From neuroanatomy to gene therapy: searching for new ways to manipulate the supraspinal endogenous pain modulatory system

Abstract

The endogenous pain modulatory system is a complex network of brain areas that control nociceptive transmission at the spinal cord by inhibitory and facilitatory actions. The balance between these actions ensures effective modulation of acute pain, while during chronic pain the pronociceptive effects appear to prevail. The mechanisms underlying this imbalance were studied as to the role of two medullary components of the pain modulatory system: the dorsal reticular nucleus and the caudal ventrolateral medulla, which function primarily as pronociceptive and antinociceptive centres, respectively. Both areas are connected with the spinal dorsal horn by closed reciprocal loops. In the spino-dorsal reticular nucleus loop, the ascending branch is strongly inhibited by spinal GABAergic neurons, which may act as a buffering system of the dorsal reticular nucleus-centred amplifying effect. In the spinocaudal ventrolateral medulla loop, the ascending branch is under potent excitation of substance P (SP) released from primary afferents, which is likely to trigger the intense descending inhibition detected in acute pain. During chronic pain, the activity in the lateral reticular formation of the caudal ventrolateral medulla changes, so that the action of the caudal ventrolateral medulla upon SP-responsive spinal neurons shifts from inhibitory to excitatory. The mechanisms of this modulatory shift are unknown but probably relate to the decresed expression of µ -opioid, δ -opioid and GABA B receptors. Normalizing receptor expression in the caudal ventrolateral medulla or controlling noci-evoked activity at the dorsal reticular nucleus or caudal ventrolateral medulla by interfering with neurotransmitter release is now possible by the use of gene therapy, an approach that stands out as a unique tool to manipulate the supraspinal endogenous pain control system.

Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

“…The analgesia induced upon cVLMlat stimulation is more intense, 75 and the neurons project to the spinal laminae involved in pain transmission (laminae I, IV, V and X). 74,76 The cVLMlat also targets the dorsal horn indirectly through other components of the pain modulatory system, specifically through the pontine A5 noradrenergic cell group. 74,77 Terminals of descending pathways originating in the rostroventral medulla (RVM) and other brainstem nuclei (for example, nucleus raphe magnus, A5, A6 and A7 nuclei) interact with afferent fibers, interneurons and projection neurons in the dorsal horn.…”

“…74,76 The cVLMlat also targets the dorsal horn indirectly through other components of the pain modulatory system, specifically through the pontine A5 noradrenergic cell group. 74,77 Terminals of descending pathways originating in the rostroventral medulla (RVM) and other brainstem nuclei (for example, nucleus raphe magnus, A5, A6 and A7 nuclei) interact with afferent fibers, interneurons and projection neurons in the dorsal horn. 78 Several neurotransmitters are involved in these descending pathways, but serotonin and noradrenaline are the main neurotransmitters.…”

“…74 cVLM is one of the main inhibitory components of the endogenous pain modulatory system, and its stimulation induces analgesia in acute pain. 74 The reticular formation known as cVLMlat, located in the most lateral part of the cVLM between the spinal trigeminal nucleus (pars caudalis) and the lateral reticular nucleus, appears to be the cVLM region responsible for pain modulation. The analgesia induced upon cVLMlat stimulation is more intense, 75 and the neurons project to the spinal laminae involved in pain transmission (laminae I, IV, V and X).…”

The inhibitory effect of granisetron on ventrolateral medulla neuron responses to colorectal distension in rats

“…The present study is the first one to demonstrate the long-lasting dosedependent inhibitory effects of granisetron on VLM neuron evoked activity and depressor reactions to noxious CRD as well as the changes in these over time. As the VLM receives nociceptive inputs from gut via ascending afferent fibers of the spinothalamic tract and is implicated in the descending modulation of nociceptive inputs via direct projections to the spinal dorsal horns (Gebhart and Ossipov, 1986;Janss and Gebhart, 1988;Tavares and Lima, 2007;Heinricher et al, 2009). It is obvious that the granisetron-induced decrease in the VLM-evoked activity is related to 5-HT 3 receptor blockade either within the spinal cord or immediately within the brainstem.…”

The Analgesic Effect of Paeoniflorin on Neonatal Maternal Separation–Induced Visceral Hyperalgesia in Rats

“…21,24 Serotoninergic, noradrenergic, and opioidergic networks comprise major components of these descending mechanisms. 31 Drugs such as opioid substances, serotonergic agents, a 2 -adrenergic antagonists, and so forth, have been proposed to interfere with visceral sensitivity in IBS; these drugs should reduce visceral pain as well as reverse the processes underlying the persistence of visceral hypersensitivity. 13 Recent research has provided strong evidence to demonstrate the involvement of -opioid and ␣ 2 -adrenoceptors receptors in centrally controlled inhibition of visceral pain.…”