Sex-Related Differences in Human Pain and Rat Afferent Discharge Evoked by Injection of Glutamate Into the Masseter Muscle

Abstract

Animal studies have suggested that tissue injury-related increased levels of glutamate may be involved in peripheral nociceptive mechanisms in deep craniofacial tissues. Indeed, injection of glutamate (0.1-1 M, 10 microl) into the temporomandibular region evokes reflex jaw muscle responses through activation of peripheral excitatory amino acid receptors. It has recently been found that this glutamate-evoked reflex muscle activity is significantly greater in female than male rats. However, it is not known whether peripheral administration of glutamate, in the same concentrations that evoke jaw muscle activity in rats, causes pain in humans or activates deep craniofacial nociceptive afferents. Therefore we examined whether injection of glutamate into the masseter muscle induces pain in male and female volunteers and, since masseter afferent recordings were not feasible in humans, whether glutamate excites putative nociceptive afferents supplying the masseter muscle of male and female rats. Injection of glutamate (0.5 M or 1.0 M, 0.2 ml) into the masseter muscle of both men and women caused significantly higher levels of peak pain, duration of pain, and overall pain than injection of isotonic saline (0.2 ml). In addition, glutamate-evoked peak and overall muscle pain in women was significantly greater than in men. In rats of both sexes, glutamate (10 microl, 0.5 M) evoked activity in a subpopulation of masseter muscle afferents (n = 36) that projected to the subnucleus caudalis, an important relay of noxious input from the craniofacial region. The largest responses to glutamate were recorded in muscle afferents with the slowest conduction velocities (2.5-5 m/s). Further, glutamate-evoked masseter muscle afferent activity was significantly greater in female than in male rats. These results indicate that glutamate injection into the masseter muscle evokes pain responses that are greater in women than men and that one possible mechanism for this difference may be a greater sensitivity to glutamate of masseter muscle afferents in females. These sex-related differences in acute experimental masseter muscle pain are particularly interesting given the higher prevalence of many chronic muscle pain conditions in women.

p-Cymene reduces orofacial nociceptive response in mice

“…Noxious stimulation of primary afferent fibers results in the release of glutamate from the peripheral as well as central terminals of trigeminal and spinal afferent fibers (Keast & Stephensen, 2000;Lam et al, 2005). In addition, glutamate injection into the rat masseter muscle or temporomandibular joint (TMJ) reflexly evokes a dose-dependent increase in jaw muscle electromyographic (EMG) activity (Cairns et al, 1998;Cairns et al, 2001a;Cairns et al, 2001b, Cairns et al, 2002 and central sensitization of trigeminal brainstem nociceptive neurons (Lam et al, 2009b). Similarly, glutamate injection into the human masseter muscle causes pain and mechanical hyperalgesia that may be attenuated by co-injection of a NMDA receptor antagonist (Cairns et al, 1998).…”

Studying sex and gender differences in pain and analgesia: A consensus report

“…This dearth of information makes it premature to suggest which protocols or animal species are most relevant to any particular human pain condition. One valuable approach involves parallel testing in the animal and human laboratory (e.g., [29]). …”

“…Studies of experimentally induced hyperalgesia have demonstrated robust sex differences [29,70,71], but not all aspects of pain show significant sex differences in these models. Such observations provide the opportunity to selectively evaluate different mechanisms of hyperalgesia, and identify those in which sex is a significant factor.…”

Potential Muscle Biomarkers of Chronic Myalgia in Humans - A Systematic Review of Microdialysis Studies

“…Glutamate, a pain modulator in the human central nervous system, acts via the N-methyl-Daspartate (NMDA) receptor (Coggeshall & Carlton, 1997) (Hudspith, 1997) and influences peripheral pain processing (Carlton, 2001;Varney & Gereau, 2002 ), e.g., muscle inflammation and delayed onset muscle soreness (Cairns et al, 2001a;Cairns et al, 2001b;Cairns et al, 2003;Svensson et al, 2003;Svensson et al, 2005;Tegeder et al, 2002 ). Glutamate is released from peripheral afferent nerve terminals (Miller et al, 2011).…”