Developmental learning in a pain-related system: evidence for a cross-modality mechanism

Abstract

The nociceptive spinal reflex system performs highly precise sensorimotor transformations that require functionally specified synaptic strengths. The specification is gradually attained during early development and appears to be learning dependent. Here we determine the time course of this specification for heat-nociceptive tail withdrawal reflexes and analyze which types of primary afferents are important for the learning by applying various forms of noninvasive sensory deprivations. The percentage of erroneous heat-nociceptive tail withdrawal reflexes (i.e., movements directed toward the stimulation) decreased gradually from 64.1 +/- 2.5% (mean +/- SEM) to <10% during postnatal days 10-21. This improvement was completely blocked by anesthetizing the tail during the adaptation period, confirming that an experience-dependent mechanism is involved in the specification of synaptic strengths. However, the results show that the adaptation occurs to a significant extent despite local analgesia and protection of the tail from noxious input, provided that tactile sensitivity is preserved. Therefore, it appears that a nociceptive input is not necessary for the adaptation, and that input from tactile receptors can be used to guide the nociceptive synaptic organization during development. Sensory deprivation in the adult rat failed to affect the heat-nociceptive withdrawal reflex system, indicating that the adaptation has a "critical period" during early development. These findings provide a key to the puzzle of how pain-related systems can be functionally adapted through experience despite the rare occurrence of noxious input during early life.

Figure 1.

Method of sensory deprivation of the tail. A, Sensory deprivation of the tail was achieved by attaching a tube to a plastic ring glued to the ventral side of the proximal tail. The tube was either empty or filled with salve. B, A modified tube with two compartments separated by a membrane was used to study possible systemic effects of EMLA. Note that the plastic ring was glued more proximal on the tail than in A. The proximal compartment was filled with EMLA.

Figure 2.

Time course of nociceptive withdrawal reflex (NWR) postnatal adaptation. Graph shows percentage of error rate of heat-nociceptive withdrawal reflex in three litters. The distal tail was stimulated daily, twice bilaterally during P1-P28 in two litters (•n = 12; ^*n = 8), and six times on each side in a third litter (○n = 13). Mean ± SEM are shown. The inset shows a schematic of the experimental set-up. Tail movements in the horizontal plane, elicited by CO₂ laser, were classified as erroneous (directed toward stimulation) or correct (directed away from stimulation).

Figure 3.

Effects of different forms of sensory deprivations applied during P14-P21 on the heat-nociceptive withdrawal reflex adaptation. Comparisons were made between all groups at P21. All significant differences are indicated. The gray bars signify treatment with deprived or absent nociceptive input but preserved tactile sensitivity. The black bar signifies treatment that produced anesthesia. Solid lines indicate comparisons with the group treated with tube-EMLA and depilation; ^*p < 0.05; ^**p < 0.01; ^***p < 0.001. Dotted lines indicate comparisons with the control group; ⁺p < 0.05; ⁺⁺⁺p < 0.001. The χ² test was used for statistics. Corrections for multiple comparisons were made using the Bonferroni method. NWR, Nociceptive withdrawal reflex.

Figure 4.

Time course of nociceptive withdrawal reflex (NWR) adaptation after complete sensory block. Tails were depilated and EMLA-treated in A (P14-P21) and B (P17-P24). Arrows indicate start and end of treatment (↑ and ↓, respectively). The error rate of heat-nociceptive withdrawal reflex before and up to 5 d after treatment is shown. ^*p < 0.05; ^**p < 0.01; ns, not significant. The χ² test was used for statistics.

Figure 5.

A proposed self-organizing circuitry that uses tactile information related to withdrawal efficacy to adjust the strength of nociceptive connections. One learning cycle (indicated by circular arrow) consists of the following chain of events: (1) spontaneous bursts in REs (i.e., neurons that encode the reflex magnitude); (2) motoneuron (MN) activation leading to a muscle twitch that causes skin movement (indicated by a thin long upward arrow); (3) increased or decreased skin pressure (indicated by upward and downward thick arrows, respectively) resulting in altered sensory input to prereflex encoder interneurons. Thick and thin lines represent afferents from skin areas on the tail from where an increase (+) and decrease (-), respectively, in low-threshold mechanoreceptor input would occur. Dashed lines symbolize the rare occurrence of nociceptive input; and (4) the strength of erroneous connections (receiving increased mechanoreceptive input) between pre-RE interneurons and RE is weakened (W) and that of appropriate ones (receiving reduced mechanoreceptive input) is strengthened (S). Dotted lines indicate that the number of pre-RE interneurons is not known. Evidence that synaptic strength can be reduced if action potentials in postsynaptic neurons precede activity in the presynaptic neuron has been presented for other systems (Debanne et al., 1994; Markram et al., 1997; Zhang and Poo, 2001). Note that although the nociceptive input is not required for the learning to take place in this model, nociceptive input, if present, would indeed cause learning effects.