The structural and electrophysiological properties of the spinal cord during diabetes described earlier present a picture that resembles the paradox often noted in studies of the peripheral nerve, namely structural and electrophysiological indices of progressive degeneration and functional loss that are accompanied by increased activity in some sensory fibers and associated with hyperalgesia, allodynia, or spontaneous pain. There has been speculation that the spontaneous or enhanced activity of spinal sensory pathways is responsible for diabetic neuropathic pain and is secondary to enhanced excitatory input from peripheral nerve primary afferent fibers. This is difficult to verify in clinical studies, whereas evidence of spontaneous or exaggerated evoked activity of primary afferents in animal models of diabetes has been reported in some studies (56-59) but also discounted in others (60,61). Of course, electrical activity of sensory fibers is only one component of any altered input to the spinal cord and other factors, such as the amount of available neurotransmitters and patency of vesicular release mechanisms, must also be considered. To date, few studies have addressed spinal neu-rotransmitter release properties during diabetes. Current evidence obtained using in vitro perfusion and in vivo spinal microdialysis techniques indicates that evoked release of the excitatory amino acid neurotransmitter glutamate that drives nociception and of neuropeptides that modulate nociceptive processing are diminished, rather than exaggerated, in diabetic animals (62-65). Such depression of sensory input is consistent with the general view of peripheral nerve as developing a degenerative phenotype during prolonged diabetes where, even if overt degenerative pathology is not observed in rodents, loss of neurotrophic support leads to decreased synthesis, axonal transport and therefore evoked release of neuropeptides (see ref. 66). While the stimulus-evoked release of excitatory neurotransmitters is reduced in diabetic rats, the appearance of prostaglandin E2 (PGE2) in spinal dialysates after paw stimulation is prolonged and accompanied by an increase in paw flinching behavior indicative of hyperalgesia (67). The release of PGE2 in the spinal cord is triggered by primary afferent input and is responsible for the subsequent sensitization of spinal sensory processing systems that contributes to hyper-algesia in a number of models of neuropathic pain (68,69). Increased PGE2 release in the cord of diabetic rats after paw stimulation with formalin is accompanied by an increase in the amount of protein for the enzyme cyclooxygenase-2 (COX-2), which converts arachidonate to prostaglandins (67). Moreover, spinal delivery of inhibitors of cyclooxygenase prevents the increase in formalin-evoked flinching of diabetic rats. Together, these data suggest that a diabetes-induced increase in spinal COX-2 may underlie spinal sensitization and hyperalgesia in rats, although presently it is not clear how diabetes causes the increase in COX-2 or which cells of the spinal cord are involved in modifying spinal sensory processing.
The complexities of the distribution and actions of neurotransmitter receptors in the spinal cord and their role in spinal pain processing are still being unravelled for many neuropathic pain conditions, including diabetes. Models of simple synaptic transmission involving excitatory postsynaptic receptors have been augmented by including consideration of the role of descending inhibitory systems that can act on both pre- and postsynap-tic receptors and by the growing appreciation that modulation of synaptic function can also occur through both the postsynaptic neuron and other cells, such as astrocytes and microglia (reviewed in refs. 70,71). A thorough appreciation of the involvement of a particular receptor in diabetic neuropathy requires understanding of a number of parameters including: the amount of receptor protein; location of the receptor (both within the cell and in different cell types); receptor turn-over patterns; ligand binding and channel activation properties, and the function of downstream signaling cascades. At present, the literature offers some interesting snapshots of the effects of diabetes on spinal receptors (see Table 1) but a detailed evaluation of spinal sensory processing mechanisms is lacking.
It has been previously speculated that decreased excitatory neurotransmitter input to the spinal cord as a result of a hyperglycemia-induced shift in the phenotype of primary afferents could lead to a sensitized postsynapse through upregulation of receptors for the excitatory neurotransmitter glutamate and the modulating neuropeptides substance P and CGRP. This hypothesis was prompted by the observation that whereas peripherally-evoked spinal release of substance P is reduced in diabetic rats, direct delivery of substance P to the spinal cord of diabetic rats elicits a protracted hyperalgesic response (52,65). The biological precedent for such a mechanism is seen in skeletal muscle, which responds to denervation and loss of cholinergic excitatory input by increasing the amount of ACH receptor protein and progressing to a state of denervation hypersensitivity (see ref. 72). Of the few studies published to date, ligand binding experiments have reported increased binding of substance P in the spinal cord of diabetic rats (73) and of ligands for both the AMPA and NMDA glutamate receptors in genetically diabetic ob/ob mice (74). Increased ligand binding could reflect elevated protein production, as mRNA levels for the glutamatergic AMPA receptor, the R2 subunit of the glutamatergic NMDA receptor and assorted metabotropic glutamate receptors are also increased in the dorsal horn of the spinal cord from diabetic rats (75), although the own studies have been unable to detect increased protein for either the NK-1 substance P receptor or the NMDA R1 subunit in the cord of diabetic rats (Jolivalt and Calcutt, unpublished observations).
A variety of neurotransmitters regulate spinal synaptic activity after release from descending inhibitory systems, interneurons or glial cells. Opiates have long been known to have a spinal site of analgesic action. Although there appears to be no change in the amount of protein for the ^-opioid receptor in the cord of diabetic rats (76), receptor functions, as indicated by measuring downstream signaling activity, is reduced (77). Suppression of opioid receptor function could account for reports of reduced efficacy of agents, such as morphine, against pain in diabetic subjects and perhaps also impede any tonic inhibitory tone acting through this mechanism. Other plausible contributors to inhibitory tone in the spinal cord include adrenergic and GABAergic systems. Both mRNA for the a2-adrenoceptor sub-type and ligand binding to the a2-adrenoceptor are reduced in the cord of diabetic rats (78) so that a loss of inhibitory tone could well contribute to spinal sensitization. In contrast, there have been reports suggesting increased number or activity of spinal muscarinic ACH receptors (79), bradykinin B1 receptors (80), and serotonin receptors (Jolivalt and Calcutt, unpublished), although the significance of these findings to spinal sensory processing remains to be established.
Many studies have used receptor agonists or antagonists in attempts to address the effects of diabetes on spinal sensory processing and to develop treatments for neuropathic pain (reviewed in ref. 81). However, there are a number of caveats that prompt caution
Effects of Diabetes on Spinal Cord Receptors
Effects of Diabetes on Spinal Cord Receptors
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