Spontaneous pain following spinal nerve injury in mice

Minert, Anne; Gabay, Eran; Dominguez, Cecilia A.; Wiesenfeld‐Hallin, Zsuzsanna; Devor, Marshall

doi:10.1016/j.expneurol.2007.04.011

Cited by 30 publications

(35 citation statements)

References 46 publications

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“…Although knowledge of the existence of genetic factors controlling pain susceptibility does not exclude the possibility of fraud and malingering, it ought to reduce unwarranted stigmatization of patients with severe pain due to no fault of their own. Second, although abundant functional evidence indicates that autotomy behavior in the Neuroma model indeed reflects spontaneous neuropathic pain (Devor 2007;Minert et al 2007), the documentation that a pain susceptibility gene discovered using this model also affects a corresponding pain phenotype in humans lends further support to the model's validity. Hence, it supports the potential usefulness of this and related animal models for the study of pain and for the screening of potential therapeutic agents.…”

Section: Discussionmentioning

confidence: 91%

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2

Nissenbaum¹,

Devor²,

Seltzer³

et al. 2010

Genome Res.

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123

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Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes for stargazin, a protein intimately involved in the trafficking of glutamatergic AMPA receptors. The protein might also be a Ca 2+ channel subunit. CACNG2 has previously been implicated in epilepsy. Initially, using two fine-mapping strategies in a mouse model (recombinant progeny testing [RPT] and recombinant inbred segregation test [RIST]), we mapped a painrelated quantitative trait locus (QTL) (Pain1) into a 4.2-Mb interval on chromosome 15. This interval includes 155 genes. Subsequently, bioinformatics and whole-genome microarray expression analysis were used to narrow the list of candidates and ultimately to pinpoint Cacng2 as a likely candidate. Analysis of stargazer mice, a Cacng2 hypomorphic mutant, provided electrophysiological and behavioral evidence for the gene's functional role in pain processing. Finally, we showed that human CACNG2 polymorphisms are associated with chronic pain in a cohort of cancer patients who underwent breast surgery. Our findings provide novel information on the genetic basis of neuropathic pain and new insights into pain physiology that may ultimately enable better treatments.[Supplemental material is available online at http://www.genome.org. The human data from this study have been submitted to the Human Genome Variation Database of Genotype-to-Phenotype (http://www.hgvbaseg2.org) under accession no. HGVST514.]Chronic pain is a healthcare problem of enormous proportions, directly affecting nearly 20% of adults and associated with massive financial costs (Breivik et al. 2006). At least 25% of this burden is attributable to ''neuropathic pain,'' pain that follows nerve damage (Bouhassira et al. 2008). In patients with neuropathy spontaneous pain is typically the most prominent cause of suffering, rather than stimulus-provoked pain. A striking example is phantom pain. Virtually all limb amputees report feeling a phantom limb, and most report spontaneous burning, stabbing, or electric shocklike pain, at least occasionally (Sherman et al. 1996;Nikolajsen and Jensen 2001). Phantom pain is also common after breast removal (Tytherleigh et al. 1998;Rothemund et al. 2004;Vadivelu et al. 2008) and in body parts that have been denervated but are still present (''anesthesia dolorosa'') (Wynn Parry 1980). Neuropathic pain, including phantom pain, is a complex trait affected by both the nature of the neural injury and by psychosocial factors. Its notorious variability among individuals, even when the underlying nerve pathology is identical, has prompted awareness of a significant genetic contribution to the amount of pain felt (Diatchenko et al. 2007;Lacroix-Fralish and Mogil 2008;LaCroix-Fralish et al. 2009). At present, the biological process ...

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Section: Discussionmentioning

confidence: 91%

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2

Nissenbaum¹,

Devor²,

Seltzer³

et al. 2010

Genome Res.

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123

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“…I Nap ¼ g Nap p 3 ðV m − E Na Þ [6] α p ¼ 0:01ðV m þ 27Þ f1 − e ½ − ðVmþ27Þ=10:2 g [7] β p ¼ 0:00025½ − ðV m þ 34Þ f1 − e ½ðVmþ34Þ=10 g [8] Kv3.1:…”

Section: Methodsunclassified

“…Regardless of the precise etiology, clinical presentation often involves negative (loss-of-function) symptoms, including loss of motor control (i.e., paresis) and sensory deficits such as blindness and numbness, as well as positive (gain-of-function) symptoms, including muscle spasms, tactile allodynia, and chronic pain that is constant or paroxysmal (1,(4)(5)(6)(7). Which muscles or sensory modalities are affected depends on where in the nervous system the demyelinating lesions develop, but changes in conduction velocity alone are clearly insufficient to explain the breadth of symptoms observed, especially the positive ones.…”

mentioning

confidence: 99%

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Coggan

Prescott

Bartol

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Fast axonal conduction of action potentials in mammals relies on myelin insulation. Demyelination can cause slowed, blocked, desynchronized, or paradoxically excessive spiking that underlies the symptoms observed in demyelination diseases. The diversity and timing of such symptoms are poorly understood, often intermittent, and uncorrelated with disease progress. We modeled the effects of demyelination (and secondary remodeling) on intrinsic axonal excitability using Hodgkin-Huxley and reduced Morris-Lecar models. Simulations and analysis suggested a simple explanation for the breadth of symptoms and revealed that the ratio of sodium to leak conductance, g Na /g L , acted as a four-way switch controlling excitability patterns that included spike failure, single spike transmission, afterdischarge, and spontaneous spiking. Failure occurred when this ratio fell below a threshold value. Afterdischarge occurred at g Na /g L just below the threshold for spontaneous spiking and required a slow inward current that allowed for two stable attractor states, one corresponding to quiescence and the other to repetitive spiking. A neuron prone to afterdischarge could function normally unless it was switched to its "pathological" attractor state; thus, although the underlying pathology may develop slowly by continuous changes in membrane conductances, a discontinuous change in axonal excitability can occur and lead to paroxysmal symptoms. We conclude that tonic and paroxysmal positive symptoms as well as negative symptoms may be a consequence of varying degrees of imbalance between g Na and g L after demyelination. The KCNK family of g L potassium channels may be an important target for new drugs to treat the symptoms of demyelination. O ligodendrocytes and Schwann cells tightly wrap axons at regular intervals to form the myelin sheath that allows for rapid axonal conduction. Neuropathies involving axonal demyelination are characterized by the unraveling of this insulation and can affect both the central nervous system, as in the case of multiple sclerosis (MS), and the peripheral nervous system, as in Guillain-Barré syndrome.Causes of demyelination include immunologic disease processes, as well as lesions such as traumatic nerve damage, nonpenetrating spinal cord injuries, and chronic nerve compression (1-4). Regardless of the precise etiology, clinical presentation often involves negative (loss-of-function) symptoms, including loss of motor control (i.e., paresis) and sensory deficits such as blindness and numbness, as well as positive (gain-of-function) symptoms, including muscle spasms, tactile allodynia, and chronic pain that is constant or paroxysmal (1, 4-7). Which muscles or sensory modalities are affected depends on where in the nervous system the demyelinating lesions develop, but changes in conduction velocity alone are clearly insufficient to explain the breadth of symptoms observed, especially the positive ones. In particular, MS often produces confounding symptoms that can present intermittently, resolving and retu...

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“…Indeed, since differences between strains in the number of lumbar vertebrae may result in ligation of different spinal nerves, genetically determined variability in lumbosacral bony segmentation may be an important factor contributing to different degrees of neuropathic pain after anatomically targeted spinal nerve injury in various strains [19,20], if this resulted in ligation of different spinal nerves.…”

Section: Technical Considerations For Identifying Lumbar Vertebral Lementioning

confidence: 99%

Species and strain differences in rodent sciatic nerve anatomy: Implications for studies of neuropathic pain

Rigaud

Gemes

Barabas

et al. 2008

Pain

254

235

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Hindlimb pain models developed in rats have been transposed to mice, but assumed sciatic nerve neuroanatomic similarities have not been examined. We compared sciatic nerve structural organization in mouse strains (C57BL/6J, DBA/2J, and B6129PF2/J) and rat strains (Wistar, Brown Norway, and Sprague-Dawley). Dissection and retrograde labeling showed mouse sciatic nerve origins predominantly from the third lumbar (L3) and L4 spinal nerves, unlike the L4 and L5 in rats. Proportionate contributions by each level differed significantly between strains in both mice and rats. Whereas all rats had six lumbar vertebrae, variable patterns in mice included mostly five vertebrae in DBA/2J, mostly six vertebrae in C57BL/6J, and a mix in B6129PF2/J. Mice with a short lumbar vertebral column showed a rostral shift in relative contributions to the sciatic nerve by L3 and L4. Ligation of the mouse L4 nerve created hyperalgesia similar to that in rats after L5 ligation, and motor changes were similar after mouse L4 and rat L5 ligation (foot cupping) and after mouse L3 and rat L4 ligation (flexion weakness). Thus, mouse L3 and L4 neural segments are anatomically and functionally homologous with rat L4 and L5 segments. Neuronal changes after distal injury or inflammation should be sought in the mouse L3 and L4 ganglia, and the spinal nerve ligation model in mice should involve ligation of the L4 nerve while L3 remains intact. Strain-dependent variability in segmental contributions to the sciatic nerve may account in part for genetic differences in pain behavior after spinal nerve ligation.

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Spontaneous pain following spinal nerve injury in mice

Cited by 30 publications

References 46 publications

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Species and strain differences in rodent sciatic nerve anatomy: Implications for studies of neuropathic pain

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