Central neural alterations predominate in an insect model of nociceptive sensitization

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Organisms typically exhibit defensive behaviors, termed nocifensive behaviors, when presented with a noxious stimulus. These behaviors provide a useful metric to quantify changes in the sensitivity of nociception. After tissue damage, the frequency of nocifensive behaviors can increase and the activation threshold can decrease (e.g., Walters et al., 1994). This sensitization is a type of nonassociative learning, akin to clinically relevant conditions such as hyperalgesia and allodynia (Walters et al., 1994; Zigmond et al., 1999).
Many nociception studies focus on invertebrate models, which have been indispensable tools for studying the electrophysiological properties of both nociception and sensitization (Walters et al., 1994; Tobin and Bargmann, 2004; Kandel, 2012), but the majority of invertebrate studies have been on aquatic organisms. Only recently have studies been expanded to terrestrial invertebrates such as Drosophila melanogaster (Tracey et al., 2003; Hwang et al., 2007; Im and Galko, 2012; Im et al., 2015) and the hornworm, Manduca sexta (Waldrop and Levine, 1992; Walters et al., 2001; van Griethuijsen et al., 2013; van Griethuijsen and Trimmer, 2014; McMackin et al., 2016). Studies in D. melanogaster have revealed conservation of nociceptive signaling (Tracey et al., 2003; Hwang et al., 2007; Im and Galko, 2012; Im et al., 2015), and it has been suggested that they may be useful models for studying medical conditions (Neely et al., 2011; Babcock et al., 2011). Paralleling this, Walters et al. (2001) first characterized tissue damage‐induced sensitization of a nocifensive strike response (a rapid bending of the head to the stimulated site) in M. sexta, and found that the number of strikes increased after delivery of a noxious stimulus. McMackin et al. (2016) described a reduction in the strike threshold as well, in response to the same noxious stimulus, and quantified this defensive behavior in vivo using a variety of methods with von Frey monofilaments (e.g., up‐and‐down and simplified up‐and‐down methods) previously established in rodents (Dixon and Mood, 1948; Dixon, 1965; Chaplan et al., 1994; Bonin et al., 2014). Building on this work, our goal was to develop electrophysiological preparations to study sensitization and nociception in M. sexta to complement studies in the leech, Hirudo medicinalis (Ehrlich et al., 1992; Sahley et al., 1994), Aplysia californica (Walters et al., 1983; Clatworthyet al., 1993), and most recently in D. melanogaster (Im and Galko, 2012; Im et al., 2015).
One common theme in the induction of sensitization, first described and later reviewed by Kandel (2012), is the role played by cyclic nucleotides and associated kinases. In addition, a growing body of evidence indicates that direct activation of ion channels by cyclic nucleotides also contributes to nociceptive sensitization (Beaumont and Zucker, 2000; Robinson and Siegelbaum, 2003; Chaplan et al., 2003; Jiang et al., 2008a; Biel et al., 2009; Emery et al., 2011; Young et al., 2014). In particular, hyperpolarization‐activated, cyclic nucleotide‐gated (HCN) channels are nonselective cation channels that interact directly with molecules such as cAMP or cGMP. These nucleotides shift the channels' voltage dependence, opening the channels at resting membrane potentials to generate a depolarizing current known as Ih (syn. IHCN, If “funny,” Iq “queer”). These changes can cause the cell to reach threshold, triggering action potentials (Beaumont and Zucker, 2000; Craven and Zagotta, 2006; Jiang et al., 2008a; Biel et al., 2009). If HCN channels prove to play a significant role in pain sensitization, it opens the door to development of a novel class of analgesics (Chaplan et al., 2003; Biel et al., 2009; Heine et al., 2011; Emery et al., 2011; Young et al., 2014).
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