Pain
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The synaptic vesicle protein synapsin II is specifically expressed in synaptic terminals of primary afferent nociceptive neurons and regulates transmitter release in the spinal cord dorsal horn. Here, we assessed its role in nerve injury-evoked molecular and behavioral adaptations in models of peripheral neuropathic pain using mice genetically lacking synapsin II. Deficiency of synapsin II resulted in reduced mechanical and cold allodynia in two models of peripheral neuropathic pain. ⋯ In addition, the expression of the vesicular glutamate transporters, VGLUT1 and VGLUT2, was strongly reduced in synapsin II knockout mice in the spinal cord. Conversely, synapsin II knockout mice showed a stronger and longer-lasting increase of GABA in lamina II of the dorsal horn after nerve injury than wild type mice. These results suggest that synapsin II is involved in the regulation of glutamate and GABA release in the spinal cord after nerve injury, and that a imbalance between glutamatergic and GABAergic synaptic transmission contributes to the manifestation of neuropathic pain.
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Anxiety has been described as an important comorbidity in patients suffering from chronic pain. However, in animals the connection between persistent pain and anxiety has hardly been investigated. Therefore, in the current study it was assessed whether chronic pain also causes anxiety-like behaviour in animals and if it can be reversed by analgesic or anxiolytic drugs. ⋯ Morphine (3mg/kg; i.p.) and gabapentin (30 mg/kg; i.p.) significantly attenuated anxiety-like behaviour in the CCI lesioned rats: morphine increased entries into open arms from 3.0+/-0.4 to 7.7+/-1.4 (P=0.01), gabapentin elevated this value from 4.7+/-1 to 7.5+/-0.9 (P=0.02). These data suggest that rats subjected to neuropathic pain models develop anxiety-like behaviour which can be reversed by appropriate analgesic treatment. Morphine and gabapentin had no anxiolytic-like effect in sham treated animals, thus their effect on anxiety-like behaviour in the neuropathic pain model is likely indirect via their anti-nociceptive properties.
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Ralfinamide is analgesic when applied as a single dose in rodent models of stimulus-evoked chronic pain. However, it is unknown whether its chronic application after nerve injury can suppress spontaneous chronic pain, the main symptom driving patients to seek treatment. In this study ralfinamide was administered to rats at doses producing plasma levels similar to those causing analgesia in pain patients. ⋯ Rats treated with ralfinamide (30 or 60 mg/kg; bid) from the operation till d42, but not preoperatively, also showed delayed autotomy (P=0.05, P=0.006), and reduced autotomy scores lasting till d63 (P=0.02, P=0.01), for the two doses, respectively. Combining ralfinamide treatments for 7 days preoperatively and 42 days postoperatively also resulted in significantly suppressed scores on d42 and d63 (P=0.005, P=0.001, respectively). Suppression of neuropathic pain-related behavior was likely caused by a combination of mechanisms reported for ralfinamide, including inhibition of Na+ and Ca++ currents in Nav1.3, Nav1.7, Nav1.8, and Cav2.2 channels in rat DRG neurons, inhibition of substance P release from spinal cord synaptosomes, NMDA receptor antagonism and neuroprotection.
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Temporal summation of "second pain" (TSSP) is considered to be the result of C-fiber-evoked responses of dorsal horn neurons, termed 'windup'. TSSP is dependent on stimulus frequency (> or=0.33Hz) and is relevant for central sensitization and chronic pain. We have previously shown that compared to normal controls (NC), fibromyalgia (FM) subjects show abnormal TSSP, requiring lower stimulus intensities/frequencies to achieve similar TSSP. ⋯ In a second experiment, all aspects of individually adjusted TSSP heat pulses were kept the same except that the baseline temperature (BT) between heat pulses was surreptitiously alternated between 35 degrees C and 40 degrees C. These changes of BT resulted in significantly greater TSSP ratings of FM subjects compared to NC subjects, both at 35 degrees C and at 40 degrees C, but did not change their response to the first heat pulse of a stimulus train. These findings provide strong support for alterations of central pain sensitivity and not peripheral sensitization or rating bias as responsible for TSSP differences between NC and FM subjects.
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The termination of an unpleasant or painful somatic condition can produce a rewarding sense of relief, even if the stimulus that causes the termination is itself unpleasant or painful under normal circumstances. We aimed to identify central neural mechanisms of pain relief from capsaicin-elicited heat-hyperalgesia by administering cold stimuli. We hypothesized that cooling might facilitate endogenous descending inhibitory mechanisms. ⋯ When neural responses to the 0 degrees C-stimulus were compared between the untreated and capsaicin-treated skin condition there were stronger BOLD-responses in prefrontal cortex (PFC) and periaqueductal grey (PAG) which correlated with increasing perceived pleasantness (VAS). Based on a connectivity analysis which identified cold-dependent contributions of PFC activity with PAG in heat-hyperalgesia we propose that cold-induced pain relief partly results from activation of endogenous descending inhibition of nociception. The data illustrate that perception of nociceptive input may largely be determined by competing aversive-appetitive motivational states.