Opioids are a mainstay of pain management but can induce unwanted effects, including analgesic tolerance and paradoxical hyperalgesia, either of which leads to increased pain. Clinically, however, the relationship between these two phenomena remains elusive. By evaluating changes in mechanical nociceptive threshold in male rats, we found that in contrast to a purely analgesic control response to a single subcutaneous administration of fentanyl (25 μg/kg), in rats subjected to inflammatory pain 2 weeks previously (Day0), the same test dose (D13) induced a bi-phasic response: initial decreased analgesia (tolerance) followed by hyperalgesia lasting several hours. Both the tolerance and hyperalgesia were further enhanced in rats that had additionally received fentanyl on D0. The dose-response profiles (5 fg to 50 μg/kg) of pain- and opioid-experienced rats were very different from pain/drug-naive rats. At ultra-low fentanyl doses (<5 ng/kg and <500 ng/kg for naïve control and pain/drug-experienced rats, respectively), solely hyperalgesia was observed in all cases. At higher doses, which now produced analgesia alone in naive rats, reduced analgesia (tolerance) coupled with hyperalgesia occurred in pain/fentanyl-experienced rats, with both phases increasing with dose. Transcriptomic and pharmacological data revealed that an overactivation of the spinal N-methyl-D-aspartate receptor-inducible NO synthase cascade plays a critical role in both acute tolerance and hyperalgesia, and together with the finding that the magnitudes of analgesia and associated hyperalgesia are negatively correlated, is indicative of closely related phenomena. Finally, a polyamine deficient diet prevented inducible NO synthase transcript upregulation, restored fentanyl's analgesic efficacy and suppressed the emergence of hyperalgesia.

Neuropeptide FF receptors (NPFF1R and NPFF2R) and their endogenous ligand neuropeptide FF have been shown previously to display antiopioid properties and to play a critical role in the adverse effects associated with chronic administrations of opiates including the development of opioid-induced hyperalgesia and analgesic tolerance. In this work, we sought to identify novel NPFF receptors ligands by focusing our interest in a series of heterocycles as rigidified nonpeptide NPFF receptor ligands, starting from already described aminoguanidine hydrazones (AGHs). Binding experiments and functional assays highlighted AGH 1n and its rigidified analogue 2-amino-dihydropyrimidine 22e for in vivo experiments. As shown earlier with the prototypical dipeptide antagonist RF9, both 1n and 22e reduced significantly the long lasting fentanyl-induced hyperalgesia in rodents. Altogether these data indicate that AGH rigidification maintains nanomolar affinities for both NPFF receptors, while improving antagonist character toward NPFF1R.

Douleur & Analgésie, première revue internationale francophone consacrée à la douleur, dont le champ de son expertise s'étend de la recherche fondamentale à la clinique tant sur le plan de l'évaluation de la douleur que de ses traitements.

Although opiates represent the most effective analgesics, their use in chronic treatments is associated with numerous side effects including the development of pain hypersensitivity and analgesic tolerance. We recently identified a novel orally active neuropeptide FF (NPFF) receptor antagonist, RF313, which efficiently prevents the development of fentanyl-induced hyperalgesia in rats. In this study, we investigated the properties of this compound into more details. We show that RF313 exhibited a pronounced selectivity for NPFF receptors, antagonist activity at NPFF1 receptor (NPFF1R) subtype both in vitro and in vivo and no major side effects when administered in mice up to 30 mg/kg. When co-administered with opiates in rats and mice, it improved their analgesic efficacy and prevented the development of long lasting opioid-induced hyperalgesia. Moreover, and in marked contrast with the dipeptidic NPFF receptor antagonist RF9, RF313 displayed negligible affinity and no agonist activity (up to 100 μM) toward the kisspeptin receptor. Finally, in male hamster, RF313 had no effect when administered alone but fully blocked the increase in LH induced by RFRP-3, while RF9 per se induced a significant increase in LH levels which is consistent with its ability to activate kisspeptin receptors. Altogether, our data indicate that RF313 represents an interesting compound for the development of therapeutic tools aiming at improving analgesic action of opiates and reducing adverse side effects associated with their chronic administration. Moreover, its lack of agonist activity at the kisspeptin receptor indicates that RF313 might be considered a better pharmacological tool, when compared to RF9, to examine the regulatory roles of RF-amide-related peptides and NPFF1R in reproduction.

BackgroundOpioids are known to relieve pain, and also aggravate pre-existing hyperalgesia. In animal studies, the N-methyl-d-aspartate-receptor antagonist nitrous oxide (N2O) was able to prevent hyperalgesia. The present study evaluated the effect of N2O on hyperalgesia after remifentanil infusion in healthy volunteers.MethodsTwenty-one healthy volunteers were enrolled in this placebo-controlled cross-over study. Transcutaneous electrical stimulation at high current densities induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions: (1) 50-50% N-2-O-2 and i.v. saline; (2) 50-50% N-2-O-2 and i.v. remifentanil 0.1g/kg/min; (3) 50-50% N2O-O-2 and i.v. saline; (4) 50-50% N2O-O-2 and i.v. remifentanil 0.1g/kg/min. Inhaled gas mixtures lasted for 60min, i.v. drug administration for 30min. Visual analogue scale pain intensity, areas of pinprick hyperalgesia and touch-evoked allodynia were assessed repeatedly for 160min.ResultsData of 19 volunteers were analysed. There were significant time and treatment effects regarding areas of hyperalgesia and allodynia (p<0.02). The area of hyperalgesia was significantly reduced in the N2O+remifentanil session compared to the remifentanil session (35.8822.37 vs. 43.5518.48cm(2), p=0.004). The area of allodynia was significantly reduced in the N2O+remifentanil session compared to the remifentanil session (29.95 +/- 16.15 vs. 34.80 +/- 15.35cm(2), p=0.008). The pain intensity was significantly reduced in the N2O+remifentanil session compared to the remifentanil session (37.96 +/- 12.78 vs. 42.15 +/- 13.34mm, p<0.0001).ConclusionsNitrous oxide significantly reduced hyperalgesia, allodynia and pain intensity aggravated after remifentanil administration in a human volunteer model.What does this study add?This study brings the evidence that N2O reduces the remifentanil aggravated secondary hyperalgesia in human volunteers exposed to a well-known model of electrical pain. N2O was able to oppose the hyperalgesia, the allodynia and the pain intensity consecutive to remifentanil use in this specific pain model.

L’intensité de la sensation douloureuse n’est pas un simple reflet de l’importance de l’agression tissulaire nociceptive mais est également le reflet de processus de plasticité neuronale induits par des processus de sensibilisation périphériques et centraux, se traduisant par de l’hyperalgésie ou de l’allodynie, voire des douleurs spontanées.

Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

BACKGROUND: Despite numerous pharmacological approaches, there are no common analgesic drugs that produce meaningful relief for the majority of patients with neuropathic pain. Although nitrous oxide (N 2 O) is a weak analgesic that acts via opioid-dependent mechanisms, it is also an antagonist of the N -methyl-D-aspartate receptor (NMDAR). The NMDAR plays a critical role in the development of pain sensitization induced by nerve injury. OBJECTIVE: Using the chronic constriction injury of the sciatic nerve in male rats as a preclinical model of neuropathic pain, the first aim of the present study was to evaluate the lowest N 2 O concentration and the shortest time of N 2 O postinjury exposure that would produce persistent relief of neuropathic pain. The second aim was to compare the effects of N 2 O with gabapentin, a reference drug used in human neuropathic pain relief. METHODS: Changes in the nociceptive threshold were evaluated using the paw pressure vocalization test in rats. RESULTS: Among the various N 2 O concentrations tested, which ranged from 25% to 50%, only 50% N 2 O single exposure for 1 h 15 min induced a persistent (minimum of three weeks) and significant (60%) reduction in pain hypersensitivity. A single gabapentin dose (75 mg/kg to 300 mg/kg, intraperitoneally) induced an acute (1 h to 1 h 30 min) dose-dependent effect, but not a persistent effect such as that observed with N 2 O. CONCLUSIONS: These preclinical results suggest that N 2 O is advantageous for long-lasting neuropathic pain relief after sciatic nerve injury compared with other drugs used in humans such as gabapentinoids or NMDAR antagonists. The present preclinical study provides a rationale for developing comparative clinical studies.

BACKGROUND: Opioid-induced hyperalgesia (OIH) is a recognized complication of opioid use that may facilitate the development of exaggerated postoperative pain. OBJECTIVE: To examine the role of genetic factors on OIH by comparing four rat strains. Because the authors previously reported that the endogenous opioids released during non-nociceptive environmental stress induce latent pain sensitization, genetic and environmental factor interactions were also evaluated. METHODS: First, the propensity of Sprague Dawley, Wistar, Lewis and Fischer rats to develop OIH following single or repeated fentanyl exposures was compared by measuring the nociceptive threshold using the paw pressure vocalization test. Second, Sprague Dawley and Fischer rats were exposed to a series of three non-nociceptive environmental stress sessions to evaluate the ability of endogenous opioids to enhance hyperalgesia associated with a carrageenan-induced hind-paw inflammation test performed two weeks later. RESULTS: Sprague Dawley, Wistar and Lewis rats exhibited OIH, although differences were observed. OIH was not observed in Fischer rats. Inflammatory hyperalgesia enhancement induced through previous stress in Sprague Dawley rats was not observed in Fischer rats. CONCLUSIONS: The pain level not only reflects nociceptive inputs but also depends on both the history and genetic factors of the individual. Genetic and environmental models may provide new insights into the mechanisms that underlie individual differences observed in postoperative pain.

This prospective study aim to examine whether clinical findings and electrodiagnostic testing (EDX) in patients with lumbosacral monoradiculopathy due to herniated disc (HD) differ as a function of root involvement level (L5 vs. S1) and HD zone (paramedian vs. intraforaminal).All patients with L4, L5 or S1 monoradiculopathy were prospectively enrolled at four electromyography (EMG) labs over a 2-year period. The diagnosis was based on a congruence between patient history and MRI evidence of HD. We compared the sensitivities of clinical findings and EDX with respect to both root involvement level and HD zone. Multivariate logistic regression was performed in order to verify the association between abnormal EMG, clinical, and neuroradiological findings.One hundred and eight patients (mean age 47.7 years, 55% men) were consecutively enrolled. Sensory loss in the painful dermatome was the most frequent finding at physical examination (56% of cases). EMG was abnormal in at least one muscle supplied by femoral and sciatic nerves in 45 cases (42%). Inclusion of paraspinal muscles increased sensitivity to only 49% and that of proximal muscles was useless. Motor and sensory neurography was seldom abnormal. The most frequent motor neurographic abnormalities were a delay of F-wave minimum latency and decrease in the compound muscle action potential amplitude from extensor digitorum brevis and abductor hallucis in L5 and S1 radiculopathies, respectively. Sensory neurography was usually normal, the amplitude of sensory nerve action potential was seldom reduced when HD injured dorsal root ganglion or postganglionic root fibres. Multivariate logistic regression analysis showed that EMG abnormalities could be predicted by myotomal muscular weakness, abnormal deep reflexes, and paraesthesiae. The only clinical and electrophysiological differences with respect to root involvement level concerned deep reflexes and motor neurography of deep peroneal and tibial nerves.Only some EDX parameters are helpful for the diagnosis of lumbosacral radiculopathy. EMG was abnormal in less than 50% of cases and its abnormalities could be predicted by some clinical findings. However, neurography is useful as a tool for differential diagnosis between radiculopathy and more diffuse disorders of the peripheral nervous system (polyneuropathy, plexopathy).Cette étude prospective menée chez des patients présentant une monoradiculopathie due à une hernie discale visait à déterminer les modifications de l’examen clinique et électrophysiologique en fonction du niveau (L5 ou S1) et du site de la hernie (paramédiane ou intraforaminale).Quatre laboratoires de neurophysiologie ont inclus tous les patients admis pour une monoradiculopathie L4, L5 ou S1 sur une période de deux ans. Le diagnostic était basé sur la congruence entre l’anamnèse et l’IRM montrant une hernie discale. Nous avons comparé les sensibilités de l’examen clinique et neurophysiologique en fonction du niveau et du site de compression. Au moyen de régressions logistiques multivariées, nous avons vérifié quelles étaient les associations entre anomalies cliniques, électrophysiologiques et neuroradiologiques.Cent-huit patients consécutifs (âge moyen : 47,7 ans, 55 % d’hommes) on été inclus. Le symptôme le plus fréquent à l’examen clinique était un déficit sensitif dans le dermatome douloureux (56 %). L’EMG était anormal dans un moins un muscle dépendant du nerf fémoral et du tronc sciatique dans 42 % des cas. L’inclusion de muscles paraspinaux n’augmentait la sensibilité que de 7 % (49 %) et celle de muscles proximaux était inutile. L’examen neurographique moteur ou sensitif était rarement anormal. Les anomalies neurographiques les plus fréquentes étaient une augmentation du temps de latence minimum de l’onde F et une réduction d’amplitude du potentiel moteur au niveau du muscle pédieux ou de l’abducteur de l’hallux, pour les radiculopathies L5 et S1, respectivement. La neurographie sensitive était généralement normale, l’amplitude du potentiel d’action de nerf sensitif étant diminuée dans les rares cas de souffrance du ganglion spinal ou des fibres sensitives distales par rapport au ganglion spinal. Les études multivariées démontraient que les anomalies de l’EMG pouvaient être prédites par la faiblesse musculaire dans le myotome correspondant, l’anomalie des réflexes et les paresthésies. Les seules différences cliniques et neurophysiologiques en fonction du niveau de la hernie concernaient les réflexes et la neurographie motrice des nerfs tibiaux et péroniers profonds.Seuls quelques paramètres électrophysiologiques sont utiles pour le diagnostic des radiculopathies lombosacrées. L’EMG n’est anormal que dans 50 % des cas et ses anomalies sont prédites par la clinique. L’examen neurographique reste cependant utile pour le diagnostic différentiel avec les polyneuropathies ou les atteintes plexiques.

Clinical pain, especially chronic pain, is now known to be not just a reflection of sustained noxious input but also, to a large extent, the expression of neural plasticity. By positively modulating the excitatory glutamate/N-methyl-d-aspartate receptor (NMDA-R), polyamines could facilitate central pain sensitization. Since polyamines mainly originate from dietary intake and gut bacterial metabolism, a polyamine-deficient diet (PD diet) could be a nutritional strategy to counteract the deleterious effect of upregulated NMDA activity and subsequent pain sensitization.In rat preclinical studies, we demonstrated that a PD diet for several days reverses the sustained pain hypersensitivity associated with experimental neuropathy or monoarthritis in rats and restores the analgesic effect of morphine without inducing the adverse effects commonly induced by NMDA receptor antagonists. A PD diet also prevented hyperalgesia induced by an inflammation. In contrast, rats fed with a polyamine enriched diet (10-fold, as compared to normal diet level) reveal a strong post-inflammatory hyperalgesia enhancement (proof of concept).For humans, a polyamine free nutritional formula marketed under the trademark Polydol® by Nutrialys Medical Nutrition represents a new therapeutic strategy for reducing exaggerated acute pain and improving the management of chronic and intractable pain in association with classical analgesics. Clinical trials are ongoing.