Background & Aims
Classical trigeminal neuralgia (cTN) is a form of neuropathic pain characterized by sudden, brief, stabbing and recurrent pain in the distribution of the trigeminal nerve. The pain is considered to be amongst the worst known. Vascular compression of trigeminal nerve is most likely the primary cause of this disorder. The antiepileptic drug Carbamazepine (CBZ) is effective in a subpopulation of cTN patients. However, CBZ has failed to show efficacy in clinical trials concerning other types of neuropathic pain associated with peripheral nerve compression. CBZ is a GABAA receptor (GABAR) agonist and a blocker of voltage-gated Na+ channels (VGSC). Our data suggest that differences between trigeminal and somatic nerves with respect to the VGSC present are not sufficient to account for the therapeutic selectivity of CBZ. Hence, we hypothesized that a unique combination of changes in the GABARs in somatic and trigeminal nerves account for the therapeutic selectivity of CBZ in the context of TN
Methods
Using rat models of somatic (chronic constriction injury of sciatic nerve, CCI-SN) and trigeminal (CCI of infraorbital nerve, CCI-ION) nerve compression we compared the sensitivity of evoked (von Frey and orofacial pain tests) pain behavior, and compound action potential (CAP) to CBZ in the presence and absence of the GABAR blocker picrotoxin. We also evaluated the efficacy of the GABAR agonist muscimol in the CAP. We assessed the expression of GABAARs subunits mRNA in the DRG and TG, and protein in the SN and ION. Once we determined that GABAA-rho receptor was selectively modulated by injury, we evaluated the effect of CBZ in the presence of the rho receptor selective antagonist TPMPA. Then, we tested the effect of the agonist TACA on the CAP and evoked pain behavior. To ensure selectivity of the drug, we co-administered the GABAAR antagonist bicuculine. Finally, we silenced in-vivo the expression of the GABAA-rho receptor locally at the ION and evaluated the effect of CBZ and TACA.
Results
CBZ reduced pain behavior in rats with CCI-ION, but not with CCI-SN. The effect was dose-, sex-dependent: Females were more sensitive to CBZ. The potency and efficacy of CBZ-induced CAP inhibition was increased following CCI of the ION, but not of the SN, and this increase was reduced by picrotoxin. The effect in CAP inhibition was also greater in females. The potency of muscimol-induced block of the ION was also greater than the SN, and CCI produced a further increase in efficacy. GABAA-rho subunit mRNA and protein were increased by CCI of the ION, but not SN. TPMPA reduced CBZ-induced CAP block of the ION and CCI increased the potency of TACA-induced block of the ION, but not SN. Local administration of TACA to the ION but not SN, dose- and sex-dependently reversed CCI-induced mechanical sensitivity. Administration of TPMPA but not bicuculline reversed the effect of TACA Finally, silencing of GABAA-rho 3 but not 2 subunit reversed the effect of CBZ and TACA on the orofacial pain test
Conclusions
Taken altogether, our results suggest GABAA-rho receptors are present and functional in ION, but not SN. This differential distribution of GABAA receptors could account for the therapeutic selectivity of carbamazepine for the treatment of TN.
References
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Pineda-Farias JB, Loeza-Alcocer E, Nagarajan V, Gold MS, Sekula RF Jr. Mechanisms Underlying the Selective Therapeutic Efficacy of Carbamazepine for Attenuation of Trigeminal Nerve Injury Pain. J Neurosci. 2021 Oct 27;41(43):8991-9007. doi: 10.1523/JNEUROSCI.0547-21.2021. Epub 2021 Aug 26. PMID: 34446571; PMCID: PMC8549540.
Presenting Author
Jorge B Pineda-Farias
Poster Authors
JORGE PINEDA FARIAS
PhD
University of Pittsburgh
Lead Author
Jose E Loeza-Alcocer
PhD
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Lead Author
Raymond Sekula
Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA
Lead Author
Michael S. Gold
PhD
University of Pittsburgh
Lead Author
Topics
- Models: Chronic Pain - Neuropathic