Multi-target treatment of bone cancer pain using synergistic combinations of pharmacological compounds in experimental animals

Non peer reviewe

Mechanisms of cognitive impairment in chronic pain patients can now be studied preclinically by inducing cognitive deficits with an experimental animal model of chronic neuropathic pain

Non peer reviewe

Pain treatment with intrathecal corticosteroids: Much ado about nothing? But epidural corticosteroids for radicular pain is still an option

Non peer reviewe

Descending inhibitory systems

The authors have been supported by the Academy of Finland (grant 78582), the Sigrid Jusélius Foundation, Finland, Grünenthal Foundation, Portugal and Project no POCTI/NSE/46399/2002 from FCT and FEDER, Portugal. The authors wish to thank Dr. Denis Artchakov for illustrations

Pronociceptive changes in response properties of rostroventromedial medullary neurons in a rat model of peripheral neuropathy

The spared nerve injury (SNI) model of peripheral neuropathy produces a robust and long-lasting hypersensitivity. Previous behavioural studies suggest that brainstem–spinal pathways originating in or relaying through the rostroventromedial medulla (RVM) contribute to neuropathic hypersensitivity. We determined whether SNI induces changes in response properties of RVM neurons that might influence descending modulation of nociception. RVM neurons included in the study were classified into presumably pronociceptive ON-cells and antinociceptive OFF-cells (giving excitatory or inhibitory responses to noxious stimulation, respectively). Spontaneous activity and the response to cold, pinch and colorectal distension were assessed under light anaesthesia in the rat, 1 week and 8 weeks following nerve injury or sham operation. Spontaneous activity was increased 1 week but not 8 weeks after nerve injury in ON-cells but decreased in OFF-cells at both time points. In the SNI group, cold-evoked responses were enhanced particularly in ON-cells, independent of the postoperative time point. Responses of ON-cells to pinch and visceral stimulation were enhanced 8 weeks but not 1 week following nerve injury, whereas OFF-cell responses to pinch or colorectal distension were not changed. The results indicate that SNI induces pronociceptive changes in spontaneous activities of ON-cells and OFF-cells and peripherally evoked responses of ON-cells that vary with the postoperative time point. Increased ON-cell activity and decreased OFF-cell activity in the RVM are likely to enhance spinal nociception in a tonic fashion, whereas increased responses of ON-cells to peripheral stimulation are likely to enhance ascending nociceptive signals by a positive feedback following peripheral noxious stimulation

Spinal mechanisms contributing to the development of pain hypersensitivity induced by sphingolipids in the rat

Background Earlier studies show that endogenous sphingolipids can induce pain hypersensitivity, activation of spinal astrocytes, release of proinflammatory cytokines and activation of TRPM3 channel. Here we studied whether the development of pain hypersensitivity induced by sphingolipids in the spinal cord can be prevented by pharmacological inhibition of potential downstream mechanisms that we hypothesized to include TRPM3, sigma(1) and NMDA receptors, gap junctions and D-amino acid oxidase. Methods Experiments were performed in adult male rats with a chronic intrathecal catheter for spinal drug administrations. Mechanical nociception was assessed with monofilaments and heat nociception with radiant heat. N,N-dimethylsphingosine (DMS) was administered to induce pain hypersensitivity. Ononetin, isosakuranetin, naringenin (TRPM3 antagonists), BD-1047 (sigma(1) receptor antagonist), carbenoxolone (a gap junction decoupler), MK-801 (NMDA receptor antagonist) and AS-057278 (inhibitor of D-amino acid oxidase, DAAO) were used to prevent the DMS-induced hypersensitivity, and pregnenolone sulphate (TRPM3 agonist) to recapitulate hypersensitivity. Results DMS alone produced within 15 min a dose-related mechanical hypersensitivity that lasted at least 24 h, without effect on heat nociception. Preemptive treatments with ononetin, isosakuranetin, naringenin, BD-1047, carbenoxolone, MK-801 or AS-057278 attenuated the development of the DMS-induced hypersensitivity, but had no effects when administered alone. Pregnenolone sulphate (TRPM3 agonist) alone induced a dose-related mechanical hypersensitivity that was prevented by ononetin, isosakuranetin and naringenin. Conclusions Among spinal pronociceptive mechanisms activated by DMS are TRPM3, gap junction coupling, the sigma(1) and NMDA receptors, and DAAO.Peer reviewe

Enhanced pronociception by amygdaloid group I metabotropic glutamate receptors in nerve-injured animals

Peripheral neuropathy has been associated with structural and functional changes of the amygdala, a key player in emotions. Here we study whether peripheral neuropathy influences pain regulation by the amygdala. For this purpose, we determined discharge rates of presumably pro- and antinociceptive pain-regulatory neurons in the rostral ventromedial medulla (RVM) following microinjection of various glutamatergic compounds into the central nucleus of the amygdala. RVM neurons were recorded in pentobarbitone-anesthetized rats with a peripheral nerve injury or sham-operation. In a separate behavioral experiment, we determined whether the influence of amygdaloid administration of a glutamatergic compound on affective pain-related behavior, as assessed by an aversive place-conditioning test, is changed by neuropathy. While glutamate or an NMDA receptor antagonist in the amygdala failed to induce marked changes in discharge rates of RVM cells, amygdaloid administration of DHPG, a group I metabotropic glutamate receptor (mGluR) agonist acting on mGluR1 and mGluR5, increased discharge rates of presumably pronociceptive RVM ON-cells in nerve-injured but not sham-operated animals. This pronociceptive effect of DHPG was reversed by MPEP (mGluR5 antagonist) and CPCCOEt (mGluR1 antagonist). CHPG, an mGluR5 agonist, failed to influence ONcell activity and DHPG failed to influence activity of presumably antinociceptive RVM OFF-cells. Amygdaloid administration of DHPG increased and that of CPCCOEt decreased affective pain-related behavior in nerve-injured animals. The results suggest that following nerve injury, the amygdaloid group I mGluR, particularly subtype mGluR1, has an enhanced pronociceptive effect providing a potential mechanism for emotional enhancement of pain in peripheral neuropathy.Fundação Calouste GulbenkianFundação para a Ciência e a Tecnologia (FCT