Streptozotocin-induced diabetes in mice reduces the nociceptive threshold, as recognized after application of noxious mechanical stimuli but not of thermal stimuli

doi:10.1016/0091-3057(91)90224-P

Pharmacology Biochemistry and Behavior

Volume 39, Issue 2, June 1991, Pages 541-544

https://doi.org/10.1016/0091-3057(91)90224-P Get rights and content

Abstract

We report herein that streptozotocin (STZ)-induced diabetes selectively alters the nociceptive threshold with respect to noxious mechanical stimuli. Mice were rendered diabetic by an injection of STZ (200 mg/kg, IV). In the tail-pinch test, the latency of the biting response to forceps was significantly decreased in animals with diabetes of 2 weeks and 8 weeks duration as compared to that in age-matched controls. However, the nociceptive threshold, as determined by the tail-flick test, was not significantly altered. The level of substance P in the spinal cord was significantly increased in mice that has been diabetic for 2 weeks, while, there was a significant decrease, as compared to control levels, in level of substance P in mice diabetic for 8 weeks. However, the level of somatostatin was not significantly altered in mice diabetic for either 2 weeks or 8 weeks. These data suggest that STZ-induced diabetes selectively alters a neuronal system that involves substance P but not somatostatin in the spinal cord.

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Rodent models have been fundamental to understand chronic pain (CP) pathophysiology and to test for potential treatments. Pain assessment in CP models is most frequently based on the evaluation of allodynia or hyperalgesia. However, these correspond only to a part of CP-related problems which include ongoing pain, depression, anxiety, disrupted sleep and attentional deficits. A growing number of preclinical studies have been assessing these manifestations in CP rodent models. We reviewed and systematized this information by behavioral domain. Observational studies in ethologically relevant conditions, paradigms of anxiety- and depressive-like behavior as well as of memory and executive function were selected. A considerable number of studies reported deficits similar to those observed in CP patients. These behavioral alterations are informative regarding ongoing maladaptive plasticity in multiple brain regions and its use as pain proxies has the potential to greatly improve the predictive value of CP models. However, the inclusion of female and/or older rodents is rare which is in clear dissonance with the clinical representation of CP.
Blockade of CCR4 Diminishes Hypersensitivity and Enhances Opioid Analgesia – Evidence from a Mouse Model of Diabetic Neuropathy
2020, Neuroscience
Citation Excerpt :
Care was taken to minimize animal suffering and reduce the number of animals used in the experiments (3R policy). Streptozotocin (STZ) is often used in experimental studies (Kamei et al., 1991; Dogrul et al., 2011; Ohsawa et al., 2011; Murakami et al., 2013) to induce diabetic neuropathy by the specific necrosis of pancreatic beta cells (Lenzen, 2008; Bishnoi et al., 2011). In our experiments, a single intraperitoneal (i.p.) injection of STZ (200 mg/kg; Tocris, Bristol, United Kingdom), dissolved in water, was used to generate a model of type 1 diabetes (Lenzen, 2008; Murakami et al., 2013; Zychowska et al., 2015).
Chemokine signaling has been implicated in the pathogenesis of diabetic neuropathy; however, the role of chemokine CC motif receptor 4 (CCR4) remains unknown. The goal was to examine the function of CCR4 in hypersensitivity development and opioid effectiveness in diabetic neuropathy. Streptozotocin (STZ; 200 mg/kg, intraperitoneally administered)-induced mouse model of diabetic neuropathy were used. An analysis of the mRNA/protein expression of CCR4 and its ligands was performed by qRT-PCR, microarray and/or Western blot methods. C021 (CCR4 antagonist), morphine and buprenorphine were injected intrathecally or intraperitoneally, and pain-related behavior was evaluated by the von Frey, cold plate and rotarod tests. We observed that on day 7 after STZ administration, the blood glucose level was increased, and as a consequence, hypersensitivity to tactile and thermal stimuli developed. In addition, we observed an increase in the mRNA level of CCL2 but not CCL17/CCL22. The microarray technique showed that the CCL2 protein level was also upregulated. In naive mice, the pronociceptive effect of intrathecally injected CCL2 was blocked by C021, suggesting that this chemokine acts through CCR4. Importantly, our results provide the first evidence that in a mouse model of diabetic neuropathy, single intrathecal and intraperitoneal injections of C021 diminished neuropathic pain-related behavior in a dose-dependent manner and improved motor functions. Moreover, both single intrathecal and intraperitoneal injections of C021 enhanced morphine and buprenorphine effectiveness. These results reveal that pharmacological modulation of CCR4 may be a good potential therapeutic target for the treatment of diabetic neuropathy and may enhance the effectiveness of opioids.
Injury-induced gp130 cytokine signaling in peripheral ganglia is reduced in diabetes mellitus
2017, Experimental Neurology
Neuropathy is a major diabetic complication. While the mechanism of this neuropathy is not well understood, it is believed to result in part from deficient nerve regeneration. Work from our laboratory established that gp130 family of cytokines are induced in animals after axonal injury and are involved in the induction of regeneration-associated genes (RAGs) and in the conditioning lesion response. Here, we examine whether a reduction of cytokine signaling occurs in diabetes. Streptozotocin (STZ) was used to destroy pancreatic β cells, leading to chronic hyperglycemia. Mice were injected with either low doses of STZ (5 × 60 mg/kg) or a single high dose (1 × 200 mg/kg) and examined after three or one month, respectively. Both low and high dose STZ treatment resulted in sustained hyperglycemia and functional deficits associated with the presence of both sensory and autonomic neuropathy. Diabetic mice displayed significantly reduced intraepidermal nerve fiber density and sudomotor function. Furthermore, low and high dose diabetic mice showed significantly reduced tactile touch sensation measured with Von Frey monofilaments. To look at the regenerative and injury-induced responses in diabetic mice, neurons in both superior cervical ganglia (SCG) and the 4th and 5th lumbar dorsal root ganglia (DRG) were unilaterally axotomized. Both high and low dose diabetic mice displayed significantly less axonal regeneration in the sciatic nerve, when measured in vivo, 48 h after crush injury. Significantly reduced induction of two gp130 cytokines, leukemia inhibitory factor and interleukin-6, occurred in diabetic animals in SCG 6 h after injury compared to controls. Injury-induced expression of interleukin-6 was also found to be significantly reduced in the DRG at 6 h after injury in low and high dose diabetic mice. These effects were accompanied by reduced phosphorylation of signal transducer and activator of transcription 3 (STAT3), a downstream effector of the gp130 signaling pathway. We also found decreased induction of several gp130-dependent RAGs, including galanin and vasoactive intestinal peptide. Together, these data suggest a novel mechanism for the decreased response of diabetic sympathetic and sensory neurons to injury.
Sensitized peripheral nociception in experimental diabetes of the rat
2010, Pain
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Hyperglycemia and the activation of aldose reductase and polyol pathway are made responsible for this development of mechanical hypersensitivity [17,51]. Reports on altered thermal sensitivity are much more variable; hyperalgesia is reported as well as hypoalgesia or unchanged thresholds [13,24,33,40]. Fox et al. observed an early thermal hypoalgesia 3 days after STZ treatment which normalized within the first 4 weeks after STZ treatment; heat hyperalgesia was not found [24].
Painful neuropathy is a common complication of diabetes. Particularly in the early stage of diabetic neuropathy, patients are characterized by burning feet, hyperalgesia to heat, and mechanical stimuli, as if residual nociceptors were sensitized. Such symptoms are barely explained by common pathophysiological concepts of diabetic neuropathy. Diabetes was induced in Wistar rats by streptozotocin (STZ). After 4 weeks behavioral testing (Plantar test, Randall–Selitto) was conducted. Basal and stimulated release of calcitonin gene-related peptide (CGRP), Substance P (SP) and prostaglandin E₂ (PGE₂) from isolated skin and sciatic nerve were assessed by enzyme immunoassays. Electrophysiological properties of identified nociceptors under hyperglycemic, hypoxic, and acidotic conditions were investigated using the skin-nerve preparation. The diabetic rats showed hyperalgesia to heat and pressure stimulation. The basal CGRP/SP release was reduced, but chemical stimulation with bradykinin induced greater release of SP, CGRP and PGE₂ than in control animals. In contrast, capsaicin-stimulated CGRP release was reduced in sciatic nerves. Hypoxia per se lowered von Frey thresholds of most C-nociceptors to half. Hyperglycemic hypoxia induced ongoing discharge in all diabetic but not control C-fibers which was further enhanced under acidosis. Sensory and neurosecretory nociceptor functions are sensitized in diabetes. Diabetic C-fibers show exaggerated sensitivity to hyperglycemic hypoxia with and without additional acidosis, conditions that are thought to mimic ischemic episodes in diabetic nerves. Ongoing C-fiber discharge is known to induce spinal sensitization. Together with altered receptor and ion channel expressions this may contribute to painful episodes in diabetic neuropathy.
Effects of cytidine 5′-diphosphocholine (CDP-choline) on the thermal nociceptive threshold in streptozotocin-induced diabetic mice
2008, European Journal of Pharmacology
Neuropathy accompanied by abnormal sensory perception is the most common complication in insulin-dependent and -independent diabetes mellitus. Since there are very few effective therapeutic regimens for sensory abnormalities in diabetes, we examined the effect of cytidine 5′-diphosphocholine (CDP)-choline on the thermal nociceptive threshold in streptozotocin-induced diabetic mice using the tail-flick test. Diabetic mice showed a shorter tail-flick latency at 1–4 weeks after streptozotocin treatment and a longer tail-flick latency after 8–12 weeks. This hyper- and hypoalgesia in diabetic mice was almost completely inhibited by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning on the day of streptozotocin treatment. Daily treatment with CDP-choline beginning 5 weeks after streptozotocin treatment attenuated the development of hypoalgesia. Diabetic mice showed a significant increase in Na⁺-K⁺-ATPase activity at 3 weeks after streptozotocin treatment, whereas Na⁺-K⁺-ATPase activity was decreased at 12 weeks after treatment. These alterations were normalized by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning the day of streptozotocin treatment. These results provide evidence to support the therapeutic potency of CDP-choline on the development of thermal hyper- and hypoalgesia and the progression of thermal hypoalgesia in diabetic mice. Moreover, these effects of CDP-choline may result from the normalization of Na⁺-K⁺-ATPase activity.
Diabetes-Induced Chemogenic Hypoalgesia Is Paralleled by Attenuated Stimulus-Induced Fos Expression in the Spinal Cord of Diabetic Mice
2007, Journal of Pain
Citation Excerpt :
It is important to note that the presence of hypoalgesia versus hyperalgesia is likely dependent on the strain and species, as studies in diabetic rats have reported chemogenic hyperalgesia during both the quiescent and inflammatory phases.7-9 Similarly, studies in outbred strains of diabetic mice have reported chemogenic hyperalgesia in response to formalin.23,24,25,46 Here, we demonstrate that as the neuropathy progresses, reduced behavioral responses do not emerge in Phase 2 until 3 weeks after STZ.
Chronic hyperglycemia in diabetes induces abnormal nerve pathologies, resulting in diabetic neuropathy (DN). Sensory symptoms of DN can manifest as positive (painful), negative (insensate), or both. Streptozotocin (STZ)-induced diabetic C57Bl/6 mice have reduced cutaneous innervation and display reduced behavioral responses to noxious stimuli, reflecting the insensate aspect of the human syndrome. Current studies were undertaken to determine whether the diabetes-induced deficits in pain responses are reflected by changes in spinal activation in this model of DN. Nocifensive responses of nondiabetic and diabetic mice to formalin injection were measured 1, 3, 5, and 7 weeks after STZ, and at each time point formalin-induced spinal Fos expression was quantified. Responses of diabetic mice were significantly reduced during the second phase of the formalin test beginning 3 weeks after STZ and during Phase 1 beginning 5 weeks after STZ. Consistent with the behavioral responses, the number of Fos-positive cells in the dorsal horn of diabetic animals was significantly reduced beginning 3 weeks after STZ and continuing 5 and 7 weeks after STZ. The deficits at 5 weeks after STZ were restored by 2-week treatments with insulin or neurotrophins. These results demonstrate that the reduced sensation occurring from progressive peripheral axon loss results in functional deficits in spinal cord activation.
The reduced expression of the immediate early gene Fos as an indicator of pain transmission supports the diabetes-induced loss of sensation in this Type 1 model of diabetes. This murine model may be better suited to understanding the insensate symptoms of diabetic patients in the absence of chronic pain.

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Brief communicationStreptozotocin-induced diabetes in mice reduces the nociceptive threshold, as recognized after application of noxious mechanical stimuli but not of thermal stimuli

Abstract

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Pain

Immunohistochemical evidence for separate populations of somatostatin-contaning and substance P-containing primary afferent neurons in the rat

Neuroscience

Development of supersensitivity to substance P in the spinal cord of the streptozotocin-induced diabetic rats

Pharmacol. Biochem. Behav.

Brief communication
Streptozotocin-induced diabetes in mice reduces the nociceptive threshold, as recognized after application of noxious mechanical stimuli but not of thermal stimuli