Noxious heat‐induced CGRP release from rat sciatic nerve axons <i>in vitro</i>

Sauer, Susanne K.; Reeh, Peter W.; Bove, Geoffrey M.

doi:10.1046/j.0953-816x.2001.01741.x

Cited by 47 publications

(40 citation statements)

References 32 publications

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“…Thus, our cellular data clearly suggest that GABA A receptors account for a significant proportion of the propofol sensitivity of sensory neurons. However, we also show that propofol but not GABA or the selective GABA A receptor agonist muscimol evoke a release of CGRP from sciatic nerves in a previously established model (43,44). Similarly, GABA failed to amplify, and the selective GABA B -receptor agonist baclofen failed to inhibit high potassium-induced CGRP release from hind paw skin.…”

Section: Discussionmentioning

confidence: 52%

The General Anesthetic Propofol Excites Nociceptors by Activating TRPV1 and TRPA1 Rather than GABAA Receptors

Fischer

Leffler

Niedermirtl

et al. 2010

Journal of Biological Chemistry

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Anesthetic agents can induce a paradox activation and sensitization of nociceptive sensory neurons and, thus, potentially facilitate pain processing. Here we identify distinct molecular mechanisms that mediate an activation of sensory neurons by 2,6-diisopropylphenol (propofol), a commonly used intravenous anesthetic known to elicit intense pain upon injection. Clinically relevant concentrations of propofol activated the recombinant transient receptor potential (TRP) receptors TRPA1 and TRPV1 heterologously expressed in HEK293t cells. In dorsal root ganglion (DRG) neurons, propofol-induced activation correlated better to expression of TRPA1 than of TRPV1. However, pretreatment with the protein kinase C activator 4␤-phorbol 12-myristate 13-acetate (PMA) resulted in a significantly sensitized propofol-induced activation of TRPV1 in DRG neurons as well as in HEK293t cells. Pharmacological and genetic silencing of both TRPA1 and TRPV1 only partially abrogated propofol-induced responses in DRG neurons. The remaining propofol-induced activation was abolished by the selective ␥-aminobutyric acid, type A (GABA A ) receptor antagonist picrotoxin. Propofol but not GABA evokes a release of calcitonin generelated peptide, a key component of neurogenic inflammation, from isolated peripheral nerves of wild-type but not TRPV1 and TRPA1-deficient mice. Moreover, propofol but not GABA induced an intense pain upon intracutaneous injection. As both the release of calcitonin gene-related peptide and injection pain by propofol seem to be independent of GABA A receptors, our data identify TRPV1 and TRPA1 as key molecules for propofol-induced excitation of sensory neurons. This study warrants further investigations into the role of anesthetics to induce nociceptor sensitization and to foster postoperative pain.The intravenous general anesthetic propofol 3 (2,6-diisopropylphenol) has become one of the most widely used anesthetics.Due to a short context-sensitive half-time, propofol is used for sedations as well as for total intravenous anesthesia during surgery. A drawback of propofol, however, is its high potential to induce intense burning pain upon injection. Depending on the concentration (0.5-2%), the galenic formulation, and co-medication, 24 -90% of all patients receiving propofol experience injection pain (1). It was hypothesized that propofol might indirectly or directly interact with sensory nerve fibers located in the venous adventitia (2-4). A recent study claims that the irritant receptor TRPA1, which is expressed in nociceptive sensory neurons, is the predominant molecular entity mediating activation of peripheral nerve endings by general anesthetics (5). Also, TRPA1 was found to mediate propofol-induced pain behavior induced by intranasal propofol and flexor reflex response upon intra-arterial propofol (5). TRPA1 is an excitatory cation channel that is activated by pungent or irritating substances such as acrolein, mustard oil, and formalin (6). TRPA1 has also been demonstrated to be involved in the development of increa...

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Section: Discussionmentioning

confidence: 52%

The General Anesthetic Propofol Excites Nociceptors by Activating TRPV1 and TRPA1 Rather than GABAA Receptors

Fischer

Leffler

Niedermirtl

et al. 2010

Journal of Biological Chemistry

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“…The role of CGRP in nociception has been demonstrated in studies of migraine (Benemei et al, 2009), noxious heat (Mogil et al, 2005), mechanical hyperalgesia (Hirsch et al, 2013), and secondary hyperalgesia (Zhang et al, 2001). Moreover, blockade of the TRPV1 receptor reduces the release of both glutamate and CGRP (Puttfarcken et al, 2010), and stimulation by capsaicin, noxious heat, or protons increased CGRP release from TRPV1 neurons (Sauer et al, 2001;Fischer et al, 2003;Bernardini et al, 2004). Our data indeed show that pharmacologic blockade of either SP or CGRP transmission together with genetic ablation of VGLUT2-mediated glutamatergic signaling from Trpv1-Cre neurons prevents the development of heat hyperalgesia.…”

Section: Discussionmentioning

confidence: 95%

Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

Rogóż

Andersen

Kullander

et al. 2014

Molecular Pharmacology

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The transient receptor potential cation channel subfamily V member 1 (TRPV1) is known as a thermosensor and integrator of inflammation-induced hyperalgesia. TRPV1 is expressed in a subpopulation of primary afferent neurons that express several different neurotransmitters. The role of the TRPV1 channel in the development of hyperalgesia is established, but the role of the neurotransmitter glutamate, used partially by the same neuronal population and thus probably mediating the response, is still under investigation. We have used a Trpv1-Cre mouse line in which we either ablated Trpv1-Cre expressing neurons or induced vesicular glutamate transporter 2 (Vglut2) deficiency in Trpv1-Cre expressing neurons and investigated specific states of hyperalgesia after persistent inflammation. Furthermore, by pharmacologic inhibition of substance P (SP) or calcitonin gene-related peptide (CGRP) signaling in Vglut2-deficient mice, we also evaluated the contribution of SP or CGRP to inflammationinduced hyperalgesia, with or without the presence of vesicular glutamate transporter 2 (VGLUT2)-mediated glutamatergic transmission in Trpv1-Cre neurons. This examination, together with c-Fos analyses, showed that VGLUT2-mediated glutamatergic transmission in Trpv1-Cre afferents together with SP or CGRP is essential for the development of the heat hyperalgesia associated with persistent inflammation. Additionally, SP-, CGRP-, and VGLUT2-mediated transmission together were found to play a role in the development of mechanical hyperalgesia after persistent inflammation.

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“…To be compatible with our single-fiber recording results, this theory would require to assume an only heat-sensitive epineurial collateral of a fiber that proceeds through the nerve and terminates in a mechanoheat-sensitive RF of the skin. This assumption cannot currently be disproved, but appears feeble because heat-induced axonal CGRP release was previously discovered using desheathed peripheral nerves bare of epineurial nerve endings (Sauer et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Indirect evidence obtained from second-order neurons in the cat as well as in vivo single-fiber recordings in rats suggest that there may be a certain heat sensitivity in normal C-axons of peripheral nerves (Zimmermann and Sanders, 1982;Blenk et al, 1996). In addition, the isolated desheathed sciatic nerve of the rat responds to noxious heat with a well graded and calciumdependent release of the neuropeptide calcitonin gene-related peptide (CGRP) expressed in C-and A␦-fibers (Sauer et al, 2001). The stimulus-response relationship in this preparation shows a high thermal coefficient, Q 10 of 15, which, together with the above electrophysiology, is highly suggestive of underlying nociceptive transduction mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Sensory Transduction in Peripheral Nerve Axons Elicits Ectopic Action Potentials

Hoffmann¹,

Sauer²,

Horch³

et al. 2008

Journal of Neuroscience

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Sensory properties of unmyelinated axons in the isolated rat sciatic nerve have been revealed previously by measuring stimulated neuropeptide release in response to noxious stimuli. In addition, axonal sensitization by inflammatory mediators has been demonstrated and shown to depend on the heat-and proton-activated ion channel transient receptor potential vanilloid receptor-1. It was unclear whether this responsiveness is accompanied by ectopic generation of action potentials, which may play a crucial role in painful neuropathies. We explored this hypothesis using the isolated mouse skin-nerve preparation. This method enabled us to directly compare the sensory properties of axons in the peripheral nerve with their characterized cutaneous terminals in the receptive field using propagated action potentials as an index of axonal activation. Single-fiber recordings from 51 mechanosensitive mouse C-fibers revealed that a majority of the polymodal nociceptors responded with an encoding discharge rate to graded heating of the cutaneous receptive field (n ϭ 38) as well as of the saphenous nerve carrying the fiber under investigation (n ϭ 25; 66%). Axonal heat responses paralleled those of the receptive fields with regard to thresholds and discharge rates (41.5 Ϯ 4.3°C; 7.7 Ϯ 9.6 spikes in a 20 s 32-48°C ranged stimulation). In contrast, axonal mechanosensitivity was poor and noxious cold sensitivity more rarely encountered. In conclusion, peripheral nerve axons exhibit sensory transduction capacities similar to their nociceptive terminals in the skin with respect to noxious heat, although not to mechanical and cold sensitivity. This may become a source of ectopic discharge and pain if axonal heat threshold drops to body temperature, as may be the case during inflammation-like processes in peripheral nerves.

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Noxious heat‐induced CGRP release from rat sciatic nerve axons in vitro

Cited by 47 publications

References 32 publications

The General Anesthetic Propofol Excites Nociceptors by Activating TRPV1 and TRPA1 Rather than GABAA Receptors

The General Anesthetic Propofol Excites Nociceptors by Activating TRPV1 and TRPA1 Rather than GABAA Receptors

Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

Sensory Transduction in Peripheral Nerve Axons Elicits Ectopic Action Potentials

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