Pain
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It has been suggested that there is a significant upregulation of the NK1 receptor (NK1R) on neurons in the dorsal spinal cord after long-term somatic inflammation. This upregulation appears to play a significant role in central sensitization in chronic pain states. However, it is not clear whether such a change is also observed after chronic visceral (bladder) inflammation. ⋯ In the L6 spinal segment, CPA-treatment enhanced NK1R immunostaining in the medial and the lateral dorsal horn, as well as in the lateral laminae including the sacral parasympathetic nucleus to a lesser extent. In CPA-treated animals, substance P staining intensity increased in the same regions in which NK1R immunoreactivity was increased. This finding probably implies the upregulation of spinal NK1R and the occurrence of central sensitization within the spinal cord after chronic visceral inflammation.
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Cavernous hemangiomas (cavernomas) of the spinal cord are rare congenital malformations that comprise less than 5% of all intramedullary lesions. Despite this rarity, we describe the third case of central neuropathic itch associated with intramedullary cavernoma. Since fewer than 10 cases of central spinal itch from all causes have been published, this concurrence suggests the possibility of a specific association. ⋯ Such rats develop unilateral dermatomal hyperalgesia and self-injurious scratching and biting (autotomy). Although this pathological grooming is currently interpreted as a response to chronic pain, we propose that it more likely models scratching provoked by central neuropathic itch, as seen in our patient and others. Study of quisqualate-injected rats may provide leads towards new treatments for neuropathic itch.
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Electrical stimulation is widely used to assess the function of sensory nerves in humans. In the present study, the threshold current (CT) required to evoke a paw withdrawal response in rats was assessed with stepwise increases in current delivered as sinusoidal stimulation at frequencies of 2000 Hz (CT2000), 250 Hz (CT250) and 5 Hz (CT5). Baseline CT was 840+/-3 microA for CT2000, 267+/-2 microA for CT250 and 165+/-1 microA for CT5 (n=59). ⋯ Intraperitoneal pretreatment with indomethacin (20mg/kg) attenuated carrageenan evoked CT alterations as well as progression of paw swelling and thermal hyperalgesia. In conclusion, low, but not high, frequency stimulation activated a withdrawal response which appears mediated by morphine and capsaicin sensitive primary afferents and this threshold was reduced in the presence of inflammation. These data suggest the validity of such stimulation in defining drug action in a nontissue injurious fashion.
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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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The opioid and endocannabinoid systems mediate analgesia expressed upon re-exposure to a contextually aversive stimulus (fear-conditioned analgesia; FCA), and modulate the mitogen-activated protein kinase (MAPK) pathway. However, an interaction between the opioid and endocannabinoid systems during FCA has not been investigated at the behavioural or molecular level. FCA was modeled in male Lister-hooded rats by assessing formalin-evoked nociceptive behaviour in an arena previously paired with footshock. ⋯ None of the drugs affected formalin-evoked nociceptive behaviour or phospho-ERK1/2 expression in non-fear-conditioned rats. These data suggest that endocannabinoid-mediated enhancement of FCA is abolished by pharmacological blockade of opioid receptors as well as CB(1) or CB(2) receptors. Both pharmacological enhancement (with URB597) and attenuation (with naloxone) of this form of endogenous analgesia were associated with reduced expression of phospho-ERK1/2 in the amygdaloid complex arguing against a causal role for ERK1/2 signaling in the amygdala during expression of FCA or its modulation by opioids or cannabinoids.