Inflammatory Pain Unmasks Heterosynaptic Facilitation in Lamina I Neurokinin 1 Receptor-Expressing Neurons in Rat Spinal Cord

Torsney, Carole

doi:10.1523/jneurosci.6241-10.2011

Cited by 49 publications

(61 citation statements)

References 74 publications

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“…7C, E, F). These in vivo results are consistent with in vitro spinal cord slice studies demonstrating Aδ-fiber activation of nociresponsive second-order neurons, enhanced responses following inflammation, and reduction of Aδ-mediated field potentials by morphine [50,63,64,67,72]. The presence of μ-opioid receptors on TRPV1 + DRG neurons [18] and colocalization of TRPV1 in subpopulations of Aδ neurons are consistent with the sensitivity of Aδ neurons to pharmacological doses of morphine [23].…”

Section: Discussionsupporting

confidence: 87%

Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion

Mitchell

Lebovitz

Keller

et al. 2014

Pain

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TRPV1 is expressed in a subpopulation of myelinated Aδ and unmyelinated C-fibers. TRPV1+ fibers are essential for the transmission of nociceptive thermal stimuli and for the establishment and maintenance of inflammatory hyperalgesia. We have previously shown that high-power, short-duration pulses from an infrared diode laser are capable of predominantly activating cutaneous TRPV1+ Aδ-fibers. Here we show that stimulating either subtype of TRPV1+ fiber in the paw during carrageenan-induced inflammation or following hind-paw incision elicits pronounced hyperalgesic responses, including prolonged paw guarding. The ultrapotent TRPV1 agonist resiniferatoxin (RTX) dose-dependently deactivates TRPV1+ fibers and blocks thermal nociceptive responses in baseline or inflamed conditions. Injecting sufficient doses of RTX peripherally renders animals unresponsive to laser stimulation even at the point of acute thermal skin damage. In contrast, Trpv1−/− mice, which are generally unresponsive to noxious thermal stimuli at lower power settings, exhibit withdrawal responses and inflammation-induced sensitization using high-power, short duration Aδ stimuli. In rats, systemic morphine suppresses paw withdrawal, inflammatory guarding, and hyperalgesia in a dose-dependent fashion using the same Aδ stimuli. The qualitative intensity of Aδ responses, the leftward shift of the stimulus-response curve, the increased guarding behaviors during carrageenan inflammation or after incision, and the reduction of Aδ responses with morphine suggest multiple roles for TRPV1+ Aδ fibers in nociceptive processes and their modulation of pathological pain conditions.

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Section: Discussionsupporting

confidence: 87%

Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion

Mitchell

Lebovitz

Keller

et al. 2014

Pain

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“…NTX administration to slices taken from post-hyperalgesia animals precipitated ↑ [Ca 2+ ] I , indicating that LS survives in spinal nociceptive neurons within our slice preparation, and that opioid receptor activity tonically suppresses it (Corder et al, 2013); 3) NTX produced cAMP superactivation in the DH of post-hyperalgesia mice (Corder et al, 2013). Taken together, these data suggest that MOR actively represses signal amplification, similar to spinal GABAergic signaling (Baba et al, 2003, Torsney and MacDermott, 2006, Torsney, 2011). Our results reveal the presence of sensitized spinal nociceptive neurons that outlast the resolution of hyperalgesia and remain under the control of endogenous opioid receptor inhibitory mechanisms (Corder et al, 2013).…”

Section: Opioid Receptor-masked Sensitizationmentioning

confidence: 65%

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Taylor

Corder

2014

Current Topics in Behavioral Neurosciences

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Endogenous activation of μ-opioid receptors (MORs) provides relief from acute pain. Recent studies have established that tissue inflammation produces latent pain sensitization (LS) that is masked by spinal MOR signaling for months, even after complete recovery from injury and re-establishment of normal pain thresholds. Disruption with MOR inverse agonists reinstates pain and precipitates cellular, somatic and aversive signs of physical withdrawal; this phenomenon requires N-methyl-D-aspartate receptor-mediated activation of calcium-sensitive adenylyl cyclase type 1 (AC1). In this review, we present a new conceptual model of the transition from acute to chronic pain, based on the delicate balance between LS and endogenous analgesia that develops after painful tissue injury. First, injury activates pain pathways. Second, the spinal cord establishes MOR constitutive activity (MORCA) as it attempts to control pain. Third, over time, the body becomes dependent on MORCA, which paradoxically sensitizes pain pathways. Stress or injury escalates opposing inhibitory and excitatory influences on nociceptive processing as a pathological consequence of increased endogenous opioid tone. Pain begets MORCA begets pain vulnerability in a vicious cycle. The final result is a silent insidious state characterized by the escalation of two opposing excitatory and inhibitory influences on pain transmission: LS mediated by AC1 (which maintains accelerator), and pain inhibition mediated by MORCA (which maintains the brake). This raises the prospect that opposing homeostatic interactions between MORCA analgesia and latent NMDAR–AC1-mediated pain sensitization create a lasting vulnerability to develop chronic pain. Thus, chronic pain syndromes may result from a failure in constitutive signaling of spinal MORs and a loss of endogenous analgesic control. An overarching long-term therapeutic goal of future research is to alleviate chronic pain by either: a) facilitating endogenous opioid analgesia, thus restricting LS within a state of remission; or b) extinguishing LS altogether.

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“…Notably, it has previously been established that CFA inflammation does not alter primary afferent threshold or conduction velocity in both adult [29,30] and juvenile rats [11]. Primary afferent components could be divided into three distinct groups, which corresponded to A β -, A δ - and C-fibres (Figure 3A).…”

Section: Resultsmentioning

confidence: 82%

The Chemerin Receptor 23 Agonist, Chemerin, Attenuates Monosynaptic C-Fibre Input to Lamina I Neurokinin 1 Receptor Expressing Rat Spinal Cord Neurons in Inflammatory Pain

Dickie

Torsney

2014

Mol Pain

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BackgroundRecent evidence has shown that the chemerin receptor 23 (ChemR23) represents a novel inflammatory pain target, whereby the ChemR23 agonists, resolvin E1 and chemerin, can inhibit inflammatory pain hypersensitivity, by a mechanism that involves normalisation of potentiated spinal cord responses. This study has examined the ability of the ChemR23 agonist, chemerin, to modulate synaptic input to lamina I neurokinin 1 receptor expressing (NK1R+) dorsal horn neurons, which are known to be crucial for the manifestation of inflammatory pain.ResultsWhole-cell patch-clamp recordings from pre-identified lamina I NK1R+ neurons, in rat spinal cord slices, revealed that chemerin significantly attenuates capsaicin potentiation of miniature excitatory postsynaptic current (mEPSC) frequency, but is without effect in non-potentiated conditions. In tissue isolated from complete Freund’s adjuvant (CFA) treated rats, chemerin significantly reduced the peak amplitude of monosynaptic C-fibre evoked excitatory postsynaptic currents (eEPSCs) in a subset of lamina I NK1R+ neurons, termed chemerin responders. However, chemerin did not alter the peak amplitude of monosynaptic C-fibre eEPSCs in control tissue. Furthermore, paired-pulse recordings in CFA tissue demonstrated that chemerin significantly reduced paired-pulse depression in the subset of neurons classified as chemerin responders, but was without effect in non-responders, indicating that chemerin acts presynaptically to attenuate monosynaptic C-fibre input to a subset of lamina I NK1R+ neurons.ConclusionsThese results suggest that the reported ability of ChemR23 agonists to attenuate inflammatory pain hypersensitivity may in part be due to a presynaptic inhibition of monosynaptic C-fibre input to lamina I NK1R+ neurons and provides further evidence that ChemR23 represents a promising inflammatory pain target.

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Inflammatory Pain Unmasks Heterosynaptic Facilitation in Lamina I Neurokinin 1 Receptor-Expressing Neurons in Rat Spinal Cord

Cited by 49 publications

References 74 publications

Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion

Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

The Chemerin Receptor 23 Agonist, Chemerin, Attenuates Monosynaptic C-Fibre Input to Lamina I Neurokinin 1 Receptor Expressing Rat Spinal Cord Neurons in Inflammatory Pain

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