Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of Pregabalin

Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex, however under neuropathic conditions, it is unclear how hyperexcitability of spinal neurones converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity, and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurones in anaesthetised spinal nerve-ligated (SNL), sham-operated and naïve rats. In neuropathic rats, WDR neurones had elevated evoked responses to low and high intensity punctate mechanical stimuli, dynamic brushing, innocuous and noxious cooling, but less so to heat stimulation of the receptive field. NS neurones in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling and noxious heat. Additionally, WDR, but not NS, neurones in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR:NS neurones was comparable between SNL and naïve/sham groups suggesting relatively few NS neurones gain sensitivity to low intensity stimuli leading to a 'WDR phenotype'. After neuropathy, the proportion of cold sensitive WDR and NS neurones increased, supporting that changes in frequency dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold evoked or elevated spontaneous activity

Na(v )1.8-null mice show stimulus-dependent deficits in spinal neuronal activity

BACKGROUND: The voltage gated sodium channel Na(v )1.8 has a highly restricted expression pattern to predominantly nociceptive peripheral sensory neurones. Behaviourally Na(v )1.8-null mice show an increased acute pain threshold to noxious mechanical pressure and also deficits in inflammatory and visceral, but not neuropathic pain. Here we have made in vivo electrophysiology recordings of dorsal horn neurones in intact anaesthetised Na(v )1.8-null mice, in response to a wide range of stimuli to further the understanding of the functional roles of Na(v )1.8 in pain transmission from the periphery to the spinal cord. RESULTS: Na(v )1.8-null mice showed marked deficits in the coding by dorsal horn neurones to mechanical, but not thermal, -evoked responses over the non-noxious and noxious range compared to littermate controls. Additionally, responses evoked to other stimulus modalities were also significantly reduced in Na(v )1.8-null mice where the reduction observed to pinch > brush. The occurrence of ongoing spontaneous neuronal activity was significantly less in mice lacking Na(v )1.8 compared to control. No difference was observed between groups in the evoked activity to electrical activity of the peripheral receptive field. CONCLUSION: This study demonstrates that deletion of the sodium channel Na(v )1.8 results in stimulus-dependent deficits in the dorsal horn neuronal coding to mechanical, but not thermal stimuli applied to the neuronal peripheral receptive field. This implies that Na(v )1.8 is either responsible for, or associated with proteins involved in mechanosensation

Nerve injury increases native CaV2.2 trafficking in dorsal root ganglion mechanoreceptors

Neuronal N-type (CaV2.2) voltage-gated calcium channels are essential for neurotransmission from primary afferent terminals in the dorsal horn. In this study we have utilized a knock-in mouse expressing CaV2.2 with an inserted extracellular hemagglutinin-tag (CaV2.2_HA), to visualise the distribution of endogenous CaV2.2 in dorsal root ganglion (DRG) neurons and their primary afferents in the dorsal horn. We examined the effect of partial sciatic nerve ligation (PSNL) and found an increase in CaV2.2_HA only in large and medium dorsal root ganglion neurons, and also in deep dorsal-horn synaptic terminals. Furthermore, there is a parallel increase in co-expression with GFRα1, present in a population of low threshold mechanoreceptors, both in large DRG neurons and in their terminals. The increased expression of CaV2.2_HA in these DRG neurons and their terminals is dependent on the presence of the auxiliary subunit α2δ-1, which is required for channel trafficking to the cell surface and to synaptic terminals, and likely contributes to enhanced synaptic transmission at these synapses following PSNL. In contrast the increase of GFRα1 is not altered in α2δ-1 knockout mice. We also found following PSNL there is patchy loss of glomerular synapses immunoreactive for CaV2.2_HA and CGRP or IB4, restricted to the superficial layers of the dorsal horn. This reduction is not dependent on α2δ-1, and likely reflects partial deafferentation of C-nociceptor presynaptic terminals. Therefore, we can distinguish in this pain model two different events affecting specific DRG terminals, with opposite consequences for CaV2.2_HA expression and function in the dorsal horn

戸田采女正様御下山御泊御下宿割帳

Here we aim to present an accessible review of the pharmacological targets for pain management, and succinctly discuss the newest trends in pain therapy. A key task for current pain pharmacotherapy is the identification of receptors and channels orchestrating nociception. Notwithstanding peripheral alterations in the receptors and channels following pathophysiological events, the modulatory mechanisms in the central nervous system are also fundamental to the regulation of pain perception. Bridging preclinical and clinical studies of peripheral and central components of pain modulation, we present the different types of pain and relate these to pharmacological interventions. We firstly highlight the roles of several peripheral nociceptors, such as NGF, CGRP, sodium channels, and TRP-family channels that may become novel targets for therapies. In the central nervous system, the roles of calcium channels and gabapentinoids as well as NMDA receptors in generating excitability are covered including ideas on central sensitization. We then turn to central modulatory systems and discuss opioids and monoamines. We aim to explain the importance of central sensitization and the dialogue of the spinal circuits with the brain descending modulatory controls before discussing a mechanism-based effectiveness of antidepressants in pain therapy and their potential to modulate the descending controls. Emphasizing the roles of conditioned pain modulation and its animal's equivalent, diffuse noxious inhibitory controls, we discuss these unique descending modulations as a potential tool for understanding mechanisms in patients suffering from pain. Mechanism-based therapy is the key to picking the correct treatments and recent clinical studies using sensory symptoms of patients as surrogates for underlying mechanisms can be used to subgroup patients and reveal actions of drugs that may be lost when studying heterogenous groups of patients. Key advances in the understanding of basic pain principles will impact our thinking about therapy targets. The complexity of pain syndromes will require tailored pharmacological drugs, often in combination or through drugs with more than one action, and often psychotherapy, to fully control pain

Formalin-induced behavioural hypersensitivity and neuronal hyperexcitability are mediated by rapid protein synthesis at the spinal level

Background: The mammalian target of rapamycin ( mTOR) is a key regulator of mRNA translation whose action can be inhibited by the drug rapamycin. Forms of long-term plasticity require protein synthesis and evidence indicates that mRNA in dendrites, axon terminals and cell bodies is essential for long-term synaptic plasticity. Specific to pain, shifts in pain thresholds and responsiveness are an expression of neuronal plasticity and this likely contributes to persistent pain. We investigated this by inhibiting the activity of mTOR with rapamycin at the spinal level, of rats that were subjected to the formalin test, using both behavioural and electrophysiological techniques.Results: For in vivo electrophysiology, Sprague Dawley rats were fully anaesthetised and single-unit extracellular recordings were obtained from lamina V wide dynamic range (WDR) dorsal horn spinal neurones at the region where input is received from the hind paw. Neuronal responses from naive rats showed that rapamycin-sensitive pathways were important in nociceptive-specific C-fibre mediated transmission onto WDR neurones as well mechanically-evoked responses since rapamycin was effective in attenuating these measures. Formalin solution was injected into the hind paw prior to which, rapamycin or vehicle was applied directly onto the exposed spinal cord. When rapamycin was applied to the spinal cord prior to hind paw formalin injection, there was a significant attenuation of the prolonged second phase of the formalin test, which comprises continuing afferent input to the spinal cord, neuronal hyperexcitability and an activated descending facilitatory drive from the brainstem acting on spinal neurones. In accordance with electrophysiological data, behavioural studies showed that rapamycin attenuated behavioural hypersensitivity elicited by formalin injection into the hind paw.Conclusion: We conclude that mTOR has a role in maintaining persistent pain states via mRNA translation and thus protein synthesis. We hypothesise that mTOR may be activated by excitatory neurotransmitter release acting on sensory afferent terminals as well as dorsal horn spinal neurones, which may be further amplified by descending facilitatory systems originating from higher centres in the brain

Behavioural and electrophysiological characterisation of experimentally induced osteoarthritis and neuropathy in C57Bl/6 mice

Background: Osteoarthritis is a widespread condition affecting the elderly where similar to 70-90% of over 75 year olds are affected, representing one of the largest cost burdens to healthcare in the western world. The monosodium iodoacetate (MIA) osteoarthritis model has been well described in the rat especially in terms of the pathological progression of the disease and more recently pain behaviour. In this study, we characterise, for the first time, MIA induced osteoarthritis in mice and compare it with nerve-injured mice (partial sciatic nerve injury), using both behavioural and in vivo electrophysiological measurements. These approaches uniquely allow the threshold and suprathreshold measures to many modalities to be quantified and so form a basis for improving and expanding transgenic studies.Results: Significant mechanical hypersensitivity was observed in the ipsilateral hindpaw in MIA injected mice at all observed time points following infrapetellar MIA injection (p < 0.05). The mechanical hypersensitivity exhibited a partial biphasic temporal pattern, but thermal hypersensitivity was absent. Electrically-evoked dorsal horn neuronal responses in MIA injected mice were significantly elevated (p < 0.05) with respect to A- and C-fibre firing, input, pinch and noxious von Frey (26 and 60 g). No significant changes in A- or C-fibre thresholds were observed. Nerve-injured mice displayed significant behavioural thermal and mechanical hypersensitivity (p < 0.05) and evoked dorsal horn responses were significantly increased with respect to C-fibre firing, pinch and wind-up (p < 0.05).Conclusion: The MIA model of osteoarthritic pain in mice displays behavioural characteristics similar to those observed in rats. Changes in both behavioural measures and neuronal activity from the paw, suggest that central changes are involved in this pain state, although a role for peripheral drives is also likely. Moreover, the behavioural and neuronal measures in these two pain models showed overlapping alterations in terms of certain neuronal measures and mechanical sensitivity despite their very different pathologies and a loss of input in neuropathy, suggesting some commonalities in the central processing of different peripheral pain states. This murine model of osteoarthritis will allow the exploitation of knock out animals to better understand underlying mechanisms and identify novel molecular targets

Is tapentadol different from classical opioids?: a review of the evidence

Tapentadol is a single molecule able to deliver analgesia by two distinct mechanisms, a feature which differentiates it from many other analgesics. Pre-clinical data demonstrate two mechanisms of action: mu-opioid receptor agonist activity and noradrenaline re-uptake inhibition. From these, one may predict that tapentadol would be applicable across a broad spectrum of pain from nociceptive to neuropathic. The evidence in animal models suggests that norepinephrine re-uptake inhibition (NRI) is a key mechanism and may even predominate over opioid actions in chronic (and especially neuropathic) pain states, reinforcing that tapentadol is different to classical opioids and may, therefore, be an a priori choice for the treatment of neuropathic and mixed pain. The clinical studies and subsequent practice experience and surveillance support the concept of opioid and non-opioid mechanisms of action. The reduced incidence of some of the typical opioid-induced side effects, compared to equianalgesic doses of classical opioids, supports the hypothesis that tapentadol analgesia is only partially mediated by opioid agonist mechanisms. Both the pre-clinical and clinical profiles appear to be differentiated from those of classical opioids

Functional significance of M-type potassium channels in nociceptive cutaneous sensory endings

M-channels carry slowly activating potassium currents that regulate excitability in a variety of central and peripheral neurons. Functional M-channels and their Kv7 channel correlates are expressed throughout the somatosensory nervous system where they may play an important role in controlling sensory nerve activity. Here we show that Kv7.2 immunoreactivity is expressed in the peripheral terminals of nociceptive primary afferents. Electrophysiological recordings from single afferents in vitro showed that block of M-channels by 3 μM XE991 sensitized Aδ- but not C-fibers to noxious heat stimulation and induced spontaneous, ongoing activity at 32°C in many Aδ-fibers. These observations were extended in vivo: intraplantar injection of XE991 selectively enhanced the response of deep dorsal horn (DH) neurons to peripheral mid-range mechanical and higher range thermal stimuli, consistent with a selective effect on Aδ-fiber peripheral terminals. These results demonstrate an important physiological role of M-channels in controlling nociceptive Aδ-fiber responses and provide a rationale for the nocifensive behaviors that arise following intraplantar injection of the M-channel blocker XE991