Project Summary:
Epidemiological studies have shown that temporomandibular disorders (TMDs) pain and migraine headache are
closely associated. Specifically, migraine headache appears to be more prevalent in women with myogenic TMD.
However, the molecular mechanisms for TMD pain and its comorbidity with migraine as well as their sex
differences remain poorly understood. Our long-term goal is to identify potential targets for developing a novel
therapy for TMD and migraine overlapping pain. In our preliminary studies, we have developed an animal model
to study TMD pain and its comorbidity with migraine by combining masseter muscle tendon ligation (MMTL)-
produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like pain, and this work
has been published recently. Using RNA sequencing followed by qPCR confirmation, we identified trigeminal
dynorphin as a potential female-specific therapeutic target for this overlapping pain condition. We observed for
the first time that blockade of dynorphin in the spinal trigeminal nucleus caudalis (Sp5C) of female mice
significantly inhibits myogenic TMD pain and diminishes TMD-enhanced migraine-like pain, and that Sp5C
injection of dynorphin enables a non-sensitizing dose of NTG to produce persistent migraine-like pain in female
mice, but not male mice. We further found that Sp5C antagonism of bradykinin receptor, but not kappa opioid
receptor, inhibits such overlapping pain in female mice. Moreover, bradykinin receptor B2 (BKRB2), but not
BKRB1, is expressed in the Sp5C, and MMTL plus NTG treatment decreases the binding of BKRB2 with neuronal
nitric oxide synthase (nNOS) and increases NOS activity in the Sp5C, which will increase nitric oxide production
and then promote migraine pain development. These results suggest that Sp5C dynorphin could play a female-
specific role in TMD pain and its comorbidity with migraine through a non-opioid receptor mechanism. In this
project, we will determine the central mechanisms by which trigeminal dynorphin contributes to TMD and
migraine overlapping pain condition. Our hypothesis is that trigeminal dynorphin enhances TMD and migraine
comorbidity in female mice by activating bradykinin receptor BKRB2 and then inhibiting its binding with nNOS to
increase nitric oxide production in the Sp5C, thereby promoting TMD and migraine overlapping pain. To test this
central hypothesis, we will use multidisciplinary approaches to characterize female-specific role of trigeminal
dynorphin in TMD and migraine overlapping pain (Aim 1), determine the receptor mechanism for dynorphin in
trigeminal pain regulation (Aim 2), and define the downstream pathway of dynorphin signaling in trigeminal
nociceptive system (Aim 3). Collectively, we expect to reveal the central mechanisms by which trigeminal
dynorphin specifically contributes to TMD and migraine comorbidity in females. The proposed research is
significant since it will advance our understanding of TMD pain and its comorbidity. The proposed studies are
innovative since these studies will identify a previously unrecognized female-specific role for dynorphin in
trigeminal overlapping pain condition.
