Central Nervous Mechanisms of Muscle Pain: Ascending Pathways, Central Sensitization, and Pain-Modulating Systems

Abstract

The afferent fibers from muscle nociceptors make the first synaptic contacts in two regions of the spinal cord, the most superficial layer and the neck of the dorsal horn (lamina I and laminae IV–VI, respectively). The postsynaptic neurons send their axons into several ascending tracts that all mediate muscle pain: the spinothalamic, spinoreticular, and spinomesencephalic tracts. For orofacial muscle pain the first synaptic contacts are located in the subnucleus caudalis (the caudeal part) of the spinal trigeminal nucleus in the brainstem. The next center for the processing of nociceptive information is the thalamus, namely the most caudal parts of the ventral posterolateral nucleus (VPL) for the body and the ventral posteromedial (VPM) nucleus for the head. At the cortical level a center specific for muscle pain does not appear to exist. The nociceptive information is processed in various areas including the primary and secondary somatosensory cortices, prefrontal cortex, insula, and anterior cingulate cortex. Central sensitization consists of several processes that occur in a temporal order, albeit with great overlap: increased excitability of nociceptive neurons, opening of formerly ineffective or silent synapses, metabolic changes, and changes in gene expression of the postsynaptic neuron. In patients, the increased excitability and resting activity of central nociceptive neurons is reflected in allodynia, hyperalgesia, and spontaneous pain. The final stage involves morphological changes in the wiring of the nociceptive network which perpetuate the chronic hyperexcitability and -activity. Endogenous pain-modulating systems comprise firstly the afferent or segmental inhibition. The underlying mechanism of this type of pain modulation is the inhibition of the spinal nociceptive transmission by an input in thick myelinated afferent fibers. These fibers supply sensitive (non-nociceptive) receptors in the skin and deeper tissues. The second system is the descending inhibition, which originates in the mesencephalon and has synaptic connections with neurons in the rostral ventral medulla and the spinal cord. The system is tonically active and permanently dampens the excitability of nociceptive neurons at the origin of the spinothalamic tract. The system is tightly connected to a descending pain-facilitating pathway that has the same site of origin (mesencephalon and medulla) and facilitates nociceptive transmission in spinal nociceptive neurons. The final inhibition of spinal neurons is exerted by neurons that use enkephalin, serotonin, or norepinephrine as a transmitter. The presence of several pain-modulating systems explains why pain can occur in the absence of any noxious stimulus (for instance, in patients who have a dysfunction of the descending pain-inhibiting pathway), or why even strong injuries do not elicit subjective pain (for instance, in injured soldiers in combat).