Background & Aims
Painful Post-Traumatic Trigeminal Neuropathies (PTTN) are debilitating conditions with limited treatment options, and their underlying mechanisms remain unclear [1-4]. Current management relies on trial and error, offering only moderate pain relief and often causing side effects. Identifying better prognostic markers is crucial for targeting treatments effectively. Exercise has been proven to activate the central nervous system’s pain inhibitory modulation system, providing relief in clinical settings. Exercise-Induced Hypoalgesia (EIH) can serve as a measure of this system’s effectiveness. We demonstrated that rats with inefficient EIH (low EIH) experience more severe pain after nerve injury [5]. Although orofacial pain shares some mechanisms with other types of pain, it also presents unique characteristics. This study aims to explore the relationship between EIH profile and pain severity in PTTN-afflicted rats, along with assessing gene and protein expression levels in their trigemin
Methods
SD rats (n=40) were used in this study.
EIH profiles were assessed by measuring paw responses to mechanical stimuli before and after exercise on a rotating rod. Rats with responses reduction of ?33% were classified as low EIH and those with ?67% as high EIH. Low and high EIH rats underwent ION constriction injury and naive rats served as control (n=10/EIH profile).
Mechanical hypersensitivity was measured in the face at baseline and after ION-CCI. Allodynia was assessed with Semmes-Weinstein filaments sorted by ranks expressing the log10 of the force bending the filament (Stoelting, Wood Dale, IL). The lowest fiber to generate a response was designated as a detection threshold. Hyperalgesia was tested with pinprick stimulation. The responses were scored from 0=no response to 4 attack with excessive grooming. Increase in score indicated hypersensitivity.
Total RNA and protein were extracted from ipsilateral trigeminal ganglia and IONs for molecular analyses.
Results
Infraorbital Nerve Injury: Low EIH rats develop more significant mechano-allodynia and hyperalgesia on days 17 and 10 following ION-CCI, compared to H-EIH rats.
Gene expression changes in the TG: Prior to injury, there were no significant differences in mRNA levels of investigated genes in the I-TG of H- (n=3) vs L-EIH rats (n=3).
Following, ION-CCI, several genes including Adrb2, Csf1, and Itgam were differentially regulated between the H- (n=4) and L-EIH (n=4) rats. Additionally, cannabinoid receptor 2 (Cnr2) gene was significantly more downregulated in I-TG of H-EIH rats (FR=-3.29) than in low EIH rats (FR=-1.8, p-value=0.01). CNR2 mediates inhibition of adenylate cyclase enzyme and thus indirectly contributes to attenuation of neuropathic pain through inhibition of cAMP production [6, 7]. Finally, Dbh gene was significantly upregulated in the I-TG of H- but not L-EIH rats compared to corresponding naïve controls.
Protein expression changes in the ION: Following ION-CCI, Low EIH rats demonstrate higher levels of pro-inflammatory cytokines and lower level of anti-inflammatory cytokines in the peripheral nerve compared to high EIH rats.
Conclusions
Rats with less efficient EIH develop significantly more pain than rats with efficient EIH following nerve injury. Our preliminary findings suggest that enhanced inflammatory response in low EIH rats might contribute to enhanced hypersensitivity compared to high EIH. Additionally, transcriptional regulation in the trigeminal ganglion, particular adenylyl cyclase pathway and cAMP signaling might contribute to the observed differences in response to injury between high and low EIH rats. Taken together, our preliminary RT-PCR analyses of 84 inflammatory and neuropathic pain genes suggest that transcriptional changes in the ipsilateral TG following ION-CCI may contribute to the differences in response to mechanical stimulation between low and high EIH rats; and that it might be the enhanced immune response that drives more severe hypersensitivity in L-EIH rats. Additionally, upregulation of Dbh gene in I-TG of high EIH rats may result in enhanced conversion of dopamine to norepinephrine and
References
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3.McQuay, H.J., et al., A systematic review of antidepressants in neuropathic pain. Pain, 1996. 68(2-3): p. 217-27.
4.Moisset, X., et al., Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations. Rev Neurol (Paris), 2020. 176(5): p. 325-352.
5.Khan, J., et al., Exercise-induced hypoalgesia profile in rats predicts neuropathic pain intensity induced by sciatic nerve constriction injury. J Pain, 2014. 15(11): p. 1179-1189.
6.Liou, J.T., et al., Inhibition of the cyclic adenosine monophosphate pathway attenuates neuropathic pain and reduces phosphorylation of cyclic adenosine monophosphate response element-binding in the spinal cord after partial sciatic nerve ligation in rats. Anesth Analg, 2007. 105(6): p. 1830-7, table of contents.
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Presenting Author
Eli Eliav
Poster Authors
Eli Eliav
DMD, PhD
Eastman Institute for Oral Health, University of Rochester Medical Center
Lead Author
Olga Korczeniewska
Department of Diagnostic Sciences, Rutgers University
Lead Author
Qian Wang
Eastman Institute for oral Health, University of Rochester
Lead Author
Claire Lee
University of Rochester
Lead Author
Junad Khan
Eastman Institute for oral Health, University of Rochester
Lead Author
Yanfang Ren
Eastman Institute for oral Health, University of Rochester
Lead Author
Topics
- Models: Chronic Pain - Neuropathic