Site-specific sensitization of defensive reflexes in Aplysia: a simple model of long-term hyperalgesia

Abstract

Brief, noxious, electrical or mechanical stimulation of the skin of Aplysia produces enhancement of defensive reflexes triggered at the same site for at least a week after the noxious stimulation. This site- specific behavioral sensitization can be expressed as an increase in duration of the siphon-withdrawal reflex and as an increase in magnitude of the tail-withdrawal reflex. It is unlikely that peripheral factors play a predominant role in the long-term memory. First, long- term enhancement is blocked when the CNS is disconnected from the noxious stimulation site by nerve transection. Second, long-term enhancement is blocked by preventing neural activation at the noxious stimulation site, indicating that persistent physical damage alone is insufficient to cause the enhancement. A role for activity-dependent extrinsic modulation (ADEM) of mechanosensory neurons is suggested by similar site-specific enhancement produced when weak sensory activation is paired with general modulation elicited by strong stimulation of a distant site. Because this pairing represents a form of classical conditioning, site-specific sensitization and cutaneous classical conditioning appear to be closely related in this system. These findings suggest that site-specific sensitization reflects, at least in part, a central, long-term memory of injury. This form of memory may be phylogenetically widespread, and functionally similar to aspects of hyperalgesia. In addition, the close relationship between site-specific sensitization and cutaneous classical conditioning supports the hypothesis that some forms of classical conditioning evolved from mechanisms of sensitization.

Peripheral injury induces long-term sensitization of defensive responses to visual and tactile stimuli in the squid Loligo pealeii, Lesueur 1821

“…In blindfolded squid, tactile sensitization close to the wound site was present earlier and expressed more strongly than regional or general sensitization, indicating site-specific sensitization similar to that described in the gastropod mollusc Aplysia californica (Walters, 1987). This pattern was not present in non-blinded or sham-blinded all comparisons for that experimental group have the same d.f.…”

“…Injury-induced sensitization in squid groups, suggesting that visually mediated general sensitization is as strong as site-specific tactile sensitization is in the injured area, although the possibility remains that more pronounced sensitization occurred closer to the injury site (arm test stimuli were not applied closer than 1 cm from the injury site). This long-lasting general sensitization following injury differs from nociceptive tactile sensitization that has been reported in mammals, which is expressed most dramatically as primary hyperalgesia and allodynia close to a wound (Treede et al, 1992) and from site-specific tactile sensitization of defensive responses in opisthobranch molluscs, which is far more prominent after an injury or single session of noxious electric shock than is general tactile sensitization (Walters, 1987). Robust general sensitization in the squid bears some similarity to the general nociceptive sensitization after injury described in moth (Walters et al, 2001) and possibly fruitfly (Babcock et al, 2009) larvae.…”

“…Primarily, we aimed to approximate a relatively natural and minor injurious experience. In addition, in another mollusc, local or general anesthesia at the time of tissue injury can block development of behavioral sensitization by preventing neural activity at the injury site (Walters, 1987). Finally, the standard anesthesia for cephalopods is immersion in MgCl 2 solution (Messenger et al, 1985;Mooney et al, 2010), which causes muscle relaxation.…”

“…Studies of nociceptive sensitization in mammals have been carried out by investigators of pain mechanisms, who have focused almost exclusively on tactile sensitization (Mogil, 2009). Long-lasting sensitization in invertebrates after injury has only been described in animals possessing very limited visual capabilities -the sea hare Aplysia (Walters, 1987), leeches (Sahley, 1995), moth larvae (Walters et al, 2001) and fly larvae (Babcock et al, 2009) -and thus these studies were also restricted to tactile sensitization.…”

Nonassociative and associative modification of head-waving produced by aversive tentacular stimuli in Aplysia.

“…There are, however, several instances in which the location of an aversive US has been shown to be important for learning. First, certain training procedures (such as strong unilateral shock to the animal's body) can produce sensitization of the siphon and tail-withdrawal reflexes that is side-specific, or even site-specific (Scholz and Byrne 1987;Waiters 1987). Second, the topography of siphon withdrawal responses can be directionally modified, depending on the location of the aversive US used in a nonassociative sensitization paradigm (Erickson and Waiters 1988).…”