Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes

Abstract

Hyperalgesia to noxious stimuli is accompanied by increased spinal cyclooxygenase (COX)-2 protein in diabetic rats. The present studies were initiated to establish causality between increased spinal COX-2 activity and hyperalgesia during diabetes and to assess the potential involvement of polyol pathway activity in the pathogenesis of spinally mediated hyperalgesia. Rats with 1, 2, or 4 weeks of streptozotocin-induced diabetes exhibited significantly increased levels of spinal COX-2 protein and activity, along with exaggerated paw flinching in response to 0.5% paw formalin injection. Increased flinching of diabetic rats was attenuated by intrathecal pretreatment with a selective COX-2 inhibitor immediately before formalin injection, confirming the involvement of COX-2 activity in diabetic hyperalgesia. Chronic treatment with insulin or ICI222155, an aldose reductase inhibitor (ARI) previously shown to prevent spinal polyol accumulation and formalinevoked hyperalgesia in diabetic rats, prevented elevated spinal COX-2 protein and activity in diabetic rats. In contrast, the ARI IDD676 had no effect on spinal polyol accumulation, elevated spinal COX-2, or hyperalgesia to paw formalin injection. In the spinal cord, aldose reductase immunoreactivity was present solely in oligodendrocytes, which also contained COX-2 immunoreactivity. Polyol pathway flux in spinal oligodendrocytes provides a pathogenic mechanism linking hyperglycemia to hyperalgesia in diabetic rats. Diabetes 56: [1569][1570][1571][1572][1573][1574][1575][1576] 2007 A proportion of diabetic patients experience chronic pain that severely degrades their quality of life. The pathogenesis of painful diabetic neuropathy is unclear, and treatment options are currently limited to palliatives that do not target a pathogenic mechanism specific to painful diabetic neuropathy and provide limited efficacy before side effects become intolerable (1). Experimental models of diabetic neuropathy can spur development of novel therapies by providing an understanding of how diabetes alters sensory processing.Diabetic rats display abnormal pain-associated behaviors, measured as exaggerated responses to painful stimuli (hyperalgesia) or nocifensive responses to normally innocuous stimuli (allodynia). Hyperalgesia to paw formalin injection (2,3) and allodynia to tactile stimulation of the paw (4) develop within weeks of induction of hyperglycemia, and, as overt structural pathology in peripheral nerves is minimal, attention has focused on biochemical disorders that could exaggerate sensory processing.The formalin test is used to investigate spinal sensitization in animals (5) and allows investigation of sensory processing beyond peripheral nociceptive pathways. Diabetic rats exhibit increased nocifensive behavior during periods of the formalin test associated with spinal sensitization (6,7) in concert with paradoxically decreased spinal release of excitatory neurotransmitters (8,9). This suggests that hyperalgesia is not caused by increased primary afferent input and, toge...

Continuous -Opioid Receptor Activation Reduces Neuronal Voltage-Gated Sodium Channel (NaV1.7) Levels through Activation of Protein Kinase C in Painful Diabetic Neuropathy

“…The pathogenesis of pain in the setting of diabetes is complex. Previous studies have implicated involvement alterations in the peripheral kinin system (Gabra et al, 2006) and in peripheral vanilloid receptors (Hong and Wiley, 2005), in addition to described spinal and supraspinal mechanisms (Calcutt, 2002;Ramos et al, 2007) in the development of pain. The first study of sodium channels in peripheral nerve in PDN identified increases in RNA and protein of several voltage-gated sodium channel ␣ subunit isoforms, although in that study the investigators did not observe an increase in Na V 1.7 RNA or protein (Craner et al, 2002).…”

COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice

“…Formalin evokes an immediate short-lasting first phase due to the direct activation of TRPA1-expressing nociceptors (51) and a slower-onset, longer-lasting phase 2 that reflects a combination of ongoing sensory input and central sensitization in the spinal cord (37)(38)(39)(40). Several studies show that constitutive COX1 expression in the spinal cord is required for development of the second phase of the formalin test (36), while others point to a role for COX2 (26,49,50,52,53) or an involvement of both (48). Only a small, but significant, difference in the duration of formalin-mediated pain behavior in the second phase between nCOX2 -/-mice and their control littermates was observed, with no change in onset or peak of sensitivity.…”

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

“…Behavioral tests. Hind-paw withdrawal responses to von Frey filaments (50% paw withdrawal threshold in gram of force applied) and radiant heat (latency to withdrawal in seconds) and also paw flinching following injection of 50 μl 0.5% formalin were measured in conscious unrestrained animals (82,83).…”