Neurotrophin-3 Reverses Chronic Mechanical Hyperalgesia Induced by Intramuscular Acid Injection

Gandhi, R.; Ryals, Janelle M.; Wright, Douglas E.

doi:10.1523/jneurosci.0899-04.2004

Cited by 43 publications

(39 citation statements)

References 47 publications

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“…In support of this, recent studies suggest that NT-3 has antihyperalgesic actions by modifying the phenotype of nociceptive neurons (Gratto et al, 2003;Wilson-Gerwing et al, 2005). In our own studies, NT-3 has anti-nociceptive actions in a model of chronic pain induced by acid injection (Gandhi et al, 2004). Together, these studies illustrate the complicated interactions of NGF and NT-3 on nociceptive populations.…”

Section: Neurotrophic Modulation Of Mechanical Insensitivity and Myelsupporting

confidence: 74%

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Christianson¹,

Ryals²,

Johnson³

et al. 2007

Neuroscience

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Human diabetic patients often lose touch and vibratory sensations, but to date, most studies on diabetes-induced sensory nerve degeneration have focused on epidermal C-fibers. Here, we explored the effects of diabetes on cutaneous myelinated fibers in relation to the behavioral responses to tactile stimuli from diabetic mice. Weekly behavioral testing began prior to STZ administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to NF-H and MBP. Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pin prick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared to non-diabetic mice. To test whether two neurotrophins NGF and/or NT-3 known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for two weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared to diabetic mice treated with insulin for two weeks. NGF and insulin treatment both increased paw withdrawal to mechanical stimulation in diabetic mice, whereas NT-3 or a combination of NGF and NT-3 failed to alter paw withdrawal responses. Surprisingly, all treatments significantly increased myelinated innervation compared to control-treated diabetic mice, demonstrating that myelinated cutaneous fibers damaged by hyperglycemia respond to intrathecal administration of neurotrophins. Moreover, NT-3 treatment increased epidermal Merkel cell numbers associated with nerve fibers, consistent with increased numbers of NT-3-responsive slowly adapting A-fibers. These studies suggest that myelinated fiber loss may contribute as significantly as unmyelinated epidermal loss in diabetic neuropathy, and the contradiction between neurotrophininduced increases in dermal innervation and behavior emphasize the need for multiple approaches to accurately assess sensory improvements in diabetic neuropathy. KeywordsNeuropathy; diabetes; dermis; innervation; myelinated axon NGF; NT-3 *Correspondence: Douglas Wright, Ph.D., Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, Phone:913-588-2713, Fax: 913-588-2710, email: dwright@kumc.edu. Section Editor: Donna HammondPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. , 1984). The predominant type of diabetic neuropathy is a distal, symmetrical, sensorimotor polyneuropathy and preferentially affects sensory function in the distal regions, i...

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Section: Neurotrophic Modulation Of Mechanical Insensitivity and Myelsupporting

confidence: 74%

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Christianson¹,

Ryals²,

Johnson³

et al. 2007

Neuroscience

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“…Given that i.m. administration of neurotrophin 3 reverses the acid-induced hyperalgesia, SP may work through or in parallel with neurotrophin receptors (24). However, neurotrophin (e.g., NGF) receptors also are implicated in mediating hyperalgesia in delayed-onset muscle soreness (48).…”

Section: Discussionmentioning

confidence: 99%

“…injection of acid, CFA, or carrageenan (13,17,(21)(22)(23). Coinjection of neurotrophin-3 reverses the acid-induced chronic hyperalgesia (24). Also, some muscle-derived pain can be attenuated by treatment with pregabalin or with the voltagedependent potassium M-channel openers retigabine and flupirtine (25,26).…”

mentioning

confidence: 99%

An antinociceptive role for substance P in acid-induced chronic muscle pain

Weinan

Chen

et al. 2011

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

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Release of substance P (SP) from nociceptive nerve fibers and activation of its receptor neurokinin 1 (NK1) are important effectors in the transmission of pain signals. Nonetheless, the role of SP in muscle pain remains unknown. Here we show that a single i.m. acid injection in mice lacking SP signaling by deletion of the tachykinin precursor 1 (Tac1) gene or coadministration of NK1 receptor antagonists produces long-lasting hyperalgesia rather than the transient hyperalgesia seen in control animals. The inhibitory effect of SP was found exclusively in neurons expressing acid-sensing ion channel 3, where SP enhances M-channel-like potassium currents through the NK1 receptor in a G protein-independent but tyrosine kinase-dependent manner. Furthermore, the SP signaling could alter action potential thresholds and modulate the expression of TTX-resistant sodium currents in medium-sized muscle nociceptors. Thus, i.m. SP mediates an unconventional NK1 receptor signal pathway to inhibit acid activation in muscle nociceptors, resulting in an unexpected antinociceptive effect against chronic mechanical hyperalgesia, here induced by repeated i.m. acid injection.is an undecapeptide belonging to the tachykinin small-peptide family (1). SP is generated in primary nociceptive sensory neurons (nociceptors) and is released with noxious stimulation (2). The release from cutaneous peripheral terminals induces neurogenic inflammation and release from central terminals enhances the glutamate-dependent excitatory postsynaptic potential, thus leading to central sensitization (3-5). Although sensory neurons in muscle also contain SP, i.m. SP injection evokes a very low level of neurogenic inflammation and no pain (6, 7).Accumulating evidence has suggested that muscle pain might be closely related to acidosis and activation of proton-sensing ion channels (8-10). Lactate and ATP sensitize this acid activation (11,12). Human and animal studies have revealed that acidosis is an effective trigger of muscle pain. Thus, chronic muscle pain can be induced in rodents by repeated i.m. injection of acid (13,14), by i.m. injection of complete Freund's adjuvant (CFA), carrageenan, capsaicin, or proinflammatory cytokines (15-18), by arterial occlusion (19), and by eccentric muscle contraction (20). These stimuli might correspond to muscle pain related to acidosis, inflammatory and ischemic myalgia, or delayed-onset muscle soreness. Although these models might not reflect fully the complicated human pain conditions, and although repetitive acidosis is not known to produce chronic pain or central sensitization in humans, these rodent models are useful for probing the underlying mechanisms and analgesic modulation of chronic muscle pain. For instance, acid-sensing ion channel 3 (ASIC3) is essential for triggering acid-induced mechanical hyperalgesia in models of i.m. injection of acid, CFA, or carrageenan (13,17,(21)(22)(23). Coinjection of neurotrophin-3 reverses the acid-induced chronic hyperalgesia (24). Also, some muscle-derived pain can be attenu...

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“…Verge, 2000). Mechanotransduction is mediated by specialized channels (Garcia-Anoveros et al, 2001;Price et al, 2001;Suzuki et al, 2003a,b), but the manner in which expression or sensitization of these channels is altered by this form of injury or NT-3 is unknown; however, a role for NT-3 in the treatment of chronic mechanical hypersensitivity resulting from intramuscular acid injection indicates a potential role for NT-3 in the treatment of muscular pain (Gandhi et al, 2004).…”

Section: Nt-3 Influences Thermal Hyperalgesia But Not Mechanical Hypementioning

confidence: 99%

Neurotrophin-3 Suppresses Thermal Hyperalgesia Associated with Neuropathic Pain and Attenuates Transient Receptor Potential Vanilloid Receptor-1 Expression in Adult Sensory Neurons

Wilson-Gerwing

Dmyterko²,

Zochodne³

et al. 2005

J. Neurosci.

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Neurotrophin-3 (NT-3) negatively modulates nerve growth factor (NGF) receptor expression and associated nociceptive phenotype in intact neurons, suggesting a beneficial role in treating aspects of neuropathic pain mediated by NGF. We report that NT-3 is effective at suppressing thermal hyperalgesia associated with chronic constriction injury (CCI); however, NT-3 does not alter the mechanical hypersensitivity that also develops with CCI. Thermal hyperalgesia is critically linked to expression and activation of the capsaicin receptor, transient receptor potential vanilloid receptor-1 (TRPV1). Thus, its modulation by NT-3 after CCI was examined. CCI results in elevated TRPV1 expression at both the mRNA and protein levels in predominantly small-to-medium neurons, with the percentage of neurons expressing TRPV1 remaining unchanged at ϳ56%. Attenuation of thermal hyperalgesia mediated by NT-3 correlates with decreased TRPV1 expression such that only ϳ26% of neurons ipsilateral to CCI expressed detectable TRPV1 mRNA. NT-3 effected a decrease in expression of the activated component of the signaling pathway linked to regulation of TRPV1 expression, phospho-p38 MAPK (Ji et al., 2002), in neurons ipsilateral to CCI. Exogenous NT-3 could both prevent the onset of thermal hyperalgesia and reverse established thermal hyperalgesia and elevated TRPV1 expression 1 week after CCI. Continuous infusion is required for suppression of both thermal hyperalgesia and TRPV1 expression, because removal of NT-3 resulted in a prompt reestablishment of the hyperalgesic state and corresponding CCI-associated TRPV1 phenotype. In conclusion, although NGF drives inflammation-associated thermal hyperalgesia via its regulation of TRPV1 expression, NT-3 is now identified as a potent negative modulator of this state.

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Neurotrophin-3 Reverses Chronic Mechanical Hyperalgesia Induced by Intramuscular Acid Injection

Cited by 43 publications

References 47 publications

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

An antinociceptive role for substance P in acid-induced chronic muscle pain

Neurotrophin-3 Suppresses Thermal Hyperalgesia Associated with Neuropathic Pain and Attenuates Transient Receptor Potential Vanilloid Receptor-1 Expression in Adult Sensory Neurons

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