Molluscs and arthropods have systems that suppress nociceptive responses, but whether opioid systems play antinociceptive roles in these phyla is uncertain. Immediate responses to noxious stimulation and nociceptive sensitization have also been examined behaviorally and physiologically in a snail (Helix), octopus (Adopus), crayfish (Astacus), hermit crab (Pagurus), and shore crab (Hemigrapsus). Temporary blockade of nociceptor activity during injury subsequently increased mortality when injured squid were exposed to fish predators, providing the first demonstration in any animal of the adaptiveness of nociceptive sensitization. Squid (Doryteuthis) show injury-induced sensitization manifested as behavioral hypersensitivity to tactile and especially visual stimuli, and as hypersensitivity and spontaneous activity in nociceptor terminals. In contrast to results from Aplysia and Drosophila, nociceptive sensitization examined in moth larvae (Manduca) disclosed central hyperactivity but no obvious peripheral sensitization of nociceptive responses. Interestingly, molecular contributors examined thus far in Aplysia and Drosophila are largely different, but both sets overlap extensively with those in mammalian pain-related pathways. Studies of nociceptive sensitization in Drosophila larvae have revealed numerous molecular contributors in primary nociceptors and interacting cells. Neuromodulator-induced, activity-dependent, and axotomy-induced plasticity mechanisms have been defined in synapses, cell bodies, and axons of Aplysia primary nociceptors. In Aplysia, nociceptive sensitization has been investigated as a model for aversive memory and for hyperalgesia. Primary nociceptors have been investigated extensively in a few molluscan and arthropod species, with studies of long-lasting nociceptive sensitization in the gastropod, Aplysia, and the insect, Drosophila, being especially fruitful. Comparisons across these taxa provide clues about the contributions of convergent evolution and of conservation of ancient adaptive mechanisms to general nociceptive and pain-related functions. Five Nights at Freddys 2: Playable Animatronics starts with Freddy Fazbear in a dark background. Since then, animals in these phyla have continued to be subject to traumatic injury, often from predators, which has led to similar adaptive behaviors (e.g., withdrawal, escape, recuperative behavior) and physiological responses to injury in each group. These phyla, and the chordates that include humans, last shared a common ancestor approximately 550 million years ago. Important insights into the selection pressures and core molecular modules contributing to the evolution of pain-related processes have come from studies of nociceptive systems in several molluscan and arthropod species.
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