Effects of central nervous system free fatty acids, prostaglandins and lysophospholipids on allodynia in a mouse model of orofacial pain

INTRODUCTION Phospholipases A2 (PLA2, EC 3.1.1.4) are a diverse group of enzymes that catalyze hydrolysis of acyl ester bonds at the sn-2 position of the glycerol moiety of membrane phospholipids, to produce free fatty acids and lysophospholipids These enzymes are subdivided into several groups depending upon their structure, enzymatic properties, subcellular localization and cellular function Cytosolic PLA2 (cPLA2) catalyzes the hydrolysis of arachidonic acid (AA) from neural membrane phospholipids Secretory PLA2 (sPLA2) catalyzes the hydrolysis of neural membrane phospholipids with no strict fatty acid selectivity Brain cytosolic fraction also contains an 80 kDa calcium-independent phospholipase A2 (iPLA2) activity which preferentially hydrolyzes linoleoyl acyl chain than palmitoyl and arachidonyl acyl chains from membrane phospholipids (Yang et al., 1999) AA is a major unsaturated fatty acid in neural membranes It is released from membrane phospholipids by a number of enzymatic mechanisms involving the receptor-mediated stimulation of PLA2 and phospholipase C / diacylglycerol lipase pathways (Farooqui et al., 1989) AA can be reincorporated into neural membranes or metabolized to prostaglandins or thromboxanes (Farooqui et al., 2000; Farooqui and Horrocks, 2006) The metabolites of AA play important roles in sensitization of dorsal horn circuitry in pain states (Samad et al., 2001; Svensson and Yaksh, 2002) Lysophospholipids are important signaling molecules (Sasaki et al., 1993; Farooqui and Horrocks, 2006), and some have their own receptors (Bazan and Doucet, 1993; Moolenaar, 1994; Steiner et al., 2002) They can be hydrolyzed to fatty acids and glycerophosphocholine or glycerophosphoethanolamine by lysophospholipases (Farooqui et al., 1985) or reacylated to the native phospholipids by CoA-dependent or CoA-independent acyltransferases (Farooqui et al., 2000) These reactions not only prevent an increase in lysophospholipid levels in brain tissue but also help maintain normal phospholipid composition (Ross and Kish, 1994; Farooqui et al., 2000) High concentrations of lysophospholipids may act as detergents to disrupt membrane structures (Weltzien, 1979) and contribute to neural cell injury (Farooqui et al., 2000; Farooqui and Horrocks, 2006) A major lysophospholipid in mammalian brain, lysophosphatidylcholine (LPC) is metabolized to 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (commonly known as platelet-activating factor, PAF) The latter is not only involved in inflammatory responses and pathophysiology of many neurodegenerative diseases (Farooqui and Horrocks, 2004) but also plays an important role in pain sensitivity (Bonnet et al., 1981) Subplantar injections of PAF into the rat hindpaw increase pain sensitivity (Dallob et al., 1987), whilst systemic administration of PAF antagonists decreases inflammatory nociceptive responses in rats (Teather et al., 2002) Allodynia is defined as innocuous somatosensory stimulation that evokes abnormally intense, prolonged pain sensations (Kugelberg and Lindblom, 1959; Lindblom and Verillo, 1979), or pain due to a stimulus that is not normally painful (Walters, 1994) Recent studies have shown that inhibitors to cPLA2, sPLA2 and iPLA2 exerted pronounced anti-nociceptive effects in mice that received facial carrageenan injections (Yeo et al., 2004) The latter is used as a model of orofacial pain (Ng and Ong, 2001; Vahidy et al., 2006 under revision) The PLA2 inhibitors could act by modulating free fatty acids, and their metabolites: prostaglandins, or lysosphospholipid levels, therefore the present study was carried out to determine which of these compounds might have a pro- or perhaps anti-allodynic effect after facial carrageenan injections LITERATURE REVIEW Pain Pain is an unpleasant sensory and emotional experience which is primarily associated with tissue damage or describe in terms of tissue damage, or both (International Association for the Study of Pain 2004) Recent advances in the field of pain research have revealed that pain is not a single sensory experience; different forms of pain are mediated by different neurological mechanisms Moreover it has been argued that the neurophysiological mechanisms for all the various pain states are not the same and that normal (nociceptive) and abnormal (neuropathic) pain represent the endpoints of a sequence of possible changes that can occur in the nervous system Normally, a steady state is maintained in which there is a close correlation between injury and pain But changes induced by nociceptive input or by changes in the environment can result in variations in the quality and quantity of the pain sensation produced by a particular noxious stimulus These changes are temporary as the system would always tend to restore the normal balance However, long lasting or very intense nociceptive input would distort the nociceptive system to such an extent that the close correlations between injury and pain would be lost There are three major stages or phases of pain, each with a different neurophysiological mechanism These are (1) the processing of a brief noxious stimulus; (2) the consequences of prolonged noxious stimulation, leading to tissue damage and peripheral inflammation; and (3) the consequences of neurological damage, including neuropathies and central pain states Phases of Pain There are three phases of pain known: (a) Phase (Acute Nociceptive Pain) The mechanism involved can be viewed as a simple and direct route of transmission centrally toward the thalamus and cortex and thus the conscious perception of pain, however there is possibility of modulation occurring at synaptic relays along the way It has been suggested that Phase pain can best be explained by models based on the specificity interpretation of pain mechanisms, that is, the existence within the peripheral and central nervous systems (CNS) of a series of neuronal elements concerned solely with the processing of these simple noxious elements (b) Phase (Inflammatory Pain) If a noxious stimulus is intense or prolonged, leading to tissue damage and inflammation, there is increased afferent inflow to the CNS from the injured area due to the increased activity and responsiveness of sensitized nociceptors In this phase, the subject experiences spontaneous pain, a change in the sensations evoked by stimulation of the injured area, and also of the undamaged areas surrounding the injury This change in evoked sensation is known as hyperalgesia, defined as an increased response to a stimulus which is normally painful (IASP 2004) or a leftward shift of the stimulusresponse function that relates magnitude of pain to stimulus intensity or an increased response to a stimulus that is normally painful Many cases of hyperalgesia have features of allodynia The term allodynia pertains when there is not an increased response to a stimulus that normally provokes pain However, when there is also a response of increased pain to a stimulus that normally is painful, hyperalgesia is the appropriate word With allodynia the stimulus and the response are in different modes, whereas with hyperalgesia they are in the same mode (IASP 2004) Hyperalgesia in the area of injury is known as primary hyperalgesia, and in the area of normal tissue surrounding the injury site, as secondary hyperalgesia (c) Phase (Neuropathic Pain) These are abnormal pain states and are defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system In clinical terms, Phase and pains are symptoms of peripheral injury, whereas Phase pain is a symptom of neurological diseases that include lesions of peripheral nerves or damage to any portion of the somatosensory system within the CNS These pains are spontaneous, triggered by innocuous stimuli, or are exaggerated responses to noxious minor stimuli Role of Peripheral Mechanism of Hyperalgesia An injury to the skin or to an internal organ evokes the initial discharge in the nociceptive afferents that innervate the damaged area and, as a consequence of the ensuing inflammatory process, sensitizes these nociceptive endings (Treede et al., 1992) During the initial injury and for the duration of the repair process there will be increased nociceptive activity from the injured region It is well known that sensitized nociceptors respond to peripheral stimuli with a lower threshold and an increased excitability, hence the possibility that the afferent discharges during the inflammatory process will be greater in magnitude and duration than the initial injury-related storm These afferent storms cause, in turn, central changes in excitability mediated by positive feedback loops between spinal and supra spinal neurons and by the enhanced synaptic actions of certain neurotransmitters, possibly involving N-methyl-D-aspartate (NMDA) receptor mechanism (Woolf and Thompson, 1991; Dubner and Ruda, 1992; Cervero, 1995) The central changes are maintained by the incoming discharges in sensitized nociceptors so that, in the absence of such discharges, the central alterations decline and the system returns to normal sensory processing There is an increase in the afferent inflow to the CNS from damaged or inflamed areas due to the increased activity and responsiveness of sensitized nociceptors Moreover, the nociceptive neurons in the spinal cord modify their responsiveness and increase their excitability (Woolf and King, 1989; Cervero et al., 1992; Dubner and Ruda, 1992; Woolf et al., 1994) All of these changes indicate that due to the noxious input generated by the tissue injury and inflammation, the CNS has moved to an excitable state Primary Hyperalgesia and Sensitization Within the area of primary hyperalgesia, low intensity mechanical or thermal stimuli evoke pain It is known that an injury induces a process of nociceptor sensitization with an increase in the excitability of the nociceptors but lowered thresholds (Burgess and Perl, 1967; Bessou and Perl, 1969; Meyer and Campbell, 1981) Sensitization is defined as a leftward shift of the stimulus-response function that relates magnitude of the neural response to stimulus intensity The sensitization of the peripheral nociceptors is characterized by two main changes in their response properties: appearance of spontaneous activity that provides a continuous afferent barrage that is believed to contribute to spontaneous pain and decrease in threshold to an extent that non-noxious stimuli will activate the sensitized receptor The drop in threshold is generally agreed to underlie primary hyperalgesia (Treede et al., 1992) Mechanical Hyperalgesia Hyperalgesia to mechanical stimuli are of two different types One form is evident when the skin is gently stroked with a cotton swab and may be called stroking hyperalgesia, dynamic hyperalgesia, or allodynia The second form is evident when punctuate stimuli, such as von Frey probes, are applied and thus has been turned punctuate hyperalgesia Secondary Hyperalgesia Primary hyperalgesia is characterized by the presence of enhanced pain to heat and mechanical stimuli, whereas secondary hyperalgesia is characterized by enhanced pain to only mechanical stimuli The changes responsible for secondary hyperalgesia have two different components: (1) a change in the modality of the sensation evoked by low-threshold mechanoreceptors, from touch to pain, and (2) an increase in the magnitude of 10 Dallel R, Duale C, Molat JL Morphine administered in the substantia gelatinosa of the spinal trigeminal nucleus caudalis inhibits nociceptive activities in the spinal trigeminal nucleus oralis J Neurosci 1998; 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