Cyril Rivat

Long-lasting Hyperalgesia Induced by Fentanyl in Rats: Preventive Effect of Ketamine

Background It has been reported that &mgr;-opioid receptor activation leads to a sustained increase in glutamate synaptic effectiveness at the N-methyl-D-aspartate (NMDA) receptor level, a system associated with central hypersensitivity to pain. One hypothesis is that postoperative pain may result partly from the activation of NMDA pain facilitatory processes induced by opiate treatment per se. The authors tested here the effectiveness of the opiate analgesic fentanyl for eliciting a delayed enhancement in pain sensitivity. Methods The consequences of four bolus injections (every 15 min) of fentanyl (20–100 &mgr;g/kg per injection, subcutaneously) on immediate (for several hours) and long-term (for several days) sensitivity to nociceptive stimuli in the rat (paw-pressure vocalization test) were evaluated. The effects of the combination of the NMDA-receptor antagonist ketamine (10 mg/kg, subcutaneously) with fentanyl also were assessed. Results Fentanyl administration exhibited a biphasic time-dependent effect: first, an early response (for 2–5 h) associated with a marked increase in nociceptive threshold (analgesia), and second, a later response associated with sustained lowering of the nociceptive threshold (5 days for the longest effect) below the basal value (30% of decrease for the maximal effect) indicative of hyperalgesia. The higher the fentanyl dose used, the more pronounced was the fentanyl-induced hyperalgesia. Ketamine pretreatment, which had no analgesic effect on its own, enhanced the earlier response (analgesia) and prevented the development of long-lasting hyperalgesia. Conclusions Fentanyl activates NMDA pain facilitatory processes, which oppose analgesia and lead to long-lasting enhancement in pain sensitivity.

Opioid-induced hyperalgesia

INTRODUCTION It is well recognized that opioids are the analgesics of choice for the treatment of moderate to severe pain. However, a large number of clinical studies have reported that opioids can unexpectedly elicit hyperalgesia (enhanced responses to noxious stimulation) and allodynia (pain elicited by normal innocuous stimuli) [1–8]. Opioid-induced hyperalgesia has also been reported in animal experimental models [9–17]. This pain hypersensitivity has been classified as abnormal pain [16,18] as opposed to physiological (or normal) pain associated with nociception. Physiological pain has an important function in the preservation of an organism since it is an essential warning device that alerts the organism of impending danger from actual or potentially injurious stimuli in the environment. Does this suggest that there are good and bad pains, i.e. normal or abnormal pain? From a clinical viewpoint, the response is probably yes, if pain is only considered as a simple sensory system. However, pain is also a motivational process inducing a coordinated set of behavioral changes that serves to remember danger, some behaviors being facilitated and others inhibited. In this respect, pain sensitivity may be the result of a balance between the activity of inhibitory (antinociceptive) and facilitatory (pronociceptive) circuitries within the CNS with regard to the environmental state. If the main function of antinociceptive systems is to reduce pain during threatening situations as pain may compromise defensive behavior, it has been argued [19] that the function of pronociceptive systems might be that of motivating recuperative behaviors that would be adaptive for maintaining preservation of the organism when signals for safety succeed to threats. From an adaptive viewpoint, one hypothesis is that a pain hypersensitivity state is a normal step following defensive analgesia associated with the recruitment of endogenous antinociceptive systems. Since it is unlikely that evolution has selected mechanisms that are only activated by endogenous antinociceptive systems such as opioid systems, it might be suggested that delayed hyperalgesia following the use of exogenous opioids is a normal rather than an abnormal pain. In this review, we will first examine experimental evidences which indicate that exogenous opioids simultaneously activate both inhibitory and facilitatory pain systems leading to a long-lasting enhancement in pain sensitivity after analgesia. Second, we will assess the possible role of such an enhancement in pain sensitivity in the development of both tolerance to the analgesic effect of opioids and pain chronicisation processes.

Ketamine improves the management of exaggerated postoperative pain observed in perioperative fentanyl-treated rats.

Background:Although opioids are unsurpassed analgesics, experimental and clinical studies suggest that opioids activate N-methyl-d-aspartate pronociceptive systems leading to pain hypersensitivity and short-term tolerance. Because it is difficult in humans to differentiate pain from hyperalgesia during the postoperative period, the authors performed experimental studies with fentanyl using the rat incisional pain model for evaluating relations between hyperalgesia and short-term tolerance. Because N-methyl-d-aspartate receptor antagonists oppose both pain hypersensitivity and tolerance induced by opioids, the authors examined the capability of ketamine for improving exaggerated postoperative pain management. Methods:During halothane anesthesia, a hind paw plantar incision was performed in rats receiving four fentanyl subcutaneous injections (100 &mgr;g/kg per injection, every 15 min). In some groups, three subcutaneous ketamine injections (10 mg/kg per injection, every 5 h) were performed in saline- or fentanyl-treated rats. One day after surgery, the analgesic effect of morphine (2 mg/kg subcutaneous) was tested. Analgesia, mechanical hyperalgesia, tactile allodynia, and pain score were assessed for several days using the paw pressure vocalization test, the von Frey application test, and the postural disequilibrium test. Results:Fentanyl induced analgesia but also produced exaggerated postoperative pain as indicated by the enhancement of hyperalgesia, allodynia, and weight-bearing decrease after hind paw plantar incision. Ketamine pretreatment prevented such a fentanyl-induced enhancement of postoperative pain and improved its management by morphine. Conclusions:By opposing postoperative pain hypersensitivity and subsequent short-term tolerance induced by perioperative opioid use, ketamine not only improves exaggerated postoperative pain management but also provides better postoperative rehabilitation.

Nitrous oxide revisited: evidence for potent antihyperalgesic properties.

Background: Although opioids are unsurpassed analgesics for surgery, they also induce an N-methyl-d-aspartate–dependent enhancement of postoperative hyperalgesia. Because nitrous oxide (N2O) has anti–N-methyl-d-aspartate properties, the purpose of this study was to evaluate nitrous oxide ability to prevent such an opioid-induced hyperalgesia in rats. Methods: First, preventive effects of 50/50% N2O–O2 on the development of delayed hyperalgesia observed after inflammatory pain (hind paw carrageenan injection on D0) were examined for several days. Second, the ability of nitrous oxide (10–40%) to limit opioid-induced hyperalgesia induced by fentanyl was evaluated in nonsuffering rats. Third, antihyperalgesic effects of various nitrous oxide concentrations (20–50%) were assessed in both inflammatory and incisional pain models in fentanyl-treated rats (4 × 100 &mgr;g/kg subcutaneously). Finally, the analgesic effect of a single dose of morphine was evaluated 24 h after fentanyl administration and nitrous oxide (D0) to assess its preventive effect on acute morphine tolerance in both nonsuffering and hind paw–incised rats. Results: When applied on D0, nitrous oxide reduced delayed hyperalgesia induced by inflammation. Exposure to nitrous oxide on D0 also reduced opioid-induced hyperalgesia in nonsuffering rats in a dose-dependent manner. In fentanyl-treated rats with inflammatory or incisional pain, nitrous oxide strongly limited both magnitude and duration of hyperalgesia. Moreover, nitrous oxide exposure on D0 opposed development of acute tolerance to analgesic effects of morphine administered on D1 in both nonsuffering and incised fentanyl-treated rats. Conclusions: Nitrous oxide, an N-methyl-d-aspartate receptor antagonist, prevented the enhancement of pain sensitivity induced by both nociceptive inputs and fentanyl and opposed acute morphine tolerance. Results suggest that perioperative nitrous oxide use reduces exaggerated postoperative pain and morphine consumption.

Non-Nociceptive Environmental Stress Induces Hyperalgesia, Not Analgesia, in Pain and Opioid-Experienced Rats

It is well admitted that stress induces analgesia (SIA) via endogenous opioid release. However, there is evidence that stressful events play a role in the pathogenesis of pain, but little is known about mechanisms underlying such pain vulnerability. Previous studies reported that a single opioid exposure activates NMDA-dependent pronociceptive systems leading to long-term pain vulnerability after analgesia. Here, we studied whether prior inflammatory pain or/and opioid experiences may favour the development of pain vulnerability after non-nociceptive environmental stress (NNES). Nociceptive threshold (NT) changes were evaluated by paw pressure vocalization test. By contrast to discrete SIA observed in naive rats, 1 h stress induced hyperalgesia (SIH) for several hours (15–65% NT decrease) in pain and opioid experienced rats. Repetition of NNES induced an 18- to 22-fold SIH enhancement (3–4 days), whereas SIA decreased. SIH was still observed 4 months after pain and opioid experiences. This phenomenon is referred to as latent pain sensitization. Furthermore, a fentanyl ultra-low dose (ULD, 50 ng/kg) administration, mimicking SIA in naive rats, induced hyperalgesia (65% NT decrease, 4 h), not analgesia, in pain and opioid-experienced rats. This indicates that low levels of opioids induce opposite effects, that is analgesia vs hyperalgesia dependent on prior life events. In pain and opioid-experienced rats, NMDA receptor antagonists, ketamine or BN2572, completely prevented hyperalgesia when injected just before NNES or fentanyl ULD. This latent pain sensitization model may be important for studying the transition from acute to chronic pain and individual differences in pain vulnerability associated with prior life events.

Polyamine deficient diet to relieve pain hypersensitivity.

&NA; There is a compelling body of evidence that N‐methyl‐d‐aspartate receptors (NMDA‐R) play a critical role in the development and maintenance of pain hypersensitivity. However, long‐term treatments with NMDA‐R antagonists are limited by unacceptable side effects. Since polyamines modulate the functioning of NMDA‐R and mainly originate from normal dietary intake and bacterial metabolism in the gut, we developed a nutritional therapy based on dietary polyamine deficiency. Here, we reported that a polyamine deficient diet (PD diet) for 7 days prevented the enhancement of tyrosine phosphorylation of the spinal NR2B subunit‐containing NMDA‐R associated with inflammation in rats. Based on these data, we studied the ability of PD diet to prevent long‐lasting pain hypersensitivity associated with tissue injury on one hind paw by evaluating long‐lasting changes in both mechanical nociceptive threshold and weight bearing. A PD diet strongly reduced long‐lasting hyperalgesia induced by inflammation or incision, especially in fentanyl‐treated rats. Moreover a PD diet also prevented the exaggerated hyperalgesia induced by a second inflammation performed 7 days after the first one. A PD diet also opposed paradoxical hyperalgesia induced by non‐nociceptive environmental stress in rats with pain and opioid experiences. A PD diet reversed pain hypersensitivity associated with monoarthritis or neuropathy and restored the analgesic effect of morphine. Since PD diet was devoid of any noticeable side effects, this nutritional therapy could be part of an effective and safe strategy for pre‐emptive analgesia and for reducing the transition from acute to chronic pain and its outcomes in various pain syndromes.

TO57 Sensibilisation latente à la douleur chez des rats ayant eu une expérience douloureuse traitée par du fentanyl

Introduction Le stress induit de l’analgesie via une liberation endogene d’opioides. Cependant, des evenements stressants peuvent aussi jouer un role dans l’apparition d’episodes douloureux. De plus, il a ete montre qu’une seule exposition aux opioides activait les systemes pronociceptifs NMDA-dependants conduisant a une vulnerabilite a long terme a la douleur. Nous avons donc etudie si une experience de douleur inflammatoire traitee par du fentanyl pouvait favoriser : i) le developpement d’une vulnerabilite a long terme a la douleur apres un stress environnemental non nociceptif (SENN) et ii) la resistance aux effets antalgiques des opioides. Materiel et methode A J 0 , la carragenine, un agent pro-inflammatoire, a ete injectee dans une patte posterieure chez des rats traites par du fentanyl (4 x 100 μg/kg ; s.c.). Deux semaines apres, les rats ont ete exposes soit a : i) des SENN repetes, ii) une « ultra-low » dose de fentanyl (ULDf, 50 ng/kg) ou iii) une dose analgesique de fentanyl (25 μg/kg). La sensibilite a la douleur est evaluee quotidiennement par la determination du seuil nociceptif (SN) par le test de Randall-Selitto. Resultats Une ULDf induit une analgesie identique a celle observee apres un SENN chez les rats naifs mais provoque plusieurs heures d’hyperalgesie chez les rats ayant eu une experience douloureuse traitee par du fentanyl. Une resistance a l’effet analgesique du fentanyl 25 μg/kg est observee chez les rats ayant eu une histoire douloureuse et d’opioides. La repetition du SENN induit une importante augmentation (18 a 22 fois) de l’hyperalgesie. L’hyperalgesie induite par le SENN est toujours visible 4 mois apres l’experience douloureuse traitee par du fentanyl. Ce phenomene a ete denomme « sensibilisation latente a la douleur ». Discussion La sensibilisation latente a la douleur induite par une seule exposition aux opioides chez les rats avec une experience douloureuse pourrait jouer un role critique dans la transition de la douleur aigue a la douleur chronique apres une lesion tissulaire.

TO56 Hypersensibilité à la douleur : traitement par un régime appauvri en polyamines

Introduction Apres une lesion tissulaire, il existe une sensibilisation du SNC de longue duree via des processus NMDA-dependants. Cette neuroplasticite conduisant a des hyperalgesies post-operatoires exacerbees est consideree comme une des causes principales de chronicisation de la douleur. Cependant, des traitements au long court avec des antagonistes des recepteurs NMDA sont limites par des effets indesirables. Puisque les polyamines modulent positivement le fonctionnement des recepteurs NMDA, et proviennent principalement de notre alimentation, nous avons developpe une therapie nutritionnelle basee sur un regime appauvri en polyamines (RAP) pour prevenir les douleurs exagerees. Materiel et methode Puisque l’augmentation de phosphorylation spinale de la sous-unite NR2B du recepteur NMDA est associee avec l’hyperalgesie d’origine inflammatoire, nous avons evalue la capacite du RAP a reduire cette hyper-activation de NR2B. Des modeles de douleur inflammatoire (carragenine) ou chirurgicale ont ete utilises chez des rats traites ou non par fentanyl (4 x 100 μg/kg, s.c.). La sensibilite a la douleur est evaluee quotidiennement par la determination du seuil nociceptif (SN) par le test de Randall-Selitto. Une fois le SN de retour aux valeurs de base, les rats ont ete exposes a des stress environnementaux non nociceptifs (SENN) repetes. Resultats Le RAP donne de facon preventive (7 jours) previent l’augmentation de phosphorylation de la sous-unite NR2B induite par l’inflammation. Le RAP reduit aussi fortement l’hyperalgesie induite par une inflammation ou une incision, en particulier chez les rats traites par le fentanyl. De plus, le RAP previent aussi l’exageration de l’hyperalgesie induite par une seconde carragenine administree 7 jours apres la premiere. Le RAP s’oppose aussi a l’hyperalgesie paradoxale induite par l’exposition des rats a un SENN. Discussion Puisque le RAP est depourvu d’effets indesirables, cette therapie nutritionnelle pourrait etre une strategie ideale pour reduire la transition de la douleur aigue (en particulier chirurgicale) en douleurs chroniques.