Deletion of the insulin receptor in sensory neurons increases pancreatic insulin levels.

Insulin is known to have neurotrophic properties and loss of insulin support to sensory neurons may contribute to peripheral diabetic neuropathy (PDN). Here, genetically-modified mice were generated in which peripheral sensory neurons lacked the insulin receptor (SNIRKO mice) to determine whether disrupted sensory neuron insulin signaling plays a crucial role in the development of PDN and whether SNIRKO mice develop symptoms of PDN due to reduced insulin neurotrophic support. Our results revealed that SNIRKO mice were euglycemic and never displayed significant changes in a wide range of sensorimotor behaviors, nerve conduction velocity or intraepidermal nerve fiber density. However, SNIRKO mice displayed elevated serum insulin levels, glucose intolerance, and increased insulin content in the islets of Langerhans of the pancreas. These results contribute to the growing idea that sensory innervation of pancreatic islets is key to regulating islet function and that a negative feedback loop of sensory neuron insulin signaling keeps this regulation in balance. Our results suggest that a loss of insulin receptors in sensory neurons does not lead to peripheral nerve dysfunction. The SNIRKO mice will be a powerful tool to investigate sensory neuron insulin signaling and may give a unique insight into the role that sensory neurons play in modifying islet physiology.

Impact of Opioid and Nonopioid Drugs on Postsurgical Pain Management in the Rat.

Aim. Nonsteroidal anti-inflammatory drugs or opioids are commonly used to control surgical pain following veterinary and clinical procedures. This study evaluated the efficacy of postoperative ketorolac or buprenorphine following abdominal surgery. Main Methods. Mean arterial pressure (MAP), heart rate, animal activity, corticosterone levels, and a nociceptive sensitivity assay were used to evaluate 18 adult male Sprague-Dawley rats which underwent aortic artery occlusion for implantation of a radiotelemetry device. The animals were treated postoperatively with intraperitoneal injections of vehicle, ketorolac (10 mg/kg), or buprenorphine (0.06 mg/kg) every 8 hours for 3 days. Key Findings. There were no consistent significant changes in any of the telemetry parameters after treatment with ketorolac compared with no saline treatment with the exception of increased MAP in the buprenorphine group during the first 48 hours when compared with other treatment groups. There was a sustained increase in fecal corticosterone levels from baseline on days 2-7 with buprenorphine compared with vehicle- or ketorolac-treated animals. All treatment conditions displayed reduced paw withdrawal thresholds (PWTs) from day 1 to day 21 following surgery. Compared with the vehicle treatment group, buprenorphine-treated animals exhibited significantly lower PWT levels from day 4 to 14 days. Significance. Given the prolonged increase in fecal corticosterone levels and pronounced changes in tactile hyperalgesia behavior in rodents subjected to buprenorphine treatment, these data suggest that ketorolac may be superior to buprenorphine for the treatment of postprocedure pain behavior in rodents.

Experimental motor neuropathy in diabetes.

Motor dysfunction in diabetes is less prevalent than sensory symptoms but still remains an important clinical complication. Experimental studies using rodent models have shed light on several key components that likely contribute to motor dysfunction. Measurements of motor nerve conduction velocities have been a standard for identifying motor dysfunction; however, the validity and relevance of these early changes in axon conduction velocities to human diabetic neuropathy is questionable. This is supported by difficulties in establishing causative pathologic alterations in motor neurons or motor axons in rodents. This caveat has led to identification of additional mechanisms that contribute to motor dysfunction, including diabetes-associated abnormalities in motor units, innervation of the neuromuscular junction, and intrinsic problems in skeletal muscle. In addition, deficiencies in sensory feedback from skeletal muscles may contribute to changes in motor control. It is clear that increased studies of experimental interventions are needed, and future studies should account for diabetes-induced changes at multiple sites of motor control, ranging from the motor neurons to skeletal muscle. In addition, future experimental studies should be encouraged to extend beyond measurements of conduction velocity and include modern behavioral and imaging techniques to identify causative mechanisms and validate experimental interventions that improve motor control.

Exercise-mediated improvements in painful neuropathy associated with prediabetes in mice.

Recent research suggests that exercise can be effective in reducing pain in animals and humans with neuropathic pain. To investigate mechanisms in which exercise may improve hyperalgesia associated with prediabetes, C57Bl/6 mice were fed either standard chow or a high-fat diet for 12 weeks and were provided access to running wheels (exercised) or without access (sedentary). The high-fat diet induced a number of prediabetic symptoms, including increased weight, blood glucose, and insulin levels. Exercise reduced but did not restore these metabolic abnormalities to normal levels. In addition, mice fed a high-fat diet developed significant cutaneous and visceral hyperalgesia, similar to mice that develop neuropathy associated with diabetes. Finally, a high-fat diet significantly modulated neurotrophin protein expression in peripheral tissues and altered the composition of epidermal innervation. Over time, mice that exercised normalized with regards to their behavioral hypersensitivity, neurotrophin levels, and epidermal innervation. These results confirm that elevated hypersensitivity and associated neuropathic changes can be induced by a high-fat diet and exercise may alleviate these neuropathic symptoms. These findings suggest that exercise intervention could significantly improve aspects of neuropathy and pain associated with obesity and diabetes. Additionally, this work could potentially help clinicians determine those patients who will develop painful versus insensate neuropathy using intraepidermal nerve fiber quantification.

CXCR4 signaling mediates morphine-induced tactile hyperalgesia.

Morphine and related compounds are the first line of therapy in the treatment of moderate to severe pain. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving into a painful response to previously non-noxious stimuli (opioid-induced hyperalgesia; OIH). The mechanism underlying OIH is not well understood although complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying OIH. However, OIH may also be associated with changes in gene expression. A growing body of evidence suggests that cellular exposure to mu agonists upregulate chemokines/receptors and recent work from our laboratory implicates chemokine upregulation in a variety of neuropathic pain behaviors. Here we characterized the degree to which chemokines/receptors signaling is increased in primary afferent neurons of the dorsal root ganglion (DRG) following chronic morphine sulfate treatment and correlated these changes with tactile hyperalgesic behavior in rodents. We demonstrate that mRNA expression of the chemokine, stromal-derived factor-1 (SDF1/CXCL12) is upregulated following morphine treatment in sensory neurons of the rat. The release of SDF1 was found to be constitutive when compared with the activity dependent release of the C-C chemokine, monocyte chemoattractant protein-1 (MCP1/CCL2) in a line of F11 neuroblastoma-sensory neuron hybrid cells. We further determined that there is pronounced CXCR4 expression in satellite glial cells and following morphine treatment, increased functional CXCR4 expression in sensory neurons of the DRG. Moreover, intraperitoneal administration of the specific CXCR4 antagonist, AMD3100, completely reversed OIH in the rat. Taken together; the data suggest that opioid-induced SDF1/CXCR4 signaling is central to the development of long lasting OIH and that receptor antagonists represent a promising novel approach to the management of the side effects associated with the use of opioids for chronic pain management.

Chemokines as pain mediators and modulators.

PURPOSE OF REVIEW: Chemokines are central to the innate immune response following tissue damage, injury and some diseases. The function of chemokines in nervous system autoimmune diseases has been long recognized. There is also growing evidence that disease-associated or injury-induced functional expression of chemokines/receptors in both neural and nonneural elements of the peripheral nervous system play crucial roles in the pathophysiology of chronic pain. RECENT FINDINGS: Chemokine involvement in neuropathic pain processing has recently been established in animal models. Evidence of chemokine contribution to chronic pain includes the upregulation of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its respective receptor, CCR2, in many subpopulations of sensory neurons. Activation of CCR2 by MCP-1 elicits membrane depolarization, triggers action potentials and sensitizes nociceptors via transactivation of transient receptor potential channels TRPA1 and TRPV1. Increased signaling by stromal-derived factor-1 (SDF-1/CXCL12) and its receptor, CXCR4, has been shown to contribute to chronic pain behavior. The use of specific chemokine receptor antagonists for CCR2 and CXCR4 successfully reverses nociceptive pain behavior. SUMMARY: Our results suggest that specific chemokines/receptors are upregulated by sensory neurons following peripheral nerve injury and appear to participate in neural signal processing leading to chronic pain states. Taken together, chemokines and their receptors are potential targets for development of novel therapeutics.

Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care.

Anticonvulsant hypersensitivity syndrome (AHS) is a delayed adverse drug reaction associated with the use of aromatic anticonvulsant drugs. It has been most commonly reported with the use of phenytoin, carbamazepine, and phenobarbital. Although its occurrence is rare, 1 in every 1000-10,000 exposures, AHS is a serious adverse event often resulting in hospitalization and even death. The clinical manifestations of AHS include a triad of symptoms consisting of dermatologic rashes, fever, and evidence of systemic organ involvement. Diagnosis is most frequently based on the recognition of this triad of symptoms and clinical judgment. The exact mechanism of AHS remains to be determined but is thought to have at least three components: deficiency or abnormality of the epoxide hydroxylase enzyme that detoxifies the metabolites of aromatic amine anticonvulsants, associated reactivation of herpes-type viruses, and ethnic predisposition with certain human leukocyte antigen subtypes. Arene oxides, the toxic intermediaries in the metabolism of anticonvulsant drugs, can accumulate and directly bind to macromolecules, causing cell death, as well as act as prohaptens that bind to T cells, initiating an immune response and systemic reactions. Management of AHS primarily includes discontinuation of the associated anticonvulsant drug. Systemic corticosteroids are usually required for full recovery. An important issue regarding AHS is the cross-sensitivity among aromatic anticonvulsant drugs, which has been reported to be 40-80%. This means that patients with a history of AHS should avoid further use of any aromatic anticonvulsant drug. In addition, a familial association with AHS exists, and family members of the patient with AHS should be educated that they may be at increased risk for developing AHS if they use aromatic anticonvulsant drugs. Anticonvulsant drugs that are generally considered safe are valproic acid and benzodiazepines. Other nonaromatic anticonvulsant drugs should also be acceptable. Pharmacists as health care providers can play an important role in the diagnosis, treatment, and prevention of AHS.