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Role of nonpeptidergic subset of primary afferent neurons in inflammatory hypernociception in mice.
Pinto LG, Souza GR, Lopes AHP, Talbot J, Cunha FQ, Cunha TM, Ferreira SH (2013) Role of nonpeptidergic subset of primary afferent neurons in inflammatory hypernociception in mice. Neuroscience 2013 Abstracts 256.15. Society for Neuroscience, San Diego, CA.
Summary: Sensory information is transmitted from the periphery to the spinal cord by distinct subsets of primary afferent neurons, including small diameter unmyelinated C-fibers, which plays an important role in detecting noxious stimuli. C-fiber nociceptors have been divided into two classes, the peptidergic and nonpeptidergic. While many of the differences between peptidergic and nonpeptidergic neurons are now appreciated, a possible functional difference between these two classes of C fibers in the genesis of acute nociception as well as inflammatory pain is still unclear. Thus, this study aims to clarify the role of nonpeptidergic C fibers in acute nociception induced by mechanical, thermal and chemical stimuli as well as in inflammatory hypernociception. In order to elucidate differences between these two classes of C fibers, a neurotoxin was used to selectively eliminate the nonpeptidergic C fibers: a saporin conjugated to isolectin B4 (IB4). Nociceptive threshold was evaluated through thermal (Hargreaves) and mechanical (filaments and electronic von Frey) tests in C57BL/6 mice. Nociception models were induced by intraplantar (i.pl.) injection of capsaicin and formalin (acute nociception) or by i.pl. administration of prostaglandin E2 (PGE2), epinephrine, endothelin, NGF, GDNF and carrageenan (inflammatory hypernociception). P2X3 and TRPV1 expression were analyzed by Western blot of dorsal root ganglion (DRG). The expression of IB4-labeled in spinal cord was determined by immunofluorescense using confocal microcopy. Firstly, it was observed that the intrathecal administration of IB4-saporin did not change baseline thermal and mechanical nociceptive threshold of the mice paw when compared to saline and saporin-control groups. The intrathecal administration of IB4-saporin reduced mechanical inflammatory hypernociception induced by carrageenan, epinephrine, endothelin, PGE2 or GDNF, but not NGF, in mice. Similarly, the treatment with IB4-saporin inhibited the nociception caused by intraplantar injection of the capsaicin. By contrast, the acute nociception induced by formalin did not change by administration of IB4-saporin. In addition, the expression of TRPV1 and P2X3 in DRG were reduced after treatment with IB4-saporin. Consistent with these findings, we found that IB4-saporin injection decreased the expression of IB4-labeled in spinal cord. These results suggest that absence the nonpeptidergic C fibers does not affect basal nociceptive threshold. However, these fibers are essential for the development of nociception in the paw of mice induced by inflammatory stimuli like PGE2, epinephrine, endothelin, carrageenan and capsaicin.
Related Products: IB4-SAP (Cat. #IT-10)
Selective basal forebrain cholinergic deficits reduce glucose metabolism, cholinergic and GABAergic system in the cingulate cortex.
Lee J, Jeong D, Oh J, Lee J, Chang W, Cho Z, Chang J (2013) Selective basal forebrain cholinergic deficits reduce glucose metabolism, cholinergic and GABAergic system in the cingulate cortex. Neuroscience 2013 Abstracts 45.12. Society for Neuroscience, San Diego, CA.
Summary: Reduction of brain glucose metabolism and degeneration of cholinergic basal forebrain neurons are common features in Alzheimer’s disease and have been correlated with memory function. Although regions representing glucose hypometabolism in Alzheimer’s disease patients are target sites of cholinergic basal forebrain neurons, an interaction between cholinergic denervation and glucose hypometabolism is still unclear. To evaluate the changes in glucose metabolism in regions relevant to basal forebrain cholinergic deficits, we damaged basal forebrain cholinergic neurons of rats using 192 IgG-saporin. After 3 weeks, lesioned animals were tested by water maze test or analyzed using 18F-2-fluoro-2-deoxyglucose positron emission tomography. During the probe test in the water maze, performance of the lesion group decreased, considering time spent in both the target quadrant and platform zone. Glucose metabolism in the cingulate cortex of the lesion group decreased compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression both declined in the cingulate cortex. Our results reveal that spatial memory impairment of animals in which basal forebrain cholinergic neurons are selectively damaged is associated with a decline in functions of GABAergic, cholinergic, and glutamatergic systems associated with glucose hypometabolism in the cingulate cortex.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Substance P-saporin for bone cancer pain in dogs: Can man’s best friend solve the lost in translation problem in analgesic development?
Hayashida K (2013) Substance P-saporin for bone cancer pain in dogs: Can man’s best friend solve the lost in translation problem in analgesic development?. Anesthesiology 119(5):999-1000. doi: 10.1097/ALN.0b013e3182a951a2
Summary: This editorial describes the SP-SAP papers in this latest issue of Anesthesiology. The results of the paper are discussed, and the potential in using companion dogs for pain models is emphasized. While most pain models have been rodent-based, companion dogs provide models for chronic pain due to natural causes such as cancer and arthritis, along with frequent opportunity for behavioral assessments by the owner. Such assessments can be done without stress to the animal.
Related Products: SP-SAP (Cat. #IT-07)
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Intrathecal substance p-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation.
Wiese AJ, Rathbun M, Butt MT, Malkmus SA, Richter PJ, Osborn KG, Xu Q, Veesart SL, Steinauer JJ, Higgins D, Lappi DA, Russell B, Yaksh TL (2013) Intrathecal substance p-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation. Anesthesiology 119(5):1163-1177. doi: 10.1097/ALN.0b013e3182a95164
Summary: Here the authors investigate the safety parameters of SP-SAP on purpose-bred beagles (currently in human clinical trials). The dogs received 1.5, 15, or 150 μg intrathecal injections of the conjugate. SP-SAP pharmacology and physiological effects were assessed by behavioral and functional observations, immunohistochemistry, ELISA, blood and urine analysis, histopathology, and in situ hybridization. The general conclusions include that neurokinin-1 receptor (NK1r) positive neuron loss is detectable as soon as 7 days after administration of SP-SAP, the neuron loss is permanent, toxicity is specific to NK1r-positive neurons, and, other than the 150 μg dose, NK1r neuron loss was restricted to the superficial dorsal horn.
Related Products: SP-SAP (Cat. #IT-07), SP-SAP (Cat. #IT-07)
Intrathecal substance p-saporin in the dog: efficacy in bone cancer pain.
Brown DC, Agnello K (2013) Intrathecal substance p-saporin in the dog: efficacy in bone cancer pain. Anesthesiology 119(5):1178-1185. doi: 10.1097/ALN.0b013e3182a95188
Summary: This work demonstrates the use of naturally occurring bone cancer in dogs as a model for pain therapy. Companion dogs with bone cancer received 20-60 μg intrathecal injections of SP-SAP (currently in human clinical trials) depending on the size of the dog. Significantly more dogs in the control group required unblinding and adjustment of pain care than in the SP-SAP group, indicating the efficacy of SP-SAP in pain control. This study also demonstrates the validity of the dog model for testing analgesic protocols.
Related Products: SP-SAP (Cat. #IT-07)
Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine.
Laplante F, Dufresne MM, Ouboudinar J, Ochoa-Sanchez R, Sullivan RM (2013) Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine. Synapse 67(1):21-29. doi: 10.1002/syn.21612
Summary: The authors examined whether excessive dopamine neurotransmission in the mesolimbic system is due to higher levels of presynaptic or postsynaptic dopamine. Rats received 250-ng bilateral injections of anti-ChAT-SAP (Cat. #IT-42) into the nucleus accumbens. Rabbit IgG-SAP (Cat. #IT-35) was used as a control. The data suggest that reduction of cholinergic interneurons in the nucleus accumbens suppresses presynaptic dopamine release.
Related Products: Anti-ChAT-SAP (Cat. #IT-42), Rabbit IgG-SAP (Cat. #IT-35)
Neuroprotective effects of donepezil against cholinergic depletion.
Cutuli D, De Bartolo P, Caporali P, Tartaglione AM, Oddi D, D’Amato FR, Nobili A, D’Amelio M, Petrosini L (2013) Neuroprotective effects of donepezil against cholinergic depletion. Alzheimers Res Ther 5(5):50. doi: 10.1186/alzrt215
Summary: Acetylcholinesterase inhibitors appear to be one of the only pharmacological tools available to reduce cognitive deficits caused by the loss of cholinergic neurons in the basal forebrain. Here the authors pre-treated rats with the aceytlcholinesterase inhibitor donepezil before administering 0.5 μg of 192-IgG-SAP (Cat. #IT-01) into each side of the medial septum. Analysis of working memory, spatial discrimination, social novelty preference, and ultrasonic localizations, along with measuring hippocampal and neocortical caspase-3 activity indicates that donepezil pre-treatment ameliorates some effects of the cholinergic depletion.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Modeling fall propensity in Parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation.
Kucinski A, Paolone G, Bradshaw M, Albin RL, Sarter M (2013) Modeling fall propensity in Parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation. J Neurosci 33(42):16522-16539. doi: 10.1523/JNEUROSCI.2545-13.2013
Summary: Parkinson’s disease produces a range of symptoms, some of which are unresponsive to therapies such as levodopa. These nonmotor symptoms include cognitive impairments and deficiencies in gait and balance. Here the authors develop a system to assess fall propensity in rats and examine the interaction between loss of cortical cholinergic and striatal dopaminergic afferents. Rats received 160-ng injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis and substantia innominata of the basal forebrain. The results indicate that the dual lesions result in diminished striatal control of complex movement.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Leptin-sensitive neurons in the arcuate nucleus integrate activity and temperature circadian rhythms and anticipatory responses to food restriction.
Wiater MF, Li AJ, Dinh TT, Jansen HT, Ritter S (2013) Leptin-sensitive neurons in the arcuate nucleus integrate activity and temperature circadian rhythms and anticipatory responses to food restriction. Am J Physiol Regul Integr Comp Physiol 305(8):R949-R960. doi: 10.1152/ajpregu.00032.2013
Summary: The arcuate nucleus (Arc) of the hypothalamus is known to participate in the regulation of feeding, adiposity, and leptin-dependent metabolism. The authors examined the role of leptin-receptive neurons in locomotor and temperature rhythms. Rats received four bilateral injections of Leptin-SAP (Cat. #IT-47) into the Arc; Blank-SAP (Cat. #IT-21) was used as a control. The lesion affected learning connected to light cycles, but not learning connected to food schedules, suggesting a mechanism for internal desynchrony that might play a role in obesity and other metabolic disorders.
Related Products: Leptin-SAP (Cat. #IT-47), Blank-SAP (Cat. #IT-21)
Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia.
Khasabov SG, Simone DA (2013) Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia. Neuroscience 250C:151-165. doi: 10.1016/j.neuroscience.2013.06.057
Summary: Previous data has indicated that neurokinin-1 receptors are located on ON cells in the rostral ventromedial medulla (RVM). ON cells are considered pronociceptive because noxious stimulation is stimulatory. In this work the authors eliminated ON cells using 0.3-μl injections of 1 μM SSP-SAP (Cat. #IT-11) into the left and right side of the RVM. Blank-SAP (Cat. #IT-21) was used as a control. SSP-SAP treatment did not change mechanical or heat withdrawal responses, or change morphine-induced analgesia. A significant reduction in the duration of nocifensive behaviors induced by various hyperalgesic stimulators indicated that these neurons are involved in pain facilitation rather than modulation.
Related Products: SSP-SAP (Cat. #IT-11), Blank-SAP (Cat. #IT-21)