The impact of the opioids fentanyl and morphine on nociception and bone destruction in a murine model of bone cancer pain.

Contains fulltext : 52106.pdf (publisher's version ) (Closed access)Chronic pain resulting from metastasis into skeleton of certain neoplastic diseases remains poorly understood and relatively resistant to analgesic treatment. Opioids are the principal axis in drug therapy for this type of pain, especially at the end stage of cancer. Our aim was to examine whether, fentanyl as well as morphine, two potent analgesic opioids commonly used to treat cancer pain, would inhibit pain and bone lesion-related responses in a murine model of bone cancer pain. Repeated administration of equianalgesic doses of fentanyl (0.16 mg/kg s.c. once a day) and morphine (20 mg/kg s.c. once a day) initiated at day 1 (prophylactic treatment) or at day 7 (curative treatment) after tumor cell inoculation in the femoral cavity consistently decreased bone pain symptoms and tumor growth-induced bone destruction (micro-CT bone structure parameters). Both fentanyl and morphine treatments resulted in clear antinociceptive properties as well as reductions in cancer cell-induced bone lesions. The present results demonstrate that fentanyl, and to some lesser degree morphine, has potential benefits in the treatment and development of bone cancer pain. As such, chronic administration of high doses of certain opioids like fentanyl may have clinical utility in the management of bone cancer pain

A behavioral and pharmacological validation of the acetone spray test in gerbils with a chronic constriction injury.

Item does not contain fulltextCold and mechanical allodynia are important symptoms in patients with neuropathic pain. The study of cold allodynia in animals can help us to understand the underlying pathophysiological mechanisms of neuropathic pain and to validate drugs. The evaluation of cold allodynia in gerbils with a chronic constriction injury of the sciatic nerve on the cold plate is not always stable. We developed a new application method of acetone using a specific spray technique with an Eppendorf multistepper pipette. The chronic constriction injury of the sciatic nerve in gerbils resulted in a long-lasting mechanical and acetone spray-induced hyperreactivity throughout the testing period, which is clearly different from what was seen in sham-operated animals. The acetone spray test incorporates a multimodal stimulus different from direct cold stimulation. The reactivity to the acetone spray coincides in time and strength with the reactivity observed in mechanical allodynia in gerbils and with mechanical and thermal allodynia in other species. Furthermore, a pharmacological validation of the acetone spray test by different reference compounds was performed. Different compounds effective in neuropathic pain models in rodents influence the hyperreactivity to the acetone spray after acute and chronic administration. This study indicates that the multimodal acetone spray test is a valuable tool in the study of neuropathic pain in rodents. IMPLICATIONS: The acetone spray test is a multimodal and valuable tool in the evaluation of neuropathic pain behavior in gerbils

Pharmacological evaluation of opioid and non-opioid analgesics in a murine bone cancer model of pain.

Contains fulltext : 53583.pdf (publisher's version ) (Closed access)The intramedulary injection of osteosarcoma cells in the mouse femur has served as a laboratory model to study bone cancer pain. However, the efficacy of different classes of analgesics has not fully been analyzed in this model. Therefore, the acute antinociceptive properties of different classes of drugs were evaluated on post-inoculation day 15 when the degrees of spontaneous pain and mechanical hypersensitivity in the ipsilateral inoculated hind paw reached almost their maximal effects. At high doses, the opioids fentanyl, morphine, and tramadol had full efficacies for all pain parameters tested. Antagonism experiments with naloxone (10 mg/kg s.c.) or its peripheral analogue methylnaltrexone (10 mg/kg s.c.), suggest that the analgesic effects of fentanyl were predominantly mediated by centrally located mu-opiate receptors. Acetaminophen, the non-steroidal anti-inflammatory drug indomethacin, and the COX-2-inhibitor celecoxib did not significantly improve pain behavior. The tricyclic antidepressants amitriptyline and desipramine significantly reduced spontaneous pain behavior but this only at sedative doses; the serotonin reuptake inhibitor fluoxetine had limited efficacy. Also with the anticonvulsants lamotrigine, topiramate, and gabapentin limited or no efficacies were found. In conclusion, the present study provided integrated information about the tumor-induced bone pain in mice, and clarified acute efficacies of different categories of analgesics for the spontaneous lifting, limb-use impairment, and mechanical hypersensitivity. Moreover, the finding that bone cancer-pain behaviors are attenuated by various established compounds further supports the validity of the murine bone cancer model for the study of bone cancer pain and its use for the identification of novel treatments

Pharmacological correlation between the formalin test and the neuropathic pain behavior in different species with chronic constriction injury.

Item does not contain fulltextResearch on mechanisms of drug action, and preclinical screening of molecules with a potential activity on neuropathic pain requires extensive animal work. The chronic constriction injury model is one of the best-characterized models of neuropathic pain behavior in rats, but requires extensive time consuming operations and animal handling. The formalin test is easier to perform, and a well validated model. The latter may serve as an effective prescreening test of molecules and may facilitate drug targeting. In the present study the activity of different pharmacological reference compounds was tested in rats and gerbils on the cold plate for animals that had undergone chronic constriction injury and in the second phase of the formalin test. In rats, a comparable outcome in both test conditions was observed for morphine, fentanyl, MK-801 and flunarizine. Clonidine had more activity in the second phase of the formalin test, whereas baclofen, tramadol, amitryptiline, ketamine and topiramate showed more activity in the cold plate. In gerbils, both test conditions yielded comparable results for fentanyl and ketoprofen. Tramadol and CP-96345 tended to have more activity in the second phase of the formalin test, whereas morphine, SR-48968, SR-142801 and R116301 demonstrated more activity in the cold plate test. This study demonstrates a good correlation between the second phase of the formalin test and the cold allodynia in the CCI model for, both for rats and gerbils. Drugs with a proven activity in humans, used as reference compounds, also showed good pharmacological activity in this animal study

Exogenous interleukin-6 increases cold allodynia in rats with a mononeuropathy.

Interleukin-6 (IL-6) is a pleiotropic cytokine, signaling intracellularly via its unique membrane-bound receptor IL-6R and gp130. In peripheral nerve injury models, IL-6 and IL-6R are increased at the injured nerve and the respective dorsal root ganglion. IL-6 is increased at the ipsilateral dorsal and ventral horn of the spinal cord. IL-6 is known to affect neuronal survival, differentiation and regeneration. It is involved in synaptic plasticity and hyperexitability and induces the synthesis or release of other substances with known neuroprotective or neuromodulatory effects. In this study, intrathecal administration of recombinant rat IL-6 to rats with a chronic constriction injury of the sciatic nerve, induced a logarithmic dose-dependent increase in cold allodynia with a threshold of 10 pg IL-6 and a maximal effect at 100 ng IL-6. Intrathecal administration of saline or denaturated IL-6 was without effect. In rats with a chronic constriction injury, systemic administered IL-6 did not induce a hyperalgesic effect, illustrating that IL-6 acts at the level of the dorsal root ganglion or the spinal cord. Intraplantar injection of 100 ng IL-6 in the operated hind paw resulted in an increased cold allodynia. This study demonstrates that the sensitivity to exogenous intrathecal or peripheral IL-6 increases in rats with a mononeuropathy

Effects of pre-treatment with amantadine on morphine induced antinociception during second phase formalin responses in rats.

Contains fulltext : 48453.pdf (publisher's version ) (Closed access)The clinically available NMDA-receptor antagonist drug, amantadine, has been shown to result in morphine sparing effects in humans after surgery. However, no data are available to describe the exact form of interaction. The present study aims to profile the possible effects of amantadine (0, 12.5, 25 or 50 mgkg(-1) i.p.) pre-treatment on morphine (0, 0.63, 1.25, 2.5 or 5 mgkg(-1) s.c.) induced antinociception in rats. The (automated) formalin test (5% formalin, 50 microl) was used to assess if amantadine enhances the antinociceptive activity of morphine. Possible motor impairment was assessed with a rotarod test. Morphine was measured in serum of amantadine or vehicle treated rats to search for possible pharmacokinetic interactions between amantadine and morphine. Isobolographic analysis provided evidence for a synergistic interaction between amantadine and morphine in the second phase of the formalin test. No evidence was found to indicate that amantadine induced motor impairment at the doses potentiating morphine during the second phase of the formalin test. There was no evidence for a pharmacokinetic interaction between amantadine and morphine. Since, the second phase of the formalin test is dependent on activation of the NMDA receptor system it is concluded that an antagonistic activity of amantadine at the NMDA receptor most likely contributes to the synergistic interaction observed between amantadine and morphine in rats

Increased cold allodynia following intrathecal N-methyl-D-aspartate in rats with a mononeuropathy.

Item does not contain fulltextNMDA receptors are involved in the modulation of neuropathic pain behavior and central sensitization. In vivo, this is mostly demonstrated by the use of specific antagonists such as MK801. Because studies evaluating the direct impact of spinal NMDA in neuropathic pain models are lacking, we performed a series of experiments to study the role of spinal NMDA injection on existing cold allodynia, as a measurement of neuropathic pain behavior in rodents. Intrathecal injection of NMDA resulted in an enhanced neuropathic pain behavior in CCI rats on a cold plate. The activity was present from a dose of 5 ng/rat onward and could selectively be reversed by intraperitoneal injections of doses of > or = 0.01 mg/kg MK801. These results support the regulatory role of NMDA receptors in the hypersensitivity to cold observed in neuropathic pain behavior in rodents

Adrenalectomy affects pain behavior of rats after formalin injection.

Stressful stimuli can activate the hypothalamo-pituitary-adrenal-axis and the endogenous opioid system. In addition, corticosterone and opioid release might cause analgesia. This rat study used adrenalectomy for corticosterone withdrawal and naloxone administration for opioid antagonism in order to study pain behavior and hypophyseal hormone release in the plasma after a formalin test. Twelve days before the formalin testing, male Sprague Dawley rats underwent adrenalectomy or sham-adrenalectomy, and non-operated rats were used as reference. The number of flinches and the duration of licking or biting behavior were measured during the early and late phase. In reference and sham-operated rats, injection of formalin 5% resulted in a marked pain behavior in the early and late phase with significant increases in ACTH and corticosterone plasma levels. In adrenalectomized rats, pain behavior was decreased during both phases. Naloxone, administered before the late phase, did not alter pain behavior in sham or reference rats, whereas in adrenalectomized rats pain reactivity returned to those levels observed in reference rats. Beta-endorphin plasma levels above the detection limit were more frequently found in adrenalectomized rats. Thyrotropin and prolactin levels were not different between studied groups. We speculate that the observed reduced pain behavior in adrenalectomized rats after formalin, is the result of an increased production of pro-opiomelanocortin, the pro-drug of both adrenocorticotrophic hormone and beta-endorphin

The role of interleukin-6 in nociception and pain.

Item does not contain fulltextIMPLICATIONS: That IL-6 is an interesting target in the study of pain is underscored by its biomolecular properties, its localization after experimental pain, and its modulating effect on pain after administration

Pre-treatment with capsaicin in a rat osteoarthritis model reduces the symptoms of pain and bone damage induced by monosodium iodoacetate.

Contains fulltext : 89691.pdf (publisher's version ) (Closed access)A rat model of osteoarthritis was used to investigate the effect of pre-treatment with capsaicin on the symptoms of osteoarthritis induced by the injection of monosodium iodoacetate. This model mimics both histopathology and symptoms associated of human osteoarthritis. Injection of monosodium iodoacetate, an inhibitor of glycolysis, into the femorotibial joints of rodents promotes loss of articular trabecular bone and invokes pain symptoms similar to those noted in human osteoarthritis. Twenty rats were divided in two groups either receiving placebo or monosodium iodoacetate. Each group was subdivided in two groups either receiving pre-treatment with capsaicin two weeks before monosodium iodoacetate injection or not, resulting in four groups of five rats each. The impact of a single intra-articular administration of capsaicin (0.5%) on the generation of evoked mechanical pain (hind limb weight bearing, automated von Frey monofilament and RotaRod tests) and bone lesions (micro-CT scan radiographic analyses of bone structure) following monosodium iodoacetate-induced osteoarthritis in rats was determined. Evoked mechanical pain as monitored over a period of 4 weeks after monosodium iodoacetate injection was abolished in capsaicin pre-treated animals and pain values are comparable to those of capsaicin controls. Chronic joint pathological changes such as bone erosion and trabecular damage were significantly reduced by pre-treatment with a single administration of capsaicin. Decrease of bone volume was considerably ameliorated and trabecular connectivity was substantially better in capsaicin pre-treated animals. Capsaicin, an agonist activator of the vanilloid nociceptors (TRPV1), appears to be effective in protecting bone from arthritic damage. The present results support the hypothesis that capsaicin-sensitive sensory neurons contribute to bone lesions in the monosodium iodoacetate-induced osteoarthritis rat model