epinephrine, and also assessed whether high doses of selective adrenergic agonists mimicked the effect of epinephrine. The decrease in arthritis induced by epinephrine (0.5 mg/kg in chronic implant injected every 3 days) was significantly antagonized by the selective alpha 2-adrenergic antagonist, yohimbine, but not by selective alpha 1 (prazosin), beta 1 (metoprolol) or beta 2 (butoxamine) antagonists. In addition, chronic infusion of the alpha 2-adrenergic agonist clonidine, but not selective alpha 1 (phenylephrine), beta 1/beta 2 (isoproterenol) or beta 2 (salbutamol) agonists, resulted in decreased arthritis severity. These data suggest that the suppressive effect of high-dose epinephrine on joint injury in experimental arthritis is mediated by action at the alpha 2-adrenergic receptor.
Adrenergic alpha-Agonists↗
Increasing sympathetic nerve terminal-dependent plasma extravasation correlates with decreased arthritic joint injury in rats.
This study compared the pharmacology of adrenergic agents that influence plasma extravasation in normal animals with those agents that influence tissue injury in an inflammatory disease model. Specifically we studied the effects of beta 2- and alpha 2-adrenergic receptor agonists and antagonists on bradykinin-induced plasma extravasation in normal Sprague-Dawley rats and on joint injury in rats with experimental arthritis. Plasma extravasation induced by infusion of bradykinin in the rat knee joint was attenuated by the beta 2-agonist salbutamol or by the alpha 2-antagonist yohimbine, and was enhanced by the beta 2-antagonist, ICI-118,551, or by the alpha 2-agonist, clonidine. In rats that had undergone chemical symphathectomy, bradykinin-induced plasma extravasation was markedly reduced, and there was no enhancement of bradykinin-induced plasma extravasation by either ICI-118,551 or clonidine. Although ICI-118,551 and clonidine enhanced bradykinin-induced plasma extravasation, these drugs significantly reduced joint injury in rats with adjuvant-induced arthritis. Neither salbutamol nor yohimbine, however, significantly increased joint injury in the arthritic rats, presumably because arthritis severity is already high in these animals. Consistent with this hypothesis, both salbutamol and yohimbine did significantly increase the joint injury associated with experimental arthritis in Wistar-Kyoto rats, a strain which develops a mild adjuvant arthritis. The fact that increased plasma extravasation is associated with decreased arthritis severity suggests that plasma extravasation, a major sign of acute inflammation, contributes to tissue reparative processes.
Animals↗
Neutrophils contribute to sympathetic nerve terminal-dependent plasma extravasation in the knee joint of the rat.
Infusion of bradykinin or 6-hydroxydopamine into the knee joint of the rat activates sympathetic postganglionic nerve terminals and increases plasma extravasation, a major sign of acute inflammation. Since bradykinin attracts and activates neutrophils in vivo and since neutrophils can release factors leading to plasma extravasation, we evaluated the contribution of the neutrophil to bradykinin-induced plasma extravasation. We report that perfusion of bradykinin into the rat knee joint produces a prolonged increase in plasma extravasation which is markedly reduced not only by sympathectomy (chronic pretreatment with systemic 6-hydroxydopamine) but also by depletion of circulating polymorphonuclear leukocytes (intravenous infusion of hydroxyurea combined with intraperitoneal glycogen). Depletion of polymorphonuclear leukocytes also reduced the plasma extravasation induced by intra-articular infusion of 6-hydroxydopamine, which acutely activates sympathetic postganglionic terminals. We next tested whether attraction of neutrophils into the joint, in the absence of bradykinin, was sufficient to enhance plasma extravasation. Although the classical neutrophil attractant glycogen attracted neutrophils into the knee joint, it did not increase plasma extravasation. Co-infusion of bradykinin and glycogen into the knee joint, however, provoked plasma extravasation that was significantly greater than that produced by bradykinin alone. We hypothesize, therefore, that bradykinin not only attracts neutrophils but also activates them, by an as yet undefined mechanism that requires the sympathetic terminal. The activated neutrophils release factors that lead to plasma extravasation. The next series of studies evaluated the role of the sympathetic nervous system in neutrophil attraction in vivo by bradykinin and glycogen. Since quantification of neutrophil attraction was not possible in the knee joint, we performed these studies in the peritoneal cavity, a site where neutrophils are readily attracted.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Injury prior to neurectomy alters the pattern of autotomy in rats. Behavioral evidence of central neural plasticity.
A common property of phantom limb pain is that a preamputation lesion continues to be felt in the same location of the phantom limb after amputation. A model of the phantom limb in the rat is provided by sectioning the sciatic and saphenous nerves. This procedure leads to self-mutilation of the denervated hindpaw, a behavior known as autotomy. There is strong evidence that autotomy is a response to painful or dysesthetic sensations referred to the anesthetic limb. The present study examined the hypothesis that the site of autotomy behavior can be altered by an injury given prior to denervation. Experiment 1 evaluated the effects of a thermal injury applied (under sodium pentobarbital anesthesia) to the medial or lateral hindpaw and digits before or after sciatic and saphenous nerve transections in order to determine whether autotomy is directed specifically to a previously injured site. The results revealed that autotomy onset occurred in the injured region of the paw in a significantly greater proportion of rats, compared to an uninjured control group, if the thermal injury had been induced before denervation: 100% of the rats with medial paw injury induced prior to neurectomy initiated autotomy in the medial digits, and 55.6% of rats with lateral paw injury initiated autotomy in the lateral digits. Rats injured after autotomy showed no such preference (medial, 33.3% and lateral, 37.5%) relative to the uninjured controls (medial, 33.3% and lateral, 17%). These results suggest that central cells, sensitized by the thermal injury, contribute to enhanced autotomy in the absence of further inputs from the injured paw.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Delayed activation of nociceptors: correlation with delayed pain sensations induced by sustained stimuli.
1. In this study we used psychophysical experiments in humans and behavioral and electrophysiological studies in rats to evaluate nociceptive and C-fiber mechanoheat nociceptor (C-MH) responses to sustained mechanical stimuli that are initially nonpainful or nonnoxious. 2. In normal rat skin, sustained subthreshold mechanical stimuli activate C-MHs (n = 36) with a delayed onset that parallels the delayed pain sensation recorded in human psychophysical tests. 3. The subthreshold stimuli did not induce a decrease in mechanical threshold (n = 11), and the effect of the subthreshold stimulus on latency to firing of C-MHs (n = 6) persists for a very short time after the stimulus is removed (less than 10 s). 4. Intradermal injection of prostaglandin E2 (PGE2; 100 ng), which induced a significant decrease in the mechanical threshold of C-MHs (n = 7), had no effect on the latency of the delayed activation of C-MHs. Also, indomethacin, which inhibits the synthesis of prostaglandins, had no effect on the latency of the delayed paw-withdrawal response in the behavioral test. 5. Intradermal injection of the calcium ionophore A23187 significantly reduced the latency of the delayed activation of C-MHs (n = 6) the calcium chelator Quin 2 (n = 6) significantly increased the latency. A23187 and Quin 2 had similar effects on the latencies to paw withdrawal in behavioral tests. The sensitization of C-MHs (n = 9) by PGE2 was not, however, affected by Quin 2.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminoquinolines↗
Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection.
Evidence is presented which suggests that central neural changes occur during the brief early phase after subcutaneous formalin injection that are essential for the expression of pain during the long-lasting (tonic) later phase. First, tonic pain responses to subcutaneous formalin injections are abolished only if the injected hindpaw is locally anesthetized at the time of injection as well as the time of testing (30-60 min later). Second, tonic formalin pain is substantially reduced by brief spinal anesthesia given 5 min before, but not 5 min after the formalin injection.
Animals↗
Denervation-induced inflammation in the rat.
We report that section of the sciatic and saphenous nerves, in the hindlimb of the rat, evokes an inflammatory response in the denervated tissue that can be distinguished from the previously described peptide-mediated neurogenic inflammation. This novel form of neurogenic inflammation has a very delayed onset (9.75 +/- 2.1 h, mean +/- S.E.M., n = 8), persists for more than 30 h, and is characterized by a marked neutrophilic cellular infiltrate. These features cannot be mimicked by electrical stimulation of the peripheral nerve and are not prevented by either prior application of local anesthetics to the nerve lesion site or by neonatal treatment with capsaicin.
Animals↗
Noxious stimulus-induced increase in spinal prostaglandin E2 is noradrenergic terminal-dependent.
Prostaglandins (PGs) were measured in perfusate from the lumbar intrathecal (IT) space of pentobarbital anaesthetized rats. The level of PGE2, but not of PGF2 alpha or 6-keto PGF1 alpha, was increased by immersion of a hindpaw in water at a noxious temperature (50 degrees C). No increase in PGE2 was produced by non-noxious thermal stimulation (35 degrees C water). The noxious stimulus-evoked increase in PGE2, and increases in PGE2 during norepinephrine infusion (10 micrograms/ml), were significantly decreased in rats pretreated with intrathecal 6-hydroxydopamine. These data suggest that noxious stimuli induce an increase in the production of spinal PGE2 and that this production derives from, or requires the presence of noradrenergic terminals in the spinal cord.
Adrenergic Fibers↗
Neural influences on synovial mast cell density in rat.
The mast cell, an immunocompetent cell that contributes to neurogenic inflammation in a variety of tissues, including synovium, is found in close proximity to peripheral terminals of unmyelinated primary afferents and sympathetic postganglionic nerve terminals. In this study we evaluated the hypothesis that the density of mast cells in synovial tissue is dependent on the neural innervation. In normal rats, we found that the density of mast cells in the ankle joint capsule, which is heavily innervated, is greater than in the capsule of the knee, which is less densely innervated. Selective lesions of unmyelinated primary afferents with capsaicin, or of sympathetic postganglionic neurons with guanethidine, produced a significant decrease in mast cells; surgical removal of the parasympathetic ganglia did not significantly affect mast cell density. Finally, the number of mast cells in the synovial joint of spontaneously hypertensive rats, which have increased sympathetic activity, was significantly greater than in normotensive control rats. These observations support the hypothesis that the innervation in the synovial joint of the rat, by unmyelinated afferents and sympathetic efferents, exerts a trophic effect on mast cell density.
Animals↗
Epinephrine exacerbates arthritis by an action at presynaptic B2-adrenoceptors.
Sympathetic efferents contribute to the severity of joint injury in experimental arthritis in the rat, [Levine J. D. et al. (1986) J. Neurosci. 6, 3423-3429] and beta 2-adrenergic receptor antagonists suppress the disease [Levine J. D. et al. (1988) Proc. natn. Acad. Sci. U.S.A. 85, 4553-4556]. The present study was directed at determining the endogenous ligand for, and target of, the beta 2-receptor contribution to arthritis. We report that adrenal medullectomy significantly reduced joint injury in experimental arthritis, but that severe joint injury was re-established in adrenal medullectomized rats chronically treated with epinephrine or the beta 2-agonist, salbutamol. The ability of these two drugs to enhance joint injury in adrenal medullectomized rats was blocked by sympathectomy. These data suggest that adrenal medulla-derived epinephrine acts at beta 2-adrenoceptors on sympathetic efferent nerve terminals, to contribute to the severity of experimental arthritis.
Adrenal Medulla↗
The contribution of training to sensitivity in the nociceptive paw-withdrawal test.
An important limitation in behavioral tests of the hyperalgesic and analgesic effects of drugs is the low sensitivity of the measuring technique associated with inter- and intra-subject variability. Since familiarity with the experimental situation and novelty of the stimulus significantly influences an animal's behavior, we have tested the hypothesis that intensive training of rats, in the Randall-Selitto paw-withdrawal test, will increase the sensitivity of this test for detecting hyperalgesic effects of intradermal injections of the inflammatory mediator, bradykinin (BK). Mean baseline of the mechanical nociceptive threshold decreased between the first and second, and stabilized by the third day of training. Although there was no significant difference between the effects of BK or its vehicle (saline) on nociceptive threshold on day 1, on subsequent days BK produced a dose-dependent decrease in nociceptive threshold that could be distinguished from the effect of vehicle. These data demonstrate that training in the experimental paradigm can increase sensitivity for detecting hyperalgesic effects of inflammatory mediators in behavioral tests.
Animals↗
Neural control of vascular permeability: interactions between primary afferents, mast cells, and sympathetic efferents.
1. This study addressed the contribution of primary afferents, mast cells, and sympathetic efferents to the control of vascular permeability in synovial joints. Extravasation of Evans blue dye into the synovial space was measured by perfusion of the knee joint in the adult rat. Plasma extravasation (PE) was evoked by pharmacologic activation of either unmyelinated primary afferents, mast cells, or sympathetic postganglionic nerve (SPGN) terminals with acute injection of either capsaicin, compound 48/80, or 6-hydroxydopamine (6-OHDA), respectively. In otherwise untreated control rats, acute infusion of capsaicin or compound 48/80 produced a brief increase in vascular permeability; infusion of 6-OHDA produced a larger and more prolonged increase. 2. To evaluate the contribution of an interaction of different cellular elements in the joint to PE, we repeated these experiments in rats pretreated with capsaicin, compound 48/80, or 6-OHDA; administered quercetin; or surgically sympathectomized by excision of the lumbar sympathetic chain. Eliminating unmyelinated afferent nerve terminals by neonatal treatment with capsaicin only reduced the increase in PE produced by acute infusion of capsaicin. Degranulating mast cells by pretreatment with compound 48/80, or preventing the degranulation of mast cells by treatment with quercetin, reduced the increase in PE evoked by infusion of either capsaicin or compound 48/80. Finally, sympathectomy, produced by excision of the lumbar sympathetic chain or by pretreatment with 6-OHDA, significantly reduced PE elicited by acute infusion of capsaicin, compound 48/80, or 6-OHDA. 3. Neither infusing substances normally localized to sympathetic efferents nor inducing changes in blood pressure could mimic the profound increase in PE evoked by activation of sympathetic postganglionic neurons with acute infusion of 6-OHDA. Thus norepinephrine produced a significant decrease in PE, adenosine triphosphate produced only a brief increase, neuropeptide Y had no effect, and manipulating blood pressure (either up or down) had no effect on either base-line or 6-OHDA-induced PE. 4. Indomethacin treatment significantly reduced the increase in PE produced by 6-OHDA. This effect of indomethacin was reversed by the addition of prostaglandin E2 (PGE2) to the 6-OHDA in the perfusion fluid. This finding implicates prostaglandins (i.e., cyclooxygenase products of arachidonic acid metabolism) in SPGN-dependent generation of PE.(ABSTRACT TRUNCATED AT 400 WORDS)
Afferent Pathways↗
Slow changes in the flexion reflex of the rat following arthritis or tenotomy.
(1) The flexor reflex was measured in control decerebrate spinal rats by recording the motor axon activity in the nerve to biceps femoris evoked by a pressure stimulus to the hindpaw. A brief (1 Hz, 20 s) conditioning stimulus to peripheral nerves with sufficient strength to activate C fibres results in a prolonged increase in this flexor reflex. If the conditioning stimulus is applied to a cutaneous nerve, the sural, the facilitation lasts 5 (5.0 +/- 1.6, n = 28) min. However, if the same conditioning stimulus is applied to the muscle nerve to gastrocnemius, the facilitation lasts up to an hour (54.0 +/- 8.3 min, n = 16). (2) Ankle joint urate arthritis was induced by the injection of 1.25 mg sodium urate crystals into one ankle joint. Two hours after the injection, conditioning of the flexor reflex by brief stimulation of the sural or gastrocnemius nerves produced the same effect as in control animals. However, 24 h after the injection, sural nerve conditioning produced the same effect on the flexor reflex as in controls but gastrocnemius nerve conditioning produced only 8 min (8.3 +/- 1.6, n = 8) of facilitation instead of the expected 54 min. (3) The decreased ability of the muscle nerve to produce prolonged facilitation was not dependent on a saturation of the flexor reflex since the reflex could still be enhanced briefly by the conditioning stimuli. It was also not dependent on a continuous input from the arthritic ankle since the decrease is still apparent when the ankle has been denervated 24 h after the beginning of the arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)
Achilles Tendon↗
Ankle joint urate arthritis in rats provides a useful tool for the evaluation of analgesic and anti-arthritic agents.
Arthritis was induced in ether anesthetised rats by injecting 1.25 mg of sodium urate crystals into the ankle joint. Twenty-four hr after the injection the ankle is swollen and the animal does not place full weight on the affected foot. The ankle is more sensitive than normal to movement and pressure. Responses to stimulation of the foot and toes on the arthritic limb are reduced due to a reluctance to move the affected limb. These measures, which reflect ongoing pain, hyperalgesia or tenderness and guarding, are attenuated in animals treated with dexamethasone, phenylbutazone, and morphine, as well as in animals whose nerves to the ankle had been pretreated with capsaicin. Guanethidine and colchicine failed to influence the behavioural responses to the urate injection. Ankle joint urate arthritis has advantages over other models of arthritis for therapeutic testing in that in a short time it affects a single joint in rats, and it produces responses which can be assessed by simple, sensitive measures.
Analgesics↗