David P. Finn

The effect of pain on cognitive function: a review of clinical and preclinical research.

Cognitive impairment is commonly associated with the pain experience. This impairment represents a major obstacle to daily activities and rehabilitation, especially in the chronic pain population. Here we review clinical and preclinical studies that have investigated pain-related alterations in cognition. These include impaired attentional, executive and general cognitive functioning. We describe the anatomical, neurochemical and molecular substrates common to both cognitive processing and supraspinal pain processing, and present the evidence for their involvement in pain-related cognitive impairment. We also examine the added complexity of cognitive impairment caused by analgesic medications and how this can further impact on morbidity in chronic pain patients. The need for a better understanding of the mechanisms of both pain-induced and treatment-related cognitive impairment is highlighted. Further research in this area will aid our understanding of patient symptoms and their underlying pathophysiology, ultimately leading to increased provision of guided therapy.

Stress-induced analgesia.

For over 30 years, scientists have been investigating the phenomenon of pain suppression upon exposure to unconditioned or conditioned stressful stimuli, commonly known as stress-induced analgesia. These studies have revealed that individual sensitivity to stress-induced analgesia can vary greatly and that this sensitivity is coupled to many different phenotypes including the degree of opioid sensitivity and startle response. Furthermore, stress-induced analgesia is influenced by age, gender, and prior experience to stressful, painful, or other environmental stimuli. Stress-induced analgesia is mediated by activation of the descending inhibitory pain pathway. Pharmacological and neurochemical studies have demonstrated involvement of a large number of neurotransmitters and neuropeptides. In particular, there are key roles for the endogenous opioid, monoamine, cannabinoid, gamma-aminobutyric acid and glutamate systems. The study of stress-induced analgesia has enhanced our understanding of the fundamental physiology of pain and stress and can be a useful approach for uncovering new therapeutic targets for the treatment of pain and stress-related disorders.

Stress-induced hyperalgesia

The importance of the modulation of pain by emotion is now widely recognised. In particular, stress and anxiety, depending on their nature, duration and intensity, can exert potent, but complex, modulatory influences typified by either a reduction or exacerbation of the pain state. Exposure to either acute or chronic stress can increase pain responding under experimental conditions and exacerbate clinical pain disorders. There is evidence that exposure to chronic or repeated stress can produce maladaptive neurobiological changes in pathways associated with pain processing, resulting in stress-induced hyperalgesia (SIH). Preclinical studies of SIH are essential for our understanding of the mechanisms underpinning stress-related pain syndromes and for the identification of neural pathways and substrates, and the development of novel therapeutic agents for their clinical management. In this review, we describe clinical and pre-clinical models used to study SIH and discuss the neural substrates, neurotransmitters and neuromodulatory systems involved in this phenomenon.

Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat

The pathogenesis of Parkinsons disease is thought to involve a self-sustaining cycle of neuroinflammation and neurodegeneration. In order to develop novel anti-inflammatory therapies to break this cycle, it is crucial that the temporal relationship between neurodegeneration and neuroinflammation is characterised in pre-clinical models to maximise their predictive validity. Thus, this study aimed to investigate the progression of neuroinflammation relative to nigrostriatal neurodegeneration in the two most commonly-used rat models of Parkinsons disease. Male Sprague-Dawley rats were lesioned by terminal or axonal administration of 6-hydroxydopamine, and were sacrificed for quantitative immunohistochemistry (to assess nigrostriatal integrity (anti-tyrosine hydroxylase), microgliosis (anti-OX42) and astrocytosis (anti-GFAP)) at 6 h 24 h 72 h or 2 weeks post-lesion. Following terminal lesion, dopaminergic deafferentation of the striatum was evident from 6 h post-lesion and was accompanied by microglial and astroglial activation. Dopamine neuron loss from the substantia nigra did not occur until 2 weeks after terminal lesion, and this was preceded by microglial, but not astroglial, activation. Following axonal lesion, retraction of nigrostriatal terminals from the striatum was not observed until the 72 h time-point, and this was associated with a slight astrocytosis, but not microgliosis. Degeneration of dopaminergic neurons from the substantia nigra was also evident from 72 h after axonal lesion, and was accompanied by nigral microgliosis and astrocytosis by 2 weeks. This study highlights the temporal relationship between neurodegeneration and neuroinflammation in models of Parkinsons disease, and should facilitate use of these models in the development of anti-inflammatory therapies for the human condition.

The effect of CB1 receptor antagonism in the right basolateral amygdala on conditioned fear and associated analgesia in rats

The endocannabinoid system mediates analgesia expressed following exposure to conditioned or unconditioned aversive stimuli, and controls the extinction of conditioned aversive behaviour. The present study investigated the effects of administration of the cannabinoid1 (CB1) receptor antagonist SR141716A into the right basolateral amygdala (BLA) on expression of conditioned fear, formalin‐evoked nociceptive behaviour, fear‐conditioned analgesia and associated alterations in monoamine levels in discrete rat brain areas. Re‐exposure to a context previously paired with footshock significantly reduced formalin‐evoked nociceptive behaviour. Intra‐BLA administration of SR141716A did not attenuate fear‐conditioned analgesia, but reduced formalin‐evoked nociceptive behaviour and attenuated the formalin‐induced decrease in freezing and 22‐kHz ultrasonic vocalizations in the early part of the trial. Furthermore, intra‐BLA SR141716A significantly prolonged the duration of these fear‐related behaviours in fear‐conditioned rats not receiving formalin. Fear‐conditioned analgesia was accompanied by increased homovanillic acid (HVA) : dopamine (DA) ratio and reduced serotonin (5‐HT) in the cerebellum, an effect not altered by SR141716A. SR141716A‐induced analgesia was accompanied by reduced DA, increased HVA : DA ratio and reduced 5‐HT levels in the cerebellum, increased hippocampal HVA levels and increased 5‐hydroxyindole‐3‐acetic acid (5‐HIAA) in the amygdaloid cortex. The SR141716A‐induced prolongation of contextually induced aversive behaviour was accompanied by reduced DA and 3,4‐dihyroxyphenylacetic acid (DOPAC), levels in the hippocampus, and increased DA and 5‐HIAA in the periaqueductal grey. These data suggest an important role for CB1 receptors in the right BLA in mediating short‐term extinction of conditioned aversive behaviour but not fear‐conditioned analgesia. The results also enhance our understanding of endocannabinoid–monoamine interactions of relevance to conditioned fear and associated analgesia.

India-Asia collision was at 24°N and 50 Ma: palaeomagnetic proof from southernmost Asia

How and when India collided with Asia is crucial for global climate and continental dynamics. We present new palaeomagnetic data showing that the Xigaze forearc basin of southern Tibet was located at 24.2±5.9°N during 54–57 Ma, providing a direct constraint on the position of the southernmost margin of Asia at this crucial stage. Our study suggests 1) the age and locus of the initial India-Asia collision are at ~50 Ma and ~24°N, respectively; 2) Tibet resisted Indias northward push during the first ~16 Ma of initial impact from the collision and experienced little latitudinal displacement; and 3) Sometime a little after 34 Ma, Greater India was consumed and thicker Indian Craton subsequently made contact with Asia, resulting in ~6° northward drift of Asia. Our model has implications for the process by which the high proto-Tibetan plateau formed and for the two slowdowns of Indias convergence rate with Asia.

Endocannabinoid-mediated modulation of stress responses: Physiological and pathophysiological significance

The stress response is associated with a broad spectrum of physiological and behavioural effects including hypothalamo-pituitary-adrenal (HPA) axis activation, altered central nervous system activity, neuroimmune alterations, anxiety- and depressive-like behaviour and analgesia. While the acute stress response has essential survival value, chronic stress and dysfunction of the stress response can be maladaptive, contributing to the development and severity of psychiatric and pain disorders. The endogenous cannabinoid (endocannabinoid) system has emerged as an important lipid signalling system playing a key role in mediating and/or modulating behavioural, neurochemical, neuroendocrine, neuroimmune and molecular responses to stress. The weight of evidence, reviewed here, points largely to a system which serves to constrain HPA axis activity, facilitate adaptation or habituation of HPA axis and behavioural responses to stress, reduce anxiety- and depressive-like behaviour and mediate analgesic responses to unconditioned or conditioned stress. Possible involvement of the immune system and associated signalling molecules (e.g. cytokines) in endocannabinoid-mediated modulation of neuroendocrine and behavioural responses to stress is considered. The goal now should be to exploit our understanding of the role of the endocannabinoid system in fundamental stress physiology and pathophysiological processes to better understand and treat a range of stress-related disorders including anxiety, depression and pain.

Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB1 receptors

Fear‐conditioned analgesia is an important survival response mediated by substrates controlling nociception and aversion. Cannabinoid1 (CB1) receptors play an important role in nociception and aversion. However, their role in fear‐conditioned analgesia has not been investigated. This study investigated the effects of systemic administration of the CB1 receptor antagonist, SR141716A (1 mg/kg, ip), on fear‐conditioned analgesia and conditioned aversion in rats. Twenty‐four hours after receiving footshock, rats exhibited reduced formalin‐evoked nociceptive behaviour, increased freezing and increased defecation when tested in the footshock apparatus, compared with non‐footshocked formalin‐injected rats. SR141716A attenuated fear‐conditioned analgesia, freezing and defecation. Importantly, SR141716A had no effect on formalin‐evoked nociceptive behaviour over an equivalent time period in rats not receiving footshock. SR141716A had no effect on contextually induced freezing during the first half of the test trial in rats receiving intra‐plantar injection of saline. Administration of SR1417176A did, however, attenuate short‐term extinction of contextually induced freezing and ultrasound emission in rats receiving intra‐plantar saline, compared with vehicle‐treated saline controls. These data suggest an important role for the CB1 receptor in mediating fear‐conditioned analgesia and provide evidence for differential modulation of conditioned aversive behaviour by CB1 receptors during tonic, persistent pain.

Minocycline modulates neuropathic pain behaviour and cortical M1-M2 microglial gene expression in a rat model of depression

There is a paucity of data on the role of microglia and neuroinflammatory processes in the association between chronic pain and depression. The current study examined the effect of the microglial inhibitor minocycline on depressive-like behaviour, spinal nerve ligation (SNL)-induced mechanical and cold allodynia and associated changes in the expression of genes encoding microglial markers (M1 vs. M2 polarisation) and inflammatory mediators in the prefrontal cortex in the olfactory bulbectomised (OB) rat model of depression. Acute minocycline administration did not alter OB-induced depressive-like behaviour but prevented SNL-induced mechanical allodynia in both OB and sham rats. In comparison, chronic minocycline attenuated OB-induced depressive-like behaviour and prevented the development of SNL-induced mechanical allodynia in OB, but not sham, rats. Further analysis revealed that SNL-induced mechanical allodynia in OB rats was attenuated by chronic minocycline at almost all time-points over a 2week testing period, an effect observed only from day 10 post-SNL in sham rats. Chronic administration of minocycline reduced the expression of CD11b, a marker of microglial activation, and the M1 pro-inflammatory cytokine IL-1β, in the prefrontal cortex of sham-SNL animals. In comparison, the expression of the M2 microglia marker (MRC2) and anti-inflammatory cytokine IL-10 was increased, as were IL-1β, IL-6 and SOCS3, in the prefrontal cortex of OB-SNL animals following chronic minocycline. Thus, chronic minocycline attenuates neuropathic pain behaviour and modulates microglial activation and the central expression of inflammatory mediators in a manner dependent on the presence or absence of a depressive-like phenotype.

A dileucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: transfer of longevity to a novel potential therapeutic.

Blockade of neurotransmitter release by botulinum neurotoxin type A (BoNTA) underlies the severe neuroparalytic symptoms of human botulism, which can last a few years. The structural basis for this remarkable persistence remains unclear. Herein, recombinant BoNTA was found to match the neurotoxicity of that from Clostridium botulinum, producing persistent cleavage of synaptosomal-associated protein of 25 kDa (SNAP-25) and neuromuscular paralysis. When two leucines near the C terminus of the protease light chain of A (LCA) were mutated, its inhibition of exocytosis was followed by fast recovery of intact SNAP-25 in cerebellar neurons and neuromuscular transmission in vivo. Deletion of 6–7 N terminus residues diminished BoNTA activity but did not alter the longevity of its SNAP-25 cleavage and neuromuscular paralysis. Furthermore, genetically fusing LCE to a BoNTA enzymically inactive mutant (BoTIMA) yielded a novel LCE-BoTIMA protein that targets neurons, and the BoTIMA moiety also delivers and stabilizes the inhibitory LCE, giving a potent and persistent cleavage of SNAP-25 with associated neuromuscular paralysis. Moreover, its neurotropism was extended to sensory neurons normally insensitive to BoNTE. LCE-BoTIMA(AA) with the above-identified dileucine mutated gave transient neuromuscular paralysis similar to BoNTE, reaffirming that these residues are critical for the persistent action of LCE-BoTIMA as well as BoNTA. LCE-BoTIMA inhibited release of calcitonin gene-related peptide from sensory neurons mediated by transient receptor potential vanilloid type 1 and attenuated capsaicin-evoked nociceptive behavior in rats, following intraplantar injection. Thus, a long acting, versatile composite toxin has been developed with therapeutic potential for pain and conditions caused by overactive cholinergic nerves.