Kirsty Bannister

Preclinical and early clinical investigations related to monoaminergic pain modulation

SummaryThe balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent α2-adrenoceptor-mediated inhibitory system and 5-HT3 (and likely also 5-HT2) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control.

Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain

BackgroundDescending facilitation, from the brainstem, promotes spinal neuronal hyperexcitability and behavioural hypersensitivity in many chronic pain states. We have previously demonstrated enhanced descending facilitation onto dorsal horn neurones in a neuropathic pain model, and shown this to enable the analgesic effectiveness of gabapentin. Here we have tested if this hypothesis applies to other pain states by using a combination of approaches in a rat model of osteoarthritis (OA) to ascertain if 1) a role for descending 5HT mediated facilitation exists, and 2) if pregabalin (a newer analogue of gabapentin) is an effective antinociceptive agent in this model. Further, quantitative-PCR experiments were undertaken to analyse the α2δ-1 and 5-HT3A subunit mRNA levels in L3–6 DRG in order to assess whether changes in these molecular substrates have a bearing on the pharmacological effects of ondansetron and pregabalin in OA.ResultsOsteoarthritis was induced via intra-articular injection of monosodium iodoacetate (MIA) into the knee joint. Control animals were injected with 0.9% saline. Two weeks later in vivo electrophysiology was performed, comparing the effects of spinal ondansetron (10–100 μg/50 μl) or systemic pregabalin (0.3 – 10 mg/kg) on evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimuli in MIA or control rats. In MIA rats, ondansetron significantly inhibited the evoked responses to both innocuous and noxious natural evoked neuronal responses, whereas only inhibition of noxious evoked responses was seen in controls. Pregabalin significantly inhibited neuronal responses in the MIA rats only; this effect was blocked by a pre-administration of spinal ondansetron. Analysis of α2δ-1 and 5-HT3A subunit mRNA levels in L3–6 DRG revealed a significant increase in α2δ-1 levels in ipsilateral L3&4 DRG in MIA rats. 5-HT3A subunit mRNA levels were unchanged.ConclusionThese data suggest descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in α2δ-1 mRNA levels, may underlie pregabalins state dependent effects in this model of chronic pain.

Mu-opioid and noradrenergic α2-adrenoceptor contributions to the effects of tapentadol on spinal electrophysiological measures of nociception in nerve-injured rats

&NA; Multiple pathological mechanisms at multiple sensory sites may underlie the pain that follows nerve injury. This provides a basis for recommending more than one agent, either sequentially or in combination, for its treatment. According to this premise, new drugs that combine different mechanisms of analgesic action in a single molecule are gaining momentum, such as tapentadol which stimulates mu‐opioid receptors (MOR) and acts as a noradrenaline reuptake inhibitor (NRI) in the CNS. Tapentadol is currently indicated for treating moderate to severe acute and severe chronic pain, and here we demonstrate its efficacy in an animal model of ongoing neuropathic pain. In particular, we performed a series of in vivo electrophysiological tests in spinal nerve ligated and sham‐operated rats to show that systemic tapentadol (1 and 5 mg/kg) dose‐dependently reduced evoked responses of spinal dorsal horn neurones to a range of peripheral stimuli, including brush, punctate mechanical and thermal stimuli. Furthermore, we showed that spinal application of the selective &agr;2‐adrenoceptor antagonist atipamezole, or alternatively the mu‐opioid receptor antagonist naloxone, produced near complete reversal of tapentadols inhibitory effects, which suggests not only that the spinal cord is the key site of tapentadols actions, but also that no pharmacology other than MOR‐NRI is involved in its analgesia. Moreover, according to the extent that the antagonists reversed tapentadols inhibitions in sham and SNL rats, we suggest that there may be a shift from predominant opioid inhibitory mechanisms in control animals, to predominant noradrenergic inhibition in neuropathic animals.

Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states

Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A3 adenosine receptor (A3AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A3AR agonist. These effects were prevented by blockade of spinal and supraspinal A3AR, lost in A3AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A3AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A3AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain.

Diffuse noxious inhibitory controls and nerve injury: restoring an imbalance between descending monoamine inhibitions and facilitations.

Abstract Diffuse noxious inhibitory controls (DNICs) utilize descending inhibitory controls through poorly understood brain stem pathways. The human counterpart, conditioned pain modulation, is reduced in patients with neuropathy aligned with animal data showing a loss of descending inhibitory noradrenaline controls together with a gain of 5-HT3 receptor-mediated facilitations after neuropathy. We investigated the pharmacological basis of DNIC and whether it can be restored after neuropathy. Deep dorsal horn neurons were activated by von Frey filaments applied to the hind paw, and DNIC was induced by a pinch applied to the ear in isoflurane-anaesthetized animals. Spinal nerve ligation was the model of neuropathy. Diffuse noxious inhibitory control was present in control rats but abolished after neuropathy. &agr;2 adrenoceptor mechanisms underlie DNIC because the antagonists, yohimbine and atipamezole, markedly attenuated this descending inhibition. We restored DNIC in spinal nerve ligated animals by blocking 5-HT3 descending facilitations with the antagonist ondansetron or by enhancing norepinephrine modulation through the use of reboxetine (a norepinephrine reuptake inhibitor, NRI) or tapentadol (&mgr;-opioid receptor agonist and NRI). Additionally, ondansetron enhanced DNIC in normal animals. Diffuse noxious inhibitory controls are reduced after peripheral nerve injury illustrating the central impact of neuropathy, leading to an imbalance in descending excitations and inhibitions. Underlying noradrenergic mechanisms explain the relationship between conditioned pain modulation and the use of tapentadol and duloxetine (a serotonin, NRI) in patients. We suggest that pharmacological strategies through manipulation of the monoamine system could be used to enhance DNIC in patients by blocking descending facilitations with ondansetron or enhancing norepinephrine inhibitions, so possibly reducing chronic pain.

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.

A pronociceptive role for the 5-HT2 receptor on spinal nociceptive transmission: An in vivo electrophysiological study in the rat

Serotonin (5-HT) plays a major yet complex role in modulating spinal nociceptive transmission as a consequence of the number of 5-HT receptor subtypes. These include the 5-HT2 receptor, which is further sub classified into 5-HT2A, B and C. Studies have described both a pro- and antinociceptive action following 5-HT2A-receptor activation; therefore, to shed light on the directional nature of spinal 5-HT2A receptor activity, we investigated the effects of spinal administration of the 5-HT2A receptor antagonist, ketanserin, on the evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimulation. We also assessed the effects of systemic administration of ritanserin, a 5-HT2A/2C receptor antagonist and spinal application of (±)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI) (3.6 and 17.8 μg/50 μl), a 5-HT2A/2C agonist, on the same evoked neuronal responses. Ketanserin (1, 10 and 100 μg/50 μl) produced a dose related inhibition of the evoked responses to noxious mechanical punctate and thermal stimuli only. Ritanserin (2 mg/kg) replicated the inhibitory effects seen with ketanserin on the natural evoked neuronal responses and also potently inhibited the C-fibre, post discharge, input and wind-up evoked responses. DOI increased the mechanical and thermal evoked responses, an effect reversed by ketanserin. Thus, our findings show that spinal ketanserin (1–100 μg/50 μl) and systemic ritanserin (2 mg/kg), at these doses, have similar antinociceptive effects, whereas the agonist, DOI, produced excitatory effects, on spinal neuronal activity. Our data, therefore, supports a pronociceptive role for 5-HT2 receptors, most likely through modulation of 5-HT2A receptor activity, on spinal nociceptive transmission under normal conditions.

Circuitry and plasticity of the dorsal horn--toward a better understanding of neuropathic pain.

Maladaptive plasticity within the dorsal horn (DH) of the spinal cord is a key substrate for development of neuropathic pain following peripheral nerve injury. Advances in genetic engineering, tracing techniques and opto-genetics are leading to a much better understanding of the complex circuitry of the spinal DH and the radical changes evoked in such circuitry by nerve injury. These changes can be viewed at multiple levels including: synaptic remodeling including enhanced excitatory and reduced inhibitory drive, morphological and electrophysiological changes which are observed both to primary afferent inputs as well as DH neurons, and ultimately circuit-level rewiring which leads to altered connectivity and aberrant processing of sensory inputs in the DH. The DH should not be seen in isolation but is subject to important descending modulation from the brainstem, which is further dysregulated by nerve injury. Understanding which changes relate to specific disease-states is essential, and recent work has aimed to stratify patient populations in a mechanistic fashion. In this review we will discuss how such pathophysiological mechanisms may lead to the distressing sensory phenomena experienced by patients suffering neuropathic pain, and the relationship of such mechanisms to current and potential future treatment modalities.

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.

Opioid-induced hyperalgesia: where are we now?

Purpose of reviewPatients receiving chronic opioid treatment who develop paradoxical pain sensations, as well as worsening existing pain, can be diagnosed as suffering from opioid-induced hyperalgesia (OIH). As the worldwide population expands so too does the proportion of patients who experience pain that requires a strong opioid. Recognizing the symptoms of OIH and optimizing the use of morphine in the hospital setting is imperative. This review focuses on clinical data relating to evidence of OIH at the bedside and the novel techniques employed by healthcare providers in order to improve the heightened pain sensations experienced by susceptible patients. Recent findingsAn increasing number of randomized prospective controlled trials report worsening patient pain following high-dose opioid treatment. Patient case reports support the premise that OIH is a clinical reality. According to recent literature, for those individuals who develop paradoxical pain sensations upon chronic opioid therapy, the most successful course of action involves a multidisciplinary attack that usually comprises early diagnosis, opioid switching and adjunct therapies. SummaryLooking to the future, improved clinician–patient communication, advanced diagnostic techniques and a refinement of prescribed adjunct pharmacotherapies will offer the most successful multimodal pain management approach to the problem of OIH.