Sex-related differences in response to masseteric injections of glutamate and nerve growth factor in healthy human participants

AbstractThe neurophysiological mechanisms underlying NGF-induced masseter muscle sensitization and sex-related differences in its effect are not well understood in humans. Therefore, this longitudinal cohort study aimed to investigate the effect of NGF injection on the density and expression of substance P, NMDA-receptors and NGF by the nerve fibers in the human masseter muscle, to correlate expression with pain characteristics, and to determine any possible sex-related differences in these effects of NGF. The magnitude of NGF-induced mechanical sensitization and pain during oral function was significantly greater in women than in men (P < 0.050). Significant positive correlations were found between nerve fiber expression of NMDA-receptors and peak pain intensity (rs = 0.620, P = 0.048), and expression of NMDA-receptors by putative nociceptors and change in temporal summation pain after glutamate injection (rs = 0.561, P = 0.003). In women, there was a significant inverse relationship between the degree of NGF-induced mechanical sensitization and the change in nerve fiber expression of NMDA-receptors alone (rs = − 0.659, P = 0.013), and in combination with NGF (rs = − 0.764, P = 0.001). In conclusion, women displayed a greater magnitude of NGF-induced mechanical sensitization that also was associated with nerve fibers expression of NMDA-receptors, when compared to men. The present findings suggest that, in women, increased peripheral NMDA-receptor expression could be associated with masseter muscle pain sensitivity.

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Sex-Related Differences in Response to Masseteric Injections of Glutamate and Nerve Growth Factor in Healthy Human Participants

10.21203/rs.3.rs-111827/v1 ◽

2020 ◽

Author(s):

Abdelrahman Alhilou ◽

Akiko Shimada ◽

Camilla Svensson ◽

Peter Svensson ◽

Malin Ernberg ◽

...

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Masseter Muscle ◽

Pain Sensitivity ◽

Nerve Fibers ◽

Receptor Expression ◽

Healthy Human ◽

Neurophysiological Mechanisms ◽

Human Participants ◽

Positive Correlations

Abstract The neurophysiological mechanisms underlying NGF-induced masseter muscle sensitization and sex-related differences in its effect are not well understood in humans. Therefore, this longitudinal cohort study aimed to investigate the effect of NGF injection on density and expression of substance P, NMDA-receptor and NGF by the nerve fibers in the human masseter muscle, to correlate expression with pain characteristics, and to determine any possible sex-related differences in these effects of NGF. The magnitude of NGF-induced mechanical sensitization and pain during the oral function was significantly greater in women than in men (P<0.050). Significant positive correlations were found between nerve fibers expression of NMDA-receptors and peak pain intensity (rs=0.620,P=0.048), and expression of NMDA-receptors by putative nociceptors and change in temporal summation pain after glutamate injection (rs=0.561,P=0.003). In women, there was a significant inverse relationship between the degree of NGF-induced mechanical sensitization and the change in nerve fibers expression of NMDA-receptors alone (rs=-0.659,P=0.013), and in combination with NGF (rs=-0.764,P=0.001). In conclusion, women displayed a greater magnitude of NGF-induced mechanical sensitization, that also was associated with nerve fibers expression of NMDA-receptors, when compared to men. The present findings suggest that, in women, increased peripheral NMDA-receptor expression could be associated with masseter muscle pain sensitivity.

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Nerve growth factor and glutamate increase the density and expression of substance P-containing nerve fibers in healthy human masseter muscles

Scientific Reports ◽

10.1038/s41598-021-95229-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Abdelrahman M. Alhilou ◽

Akiko Shimada ◽

Camilla I. Svensson ◽

Peter Svensson ◽

Malin Ernberg ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Nmda Receptors ◽

Masseter Muscle ◽

Temporomandibular Disorder ◽

Nerve Fibers ◽

Receptor Subtype ◽

Nerve Growth ◽

Afferent Fibers ◽

Pain Characteristics

AbstractNocifensive behavior induced by injection of glutamate or nerve growth factor (NGF) into rats masseter muscle is mediated, in part, through the activation of peripheral NMDA receptors. However, information is lacking about the mechanism that contributes to pain and sensitization induced by these substances in humans. Immunohistochemical analysis of microbiopsies obtained from human masseter muscle was used to investigate if injection of glutamate into the NGF-sensitized masseter muscle alters the density or expression of the NMDA receptor subtype 2B (NR2B) or NGF by putative sensory afferent (that express SP) fibers. The relationship between expression and pain characteristics was also examined. NGF and glutamate administration increased the density and expression of NR2B and NGF by muscle putative sensory afferent fibers (P < 0.050). This increase in expression was greater in women than in men (P < 0.050). Expression of NR2B receptors by putative sensory afferent fibers was positively correlated with pain characteristics. Results suggest that increased expression of peripheral NMDA receptors partly contributes to the increased pain and sensitivity induced by intramuscular injection of NGF and glutamate in healthy humans; a model of myofascial temporomandibular disorder (TMD) pain. Whether a similar increase in peripheral NMDA expression occurs in patients with painful TMDs warrants further investigation.

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