Background Injury to the trigeminal nerve often results in the development
Background Injury to the trigeminal nerve often results in the development of chronic pain states including tactile allodynia or hypersensitivity to light touch in orofacial area but its underlying mechanisms are poorly understood. and mismatch oligodeoxynucleotides were intrathecally injected into injured rats to see if antisense BMP3 oligodeoxynucleotide treatment could reverse injury-induced TSP4 upregulation and orofacial behavioral hypersensitivity. Results Our data indicated that trigeminal nerve injury induced TSP4 upregulation in Vc/C2 at a time point correlated with orofacial tactile allodynia. In addition intrathecal treatment with TSP4 antisense but not mismatch oligodeoxynucleotides blocked both injury-induced TSP4 upregulation in Vc/C2 and behavioral hypersensitivity. Conclusions Our data support that infraorbital nerve injury leads to TSP4 upregulation in trigeminal spinal complex that contributes to orofacial neuropathic pain states. Blocking this pathway may provide an alternative approach in management of orofacial neuropathic pain states. Introduction Neuropathic pain is a disorder of chronic pain resulting from injuries Tarafenacin to the peripheral or central nervous systems and adversely affecting the life quality of a large patient population (Jensen is the value of the final von Frey filament used in log units is the tabular value for the positive/negative response patterns from Chaplan et al. (1994) and is the mean differences between stimuli in log units. Scores of 0.25 g or Tarafenacin 15 g were assigned respectively when consecutive positive or negative responses were observed. A small percentage of injured rats displayed a bilateral drop in behavioral thresholds after three weeks of injury (Vos Tarafenacin tests as indicated. Significance was indicated by a two-tailed p value < 0.05. Results Infraorbital nerve injury induced TSP4 upregulation in Vc/C2 that correlated with orofacial tactile allodynia We hypothesized that if infraorbital nerve injury leads to TSP4 dysregulation that is critical in orofacial neuropathic pain development injury-induced TSP4 dysregulation should correlate temporally with the development of orofacial pain states. To test this hypothesis we examined if TSP4 protein expression was altered in Vc/C2 and associated trigeminal ganglia in the CCI-ION orofacial neuropathic pain model (Vos et al. Tarafenacin 1994 and if so whether changes in TSP4 expression correlated temporally with the development of orofacial neuropathic pain states. As indicated in Fig. 1 unilateral CCI-ION injury resulted in a orofacial hypersensitive state (about 3 weeks post injury) shown as reduced orofacial thresholds to von Frey filament stimuli in the injury side compared with that from the noninjury side (n = 10) or sham (n = 8) operated rats similar to that initially described by Vos et al (1994). The allodynic state in the injured rats lasted for about 7-8 weeks followed by a graduate recovery. Fig. 1 Chronic constriction injury to the rat infraorbital nerve (CCI-ION) caused orofacial hypersensitivity to mechanical Tarafenacin stimuli TSP4 expression levels were examined in Vc/C2 and TG samples collected from CCI-ION rats at different stages of orofacial allodynia development: 1) One-week post injury before the onset of allodynia; 2) Three-weeks post injury when the injured rats displayed severe allodynia; and 3) 10-weeks post injury when the injured animals recovered from allodynia. As shown in Fig. 2 TSP4 levels were similar between the injury and non-injury sides in both Vc/C2 and TG samples collected one-week post CCI-ION before the onset of orofacial allodynia (n = 6). However CCI-ION injury induced TSP4 upregulation in Vc/C2 but down regulation in TG from the injury side at the orofacial hypersensitive stage (three-week post CCI-ION n = 5) which were not observed from sham control samples (n = 5) collected at the same time point (data not shown). Both of these changes in the injury side were recovered to a level similar to that from the non-injury side when the injured rats were recovered from orofacial allodynia (10-weeks post CCI-ION n = 4). This temporal correlation between orofacial hypersensitivity and injury-induced TSP4 upregulation in Vc/C2 suggests that increased TSP4 in Vc/C2 may play a critical role in orofacial pain processing. Fig. 2 TSP4 dysregulation in TG and Vc/C2 of CCI-ION rats with orofacial behavioral hypersensitivity Tarafenacin Intrathecal TSP4 antisense oligodeoxynucleotide treatments.