Pain
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Neuropathic pain and epileptic seizures bear several similarities, among them is the response to anticonvulsant drugs. It has therefore been hypothesized that epileptiform activity of nociceptive spinal dorsal horn neurons may contribute to paroxysmal forms of neuropathic pain. We used patch-clamp and field potential recordings from young rat spinal cord slices to test if nociceptive dorsal horn structures are indeed able to sustain epileptiform activity. ⋯ During epileptiform activity, previously silent polysynaptic pathways from primary afferent C-fibers to superficial dorsal horn neurons were opened. Stimulation of primary afferents at Adelta- and C-fiber intensity interfered with the epileptiform rhythm, suggesting that both affect the same dorsal horn structures. Similar to neuropathic pain, spinal dorsal horn epileptiform activity was much less reduced by classical analgesics than by anticonvulsant agents.
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Hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN channels) have large influences upon neuronal excitability. However, the participation of spinal HCN channels in chronic pain states, where pathological conditions are related to altered neuronal excitability, has not been clarified. Intraperitoneally (i.p.) or intrathecally (i.t.) administered ZD7288, a selective blocker of Ih channels, reduced thermal and mechanical hypersensitivity in mice under neuropathic conditions induced by the partial ligation of the sciatic nerve, while no analgesic effect was observed in naïve animals. ⋯ Bath-applied ZD7288 reduced A-fiber- and C-fiber-mediated monosynaptic EPSCs more preferentially in slices prepared from mice after peripheral nerve injury. In addition, ZD7288 reduced the frequency of miniature EPSCs without affecting their amplitude in cells receiving monosynaptic afferent inputs, indicating that it inhibits EPSCs via presynaptic mechanisms. The present behavioral and electrophysiological data suggest that spinal HCN channels, most likely at the primary afferent terminals, contribute to the maintenance of chronic pain.
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The formalin test still surprises with its biphasic pain-related behavior resulting from a quiescent interphase that does not occur with other algogenic compounds and remains unexplained. The first phase has been attributed to TRPA1-mediated excitation of nociceptors, the second phase to their inflammatory and/or spinal sensitization. We show that the second and interphase require higher formaldehyde concentrations to emerge, and that from 12 mM on calcium influx is induced in TRPA1-deficient sensory neurons as well as in native HEK293T cells. ⋯ The parameters gained were entered into a computational model to predict the activation pattern of primary afferents. The model supports a peripherally generated biphasic response, the time course matching the behavioral results. In conclusion, the interphase is a result of hyperpolarization and transient inactivation by formaldehyde of the surviving neurons; their recovery and the centrifugal spread of formalin in the skin induce a second phase of nociceptive activity before the formalin concentration falls below threshold.
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Cancer-induced bone pain is a major clinical problem. A rat model based on intra-tibial injection of MRMT-1 mammary tumour cells was used to mimic progressive cancer-induced bone pain. At the time of stable behavioural changes (decreased thresholds to mechanical and cold stimuli) and bone destruction, in vivo electrophysiology was used to characterize natural (mechanical, thermal, and cold) and electrical-evoked responses of superficial and deep dorsal horn neurones in halothane-anaesthetized rats. ⋯ Deep WDR neurones showed less pronounced changes to the superficial dorsal horn, however, the response to thermal and electrical stimuli, but not mechanical, were significantly increased in the MRMT-1-injected rats. In conclusion, the spinal cord is significantly hyperexcitable with previously superficial NS cells becoming responsive to wide-dynamic range stimuli possibly driving this plasticity via ascending and descending facilitatory pathways. The alterations in superficial dorsal horn neurones have not been reported in neuropathy or inflammation adding to the evidence for cancer-induced bone pain reflecting a unique pain state.
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The anti-nociceptive and locomotor effects of the nicotinic acetylcholine receptor (nAChR) agonists (+)-epibatidine and ABT-594 were compared in the rat. Acute thermal nociception was measured using the tail flick test. Mechanical hyperalgesia was measured as paw withdrawal threshold (PWT) in response to a mechanical stimulus in two animal models of persistent pain; (1) 24 h following subplantar injections of Freund's complete adjuvant (FCA) into the left hind paw or (2) 11-15 days following a partial ligation of the left sciatic nerve. ⋯ In summary, ABT-594 is less potent than (+)-epibatidine in assays of acute and persistent pain and in the rotarod assay. However, ABT-594 displayed a clearer separation between its motor and anti-hyperalgesic effects. This shows that nicotinic agonists with improved selectivity between the nicotinic receptor subtypes could provide strong analgesic effects with a much improved therapeutic window.