Shafaq Sikandar

Visceral pain: the ins and outs, the ups and downs.

Purpose of reviewVisceral pain represents a major clinical problem, yet far less is known about its mechanisms compared with somatic pains, for example, from cutaneous and muscular structures. Recent findingsIn this review, we describe the neuroanatomical bases of visceral pain signalling in the peripheral and central nervous system, comparing to somatic pains and also the channels and receptors involved in these events. We include an overview of potential new targets in the context of mechanisms of visceral pain and hypersensitivity. SummaryThis review should inform on the recognition of what occurs in patients with visceral pain, why comorbidities are common and how analgesic treatments work.

Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7

Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Nav1.7 are weak analgesics. We investigated whether Nav1.7, as well as contributing to electrical signalling, may have additional functions. Here we report that Nav1.7 deletion has profound effects on gene expression, leading to an upregulation of enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurons. In contrast, Nav1.8-null mutant sensory neurons show no upregulated Penk mRNA expression. Application of the opioid antagonist naloxone potentiates noxious peripheral input into the spinal cord and dramatically reduces analgesia in both female and male Nav1.7-null mutant mice, as well as in a human Nav1.7-null mutant. These data suggest that Nav1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids.

Neural coding of nociceptive stimuli-from rat spinal neurones to human perception.

&NA; This study used radiant laser pulses to explore the central processing and spatial summation of nociceptive inputs in a novel parallel investigation between rats and humans. &NA; Translational studies are key to furthering our understanding of nociceptive signalling and bridging the gaps between molecules and pathways to the patients. This requires use of appropriate preclinical models that accurately depict outcome measures used in humans. Whereas behavioural animal studies classically involve reports related to nociceptive thresholds of, for example, withdrawal, electrophysiological recordings of spinal neurones that receive convergent input from primary afferents permits investigation of suprathreshold events and exploration of the full‐range coding of different stimuli. We explored the central processing of nociceptive inputs in a novel parallel investigation between rats and humans. Using radiant laser pulses, we first compared the electrophysiological responses of deep wide dynamic range and superficial nociceptive‐specific neurones in the rat dorsal horn with human psychophysics and cortical responses. Secondly, we explored the effects of spatial summation using laser pulses of identical energy and different size. We observed 3 main findings. Firstly, both rodent and human data confirmed that neodymium–yttrium aluminium perovskite laser stimulation is a nociceptive‐selective stimulus that never activates A&bgr; afferents. Secondly, graded laser stimulation elicited similarly graded electrophysiological and behavioural responses in both species. Thirdly, there was a significant degree of spatial summation of laser nociceptive input. The remarkable similarity in rodent and human coding indicates that responses of rat dorsal horn neurones can translate to human nociceptive processing. These findings suggest that recordings of spinal neuronal activity elicited by laser stimuli could be a valuable predictive measure of human pain perception.

Pregabalin Suppresses Spinal Neuronal Hyperexcitability and Visceral Hypersensitivity in the Absence of Peripheral Pathophysiology

Background:Opioid-induced hyperalgesia is recognized in the laboratory and the clinic, generating central hyperexcitability in the absence of peripheral pathology. We investigated pregabalin, indicated for neuropathic pain, and ondansetron, a drug that disrupts descending serotonergic processing in the central nervous system, on spinal neuronal hyperexcitability and visceral hypersensitivity in a rat model of opioid-induced hyperalgesia. Methods:Male Sprague-Dawley rats (180–200 g) were implanted with osmotic mini-pumps filled with morphine (90 &mgr;g · &mgr;l−1 · h−1) or saline (0.9% w/v). On days 7–10 in isoflurane anesthetized animals, we evaluated the effects of (1) systemic pregabalin on spinal neuronal and visceromotor responses, and (2) spinal ondansetron on dorsal horn neuronal response. Messenger ribonucleic acid concentrations of &agr;2&dgr;-1, 5HT3A, and &mgr;-opioid receptor in the dorsal root ganglia of all animals were analyzed. Results:In morphine-treated animals, evoked spinal neuronal responses were enhanced to a subset of thermal and mechanical stimuli. This activity was attenuated by pregabalin (by at least 71%) and ondansetron (37%); the visceromotor response to a subset of colorectal distension pressures was attenuated by pregabalin (52.8%; n = 8 for all measures, P < 0.05). Messenger ribonucleic acid concentrations were unchanged. Conclusions:The inhibitory action of pregabalin in opioid-induced hyperalgesia animals is neither neuropathy-dependent nor reliant on up-regulation of the &agr;2&dgr;-1 subunit of voltage-gated calcium channels—mechanisms proposed as being essential for pregabalins efficacy in neuropathy. In opioid-induced hyperalgesia, which extends to colonic distension, a serotonergic facilitatory system may be up-regulated, creating an environment that is permissive for pregabalin-mediated analgesia without peripheral pathology.

In vivo characterization of distinct modality-specific subsets of somatosensory neurons using GCaMP

In vivo imaging shows that the great majority of somatosensory neurons are modality-specific. Mechanistic insights into pain pathways are essential for a rational approach to treating this vast and increasing clinical problem. Sensory neurons that respond to tissue damage (nociceptors) may evoke pain sensations and are typically classified on the basis of action potential velocity. Electrophysiological studies have suggested that most of the C-fiber nociceptors are polymodal, responding to a variety of insults. In contrast, gene deletion studies in the sensory neurons of transgenic mice have frequently resulted in modality-specific deficits. We have used an in vivo imaging approach using the genetically encoded fluorescent calcium indicator GCaMP to study the activity of dorsal root ganglion sensory neurons in live animals challenged with painful stimuli. Using this approach, we can visualize spatially distinct neuronal responses and find that >85% of responsive dorsal root ganglion neurons are modality-specific, responding to either noxious mechanical, cold, or heat stimuli. These observations are mirrored in behavioral studies of transgenic mice. For example, deleting sodium channel Nav1.8 silences mechanical- but not heat-sensing sensory neurons, consistent with behavioral deficits. In contrast, primary cultures of axotomized sensory neurons show high levels of polymodality. After intraplantar treatment with prostaglandin E2, neurons in vivo respond more intensely to noxious thermal and mechanical stimuli, and additional neurons (silent nociceptors) are unmasked. Together, these studies define polymodality as an infrequent feature of nociceptive neurons in normal animals.

Brainstem facilitations and descending serotonergic controls contribute to visceral nociception but not pregabalin analgesia in rats

Highlights ► Descending 5-HT3 receptor-mediated controls are pro-nociceptive in visceral pain. ► Some μ-opioid receptor-expressing RVM cells, putative ON-cells, are serotonergic. ► Putative RVM ON-cells mediate basal visceral pain responses in the CRD model. ► Pregabalin inhibits evoked visceral pain in rats with ablated RVM ON-cells. ► State-dependent pregabalin analgesia in neuropathy does not apply to visceral pain.

Pregabalin modulation of spinal and brainstem visceral nociceptive processing

Summary Electrophysiology and immunohistochemistry were used to investigate rat spinal and brainstem differences in somatic and visceral nociceptive processing and pregabalin efficacy in acute visceral pain. Abstract Brainstem and spinal mechanisms mediating visceral nociception are investigated here using electrophysiology and immunohistochemistry techniques in a model of acute visceral pain. Colorectal distension (CRD) produced graded visceromotor responses (VMR) in normal rats, and these were facilitated by intracolonic mustard oil (MO) that generated acute visceral hyperalgesia. The neuropathic pain drug pregabalin (PGB) is thought to have state‐dependent effects in attenuating neuropathic, but not acute somatic pain, likely by impairing calcium‐channel trafficking. We found that systemic PGB produced antinociceptive effects on CRD‐evoked VMRs in naïve rats lacking pathophysiology and in MO‐pretreated rats. Systemic PGB also significantly reduced Fos labelling in lumbosacral spinal cords of rats given noxious repetitive CRD; however, PGB did not alter this measure of neural activity in the brainstem. Differential brainstem processing of noxious somatic and visceral stimuli may underlie the unique lack of state‐dependent actions of PGB in this visceral pain model. Single‐unit recordings in the rostral ventromedial medulla (RVM) verify that brainstem processing of somatic and visceral stimuli differs. The effects of CRD on RVM cells classed as ON, OFF, or NEUTRAL were independent of their somatic responses, with surprising changes in RVM cell activity to innocuous visceral stimulation. PGB also markedly reduced the visceral responses of RVM ON‐cells to noxious CRD. These results illustrate clear differences in the central processing of visceral and somatic stimuli, yet a common role for descending modulation by brainstem activity in mediating evoked pain measures.

Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models

Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. In both species, UVB with heat rekindling produces central sensitisation. UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively.

Genes, molecules and patients--emerging topics to guide clinical pain research.

This review selectively explores some areas of pain research that, until recently, have been poorly understood. We have chosen four topics that relate to clinical pain and we discuss the underlying mechanisms and related pathophysiologies contributing to these pain states. A key issue in pain medicine involves crucial events and mediators that contribute to normal and abnormal pain signaling, but remain unseen without genetic, biomarker or imaging analysis. Here we consider how the altered genetic make-up of familial pains reveals the human importance of channels discovered by preclinical research, followed by the contribution of receptors as stimulus transducers in cold sensing and cold pain. Finally we review recent data on the neuro-immune interactions in chronic pain and the potential targets for treatment in cancer-induced bone pain.

Scratching the surface: the processing of pain from deep tissues

Although most pain research focuses on skin, muscles, joints and viscerae are major sources of pain. We discuss the mechanisms of deep pains arising from somatic and visceral structures and how this can lead to widespread manifestations and chronification. We include how both altered peripheral and central sensory neurotransmission lead to deep pain states and comment on key areas such as top-down modulation where little is known. It is vital that the clinical characterization of deep pain in patients is improved to allow for back translation to preclinical models so that the missing links can be ascertained. The contribution of deeper somatic and visceral tissues to various chronic pain syndromes is common but there is much we need to know.