Mechanisms of tactile allodynia after primary sensory neuron injury

Tactile allodynia,defined as a pain or a nociceptive response provoked by an innocuous mechanical stimulus,in addition to hyperalgesia and spontaneous pain,is one of the common features of peripheral neuropathy in hu-mans following peripheral nerve injury.In many respects it is the development of exquisite sensitivity to light touch that many patients with post herpetic neuralgia,partial nerve trauma,and metabolic and inflammatory neuropa-thies find particularly unbearable.It is a pain hypersensi-tivity that is,moreover,resistant to most current forms of therapy.An enormous breakthrough in our understanding of the pathophysiology of neuropathic pain in general,and tactile allodynia in particular,has come through the rec-ognition that the mechanical hypersensitivity is mediated by low-threshold,large myelinated Aβfibers.These high-ly specialized sensory fibers normally never produce pain and are responsible for the detection of light touch,move- ment of hairs,pressure,flutter,and vibration [1] .However,after nerve damage,activation of these afferents elicits pain.The major question then is what mechanisms are responsible for converting sensory processing within the somatosensory system such that low-threshold Aβmechanoreceptors elicit pain?

Increased phosphorylation of cyclic AMP response element binding protein(CREB)in the dorsal root ganglia and superficial dorsal horn neurons following chronic constriction injury

Objective To investigate whether chronic constriction injury(CCI)of the sciatic nerve of rats could produce alterations in the phosphorylation of cyclic AMP response element binding(CREB)protein in dorsal root ganglia(DRG)and superficial dorsal horn neurons of the spinal cord.Methods Chronic constriction injury(CCI)of the sciatic nerve was employed as a model of neuropathic pain.Thirty-two Sprague-Dawley rats were randomly divided into Na⒍ve,Sham,CCI2w(received CCI for2weeks)and CCI4w(received CCI for4weeks)groups.Hind pawwithdrawal threshold to mechanical stimuli and withdrawal latency to thermal stimuli were used to determine the mechanical and thermal hyperalgesia.Then all the rats were deeply anesthetized and perfused intracardially with paraformaldehyde.The fixed L 4-5 spinal cord and the L 5 DRG ipsilateral to CCI were harvested for fixation.The pCREB-immunoreactive(pCREB-IR)cells in both DRG and superficial dorsal horn neurons were quantified for analysis using immunohistochemistry methods.Results On the14th day after sciatic nerve injury,all the rats exhibited significant mechanical and thermal hyperalgesia.The mechanical withdrawal thresholds to von Frey filament from CCI2w group decreased significantly compared to both baseline values and those of Sham group(P<0.01);Thermal withdwal latencies from CCI2w group decreased significantly compared to both baseline values and those of Sham group(P<0.01).Some rats from Sham group also showed mechanical hyperalgesia compared to both baseline values and those of Na⒍ve group(P<0.01).28days after CCI,both mechanical and thermal hypersensitivity were significantly alleviated,with no statistical significance compared to those of Sham group.On the14th day after CCI,the number of pCREB-IR cells significantly increased in ipsilateral L 5 DRGs and superficial dorsal horns(P<0.01)compared to Sham group.The number of phosphorylated CREB-IR cells in the ipsilateral DRGs from Sham group also increased compared to that of Naive rats(P<0.05).There were no significant statistical differences of numbers of CREB-IR neuron between Sham group and CCI4wgroup.Conclusion CCI increases CREB phosphorylation both in DRG and superficial dorsal horn neurons of the lumbar spinal cord,and may be one of the key molecular mechanisms of central and peripheral sensitization following peripheral nerve injury.