Pain in Psychiatric Disorders

D. P. Finn, B. E. Leonard

• Publisher: S. Karger
• Year: 2015
• ISBN:
  9783318055740
• Topic: Psicología
• Subtopic: Historia y teoría en psicología

This book offers a series of authoritative reviews on pain in psychiatric disorders written by leading experts. They discuss the complex interplay between pain and psychiatric disorders such as anxiety, depression and borderline personality disorder, as well as neurosteroids, epigenetic mechanisms and TRPV1, with a strong focus on neurobiological mechanisms and current and future therapeutic targets. Special attention is given to the importance of inflammation and the immune system as a common substrate in both pain and psychiatric disorders. The state-of-the-art reviews present both preclinical and clinical research, providing the reader with sound knowledge that provides a basis for further research and clinical practice. Pain in Psychiatric Disorders is of special interest to psychiatrists, neurologists, neuroscientists, pharmacologists and other healthcare professionals treating pain in psychiatric patients, as well as research students with an interest in this field.

Finn DP, Leonard BE (eds): Pain in Psychiatric Disorders. Mod Trends Pharmacopsychiatry.
Basel, Karger, 2015, vol 30, pp 80-93 (DOI: 10.1159/000435934)

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Supraspinal Transient Receptor Potential Subfamily V Member 1 (TRPV1) in Pain and Psychiatric Disorders

Manish K. Madasu^{a, c} · Michelle Roche^{b, c} · David P. Finn^{a, c}

^aPharmacology and Therapeutics, and ^bPhysiology, School of Medicine, and ^cGalway Neuroscience Centre and Centre for Pain Research, NCBES, National University of Ireland, Galway, Ireland

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Abstract

The transient receptor potential subfamily V member 1 (TRPV1) belongs to the diverse transient receptor potential (TRP) family of cation channels. It was first characterized in primary afferent fibres as a receptor for capsaicin. Peripheral TRPV1 has a very well-described role in nociception. However, TRPV1 is now recognized to have a broader distribution and function, with supraspinal/brain TRPV1 known to modulate pain processing. Recently, studies employing histological, genetic and pharmacological approaches have provided evidence that supraspinal TRPV1 also modulates brain neurobiology and behaviours related to anxiety, depression and schizophrenia. Key brain regions involved in TRPV1-mediated modulation of pain and affect include the periaqueductal grey, hippocampus and medial prefrontal cortex. Thus, TRPV1 in the brain is emerging as an important molecular substrate which is dually implicated in both pain and psychiatric disorders, and represents a novel therapeutic target for these conditions and their comorbidity.

© 2015 S. Karger AG, Basel

Introduction to Transient Receptor Potential Subfamily V Member 1

Although first identified as the receptor for capsaicin, transient receptor potential subfamily V member 1 (TRPV1) can also be activated endogenously by voltage, noxious heat (>42°C), low pH and lipoxygenase products. Capsaicin is the naturally occurring pungent constituent of capsicum peppers used in many hot/spicy foods. TRPV1 expressed on primary afferent neurones that detect and encode noxious stimuli can be activated by capsaicin, resulting in neuronal excitation and release of local inflammatory mediators [1]. Endocannabinoids/endovanilloids, including anandamide and N-arachidonoyl dopamine, are endogenous ligands that can also activate TRPV1. TRPV1 nonselectively gates cations; however, channel activation results in a 10-fold higher preference for calcium [2-4].

TRPV1 is comprised of six transmembrane domains and intracellular N- and C-termini. The N-terminal tail contains numerous phosphorylation sites and ankyrin repeats that serve as binding sites for calmodulin and adenosine triphosphate [5]. The C-terminal tail contains a TRP domain as well as binding sites for both calmodulin and phosphatidylinositol (4,5)-bisphosphate, an endogenous TRPV1 inhibitor [6]. Agonist binding and receptor activation can occur intracellularly, as lipophilic capsaicin readily crosses the membrane to bind several sites on TRPV1 [7]. TRPV1 is expressed highly in the dorsal root ganglia of C and Aδ fibres. In these fibres, TRPV1 activation leads to increases in intracellular calcium levels which in turn induces the release of neuropeptides (calcitonin gene-related peptide and substance P) in the dorsal horn of the spinal cord [8].

Studies in rat and primate brains have shown that TRPV1 is widely expressed throughout the neuroaxis, including the cortex, hippocampus, basal ganglia, cerebellum and olfactory bulb, as well as in the mesencephalon and hindbrain [9, 10]. Studies of the distribution of TRPV1 in human brain have been more restricted, but a postmortem study has shown that TRPV1 receptors have been found in the third and fifth layers of the human parietal cortex [9]. However, overall TRPV1 expression in the central nervous system (CNS) is considerably lower than in the dorsal root ganglia [10-13]. Indeed, some studies have failed to detect the presence of TRPV1 in the CNS [1, 14-16] possibly due to complexity in genes and strain-related variations [11, 17]. A sophisticated gene strategy where the TRPV1 gene was targeted by attaching two reporters, PLAP (placental alkaline phosphatase) and nlacZ (nuclear lacZ), onto the TRPV1 promoter gene and creating a specific line of mice (TRPV1^PLAP-nlacZ) was used to confirm TRPV1 expression in the CNS. This study reported that TRPV1 expression in the CNS is limited to certain brain regions and low when compared to expression in dorsal root ganglia [12]. This restricted expression of TRPV1 in the CNS was confirmed by in situ hybridization experiments in rat, monkey and human brains [12]. However, a number of recent pharmacological, genetic, radioligand-binding and immunohistochemical studies suggest widespread distribution and functionality of TRPV1 across the CNS [11, 12, 18-20].

Role of Transient Receptor Potential Subfamily V Member 1 in the Brain

Pain

Acute Pain

The periaqueductal grey-rostral ventromedial medulla (PAG-RVM) pathway is very important in pain processing and modulation. PAG-mediated antinociception involves the recruitment of pain-modulating RVM neurons via the descending pain pathway [21]. The existence of TRPV1 in the midbrain has been demonstrated by immunohistochemistry [9, 22, 23], in situ hybridization [9], binding of the TRPV1-selective radioligand [3H]-resiniferatoxin (RTX) [24] and gene reporter studies [12]. The RVM contains three different types of pain-responsive neurons: ‘neutral cells’, which show no modification in spontaneous activity associated with nociceptive stimulation; ON cells, which show a burst of activity before withdrawal reflexes, and OFF cells, which are inhibited just before withdrawal reflexes [25-27]. Capsaicin, when injected into the dorsolateral periaqueductal grey (dlPAG), increased the latency of nociceptive responding to noxious heat, indicating that stimulation of TRPV1 within the descending inhibitory pain pathway can cause antinociception [28]. Microinjection of capsaicin into the ventrolateral periaqueductal grey (vlPAG) increased the threshold of thermal pain sensitivity in rats [29]. Opposite effects were found with 5-iodoresiniferatoxin (I-RTX), a selective TRPV1 antagonist that facilitated nociceptive responses and, at an inactive dose, abolished capsaicin-mediated antinociception, implying that the effect of capsaicin is mediated by TRPV1 in the vlPAG [29]. The antinociceptive effect of intra-vlPAG capsaicin was accompanied by an increase in glutamate release in the RVM as measured by in vivo microdialysis, which was also blocked by an inactive dose of I-RTX. The TRPV1 antagonist itself reduced the release of glutamate, thus suggesting that vlPAG TRPV1 tonically stimulates glutamatergic output to the RVM with a concomitant inhibition of nociception [29]. Hyperalgesia or analgesia have been observed following intra-vlPAG administration of the fatty acid amide hydrolase (FAAH) inhibitor URB597 depending on whether vlPAG cannabinoid receptors or TRPV1 have been activated [30]. It was proposed that anandamide-mediated activation of TRPV1 leads to analgesia, while hyperalgesia may be due to increases in vlPAG 2-arachidonoylglycerol leading to CB₁ receptor stimulation, which in turn leads to inhibition of the antinociceptive PAG-RVM descending pathway [30].

The ON and OFF neurons in the RVM have been shown to respond to capsaicin administered into the PAG [29-31]. Intra-dlPAG microinjection of capsaicin is followed by a decrease in the tail flick-related ON cell burst activity and an increase in tail flick latency [31]. Later on, due to desensitization of the receptor (due to prolonged exposure to capsaicin), antinociception correlating with increased OFF cell activity was reported [31]. Similarly, Starowicz et al. [29] have shown that intra-vlPAG administration of capsaicin caused a decrease in the firing activity of RVM ON cells, and an increase in the firing of the OFF cells. Moreover, microinjections of capsaicin into the vlPAG have also been shown to increase withdrawal latency in the rat hot-plate test, with evidence that activation of TRPV1 in the vlPAG induces antinociception via mGlu receptor-mediated 2-arachidonoylglycerol retrograde signalling in the RVM [32]. Intra-vlPAG administration of the FAAH inhibitor URB597, which is known to enhance endogenous anandamide levels, stimulated OFF cell activity in the RVM and inhibited ON cell activity [30]. This effect on RVM activity was abolished by intra-vlPAG administration of the TRPV1 antagonist capsazepine, suggesting that FAAH substrates (likely anandamide) activate TRPV1 on vlPAG neurons, with projections from the PAG to the RVM mediating the subsequent stimulation of RVM OFF cells and inhibition of ON cells. De Novellis et al. [33] administered N-arachidonoyl-serotonin (AA-5-HT), a compound with a dual ability to inhibit FAAH and block TRPV1, into the vlPAG, and measured endocannabinoid levels, RVM ON and OFF cell activities, thermal nociception in the tail flick test and formalin-induced nociceptive behaviour. They found that AA-5-HT increased anandamide levels in the vlPAG and had antinociceptive effects in both the tail flick and formalin tests. Moreover, intra-vlPAG administration of AA-5-HT depressed the activity of both OFF cell and ON cells in the RVM. These effects of AA-5-HT were similar to those seen following coadministration of the FAAH inhibitor URB597 and the selective TRPV1 antagonist I-RTX into the vlPAG [33]. The FAAH substrate, palmitoylethan...