Simultaneous recordings of 135 pairs of units, located respectively in the superficial (I-IIo) and deep (V) laminae of the dorsal horn of the lumbar spinal cord of anaesthetized and paralysed animals, were performed both from normal (62 pairs) and from peripherally injured (chronically constricted sciatic nerve) rats (73 pairs). In each pair, one neuron was classified as nociceptive, responding only to noxious stimuli, and the other as a wide dynamic range neuron, responding to both non-noxious and noxious stimuli. To understand if some interaction was present between diverse neurons modulated by noxious inputs, we used cross-correlation techniques. The responses of simultaneously recorded pairs of units to suprathreshold (5 mA, 0.5 ms) electrical stimuli were used. A clearly delayed peak in the cross-correlograms of recordings from normal animals was present, indicating connectivity of superficial and deep-layer cells. This feature was not present in the cross-correlograms obtained from nerve-injured animals. Even if a specific pathway cannot be explicitly assigned to support these functional results, an overall connection between superficial and deep layers of the spinal cord is suggested. These connections are supposed to be either inactive or rearranged in the nerve-injured rats, thus suppressing a well timed coordinated connectivity. This anomaly could underlie a reduced degree of functional coherence in the modulation of nociceptive spinal inputs in cases of chronic pain.
"NK1-expressing neurons in deep dorsal horn are of particular interest in their own right because Fos expression (Doyle and Hunt 1999) and NK1 receptor internalization (Abbadie et al. 1997) studies indicate their contribution to spinal nociceptive processing after inflammation . Thus whereas NK1-expressing neurons in the superficial dorsal horn may be essential for enhanced nociceptive processing after injury, it is important to recognize that neurons in the superficial and deep dorsal horn are likely functionally connected (Biella et al. 1997) and therefore are both important contributors to nociceptive processing. To this end, it is worth noting that ablation of NK1-expressing neurons in lamina I prevented central sensitization of neurons located in both the superficial and the deep dorsal horn (Khasabov et al. 2002). "
[Show abstract][Hide abstract] ABSTRACT: We previously reported that mice with a deletion of the preprotachykinin-A (pptA) gene, from which substance P (SP) and neurokinin A (NKA) are derived, exhibit reduced behavioral responses to intense stimuli, but that behavioral hypersensitivity after injury is unaltered. To understand the contribution of SP and NKA to nociceptive transmission in the spinal cord, we recorded single-unit activity from wide dynamic range neurons in the lamina V region of the lumbar dorsal horn of urethane-anesthetized wild-type and ppt-A null mutant (-/-) mice. We found that intensity coding to thermal stimuli was largely preserved in the ppt-A -/- mice. Neither the peak stimulus-evoked firing nor the neuronal activity during the initial phase (0-4 s) of the 41-49 degrees C thermal stimuli differed between the genotypes. However, electrophysiological responses during the late phase of the stimulus (5-10 s) and poststimulus (11-25 s) were significantly reduced in ppt-A -/- mice. To activate C-fibers and to sensitize the dorsal horn neurons we applied mustard oil (MO) topically to the hindpaw. We found that neither total MO-evoked activity nor sensitization to subsequent stimuli differed between the wild-type and ppt-A -/- mice. However, the time course of the sensitization and the magnitude of the poststimulus discharges were reduced in ppt-A -/- mice. We conclude that SP and/or NKA are not required for intensity coding or sensitization of nociresponsive neurons in the spinal cord, but that these peptides prolong thermal stimulus-evoked responses. Thus whereas behavioral hypersensitivity after injury is preserved in ppt-A -/- mice, our results suggest that the magnitude and duration of these behavioral responses would be reduced in the absence of SP and/or NKA.
Journal of Neurophysiology 06/2004; 91(5):1945-54. DOI:10.1152/jn.00945.2003 · 2.89 Impact Factor
"Spinal dorsal horn neurons exhibited increased spontaneous firing following loose constriction of the sciatic nerve (Palecek et al., 1992b; Sotgiu et al., 1992, 1994; Laird and Bennett, 1993; Sotgiu, 1993; Sotgiu and Biella, 1997), partial sciatic nerve ligation (Behbehani and Dollberg-Stolik, 1994; Pertovaara et al., 1997) and tight ligation of the L5–L6 spinal nerves in rats (Leem et al., 1995) or of the L7 spinal nerve in monkeys (Palecek et al., 1992a). They also showed expanded mechanical receptive field area (Behbehani and Dollberg- Stolik, 1994; Takaishi et al., 1996), increased percentage without a mechanical receptive field (Laird and Bennett, 1993; Takaishi et al., 1996), increased response to mechanical stimuli (Palecek et al., 1992a,b; Laird and Bennett, 1993; Leem et al., 1995; Pertovaara et al., 1997), increased incidence of responsiveness to extra-territorial nerve stimulation (Sotgiu and Biella, 1995), increased after-discharge (Palecek et al., 1992b; Laird and Bennett, 1993; Sotgiu and Biella, 1997), abnormal response to cooling (Palecek et al., 1992a) and reduced inhibition by electrical stimulation of the midbrain periaqueductal gray (Pertovaara et al., 1997). WDR neurons in nerve-injured animals did not show increased responsiveness to noxious thermal stimuli (Palecek et al., 1992b; Laird and Bennett, 1993; Takaishi et al., 1996; Pertovaara et al., 1997), with the exception of one study reporting enhanced responses to noxious heat by spinothalamic neurons in primates with L7 spinal nerve tight ligation (Palecek et al., 1992a). "
[Show abstract][Hide abstract] ABSTRACT: We investigated behavioral symptoms of neuropathic pain, and associated changes in dorsal horn neurons, in a rat model involving loose ligation of lumbar dorsal roots. The L4-L6 dorsal roots were exposed unilaterally and loosely constricted central to the respective ganglia with one (1-ligation) or two (2-ligation) silk 7-O ligatures. In control groups the dorsal roots were exposed but not ligated (sham-operated), or sutures were placed lengthwise between the dorsal roots (suture control). There was a significant reduction in mechanical withdrawal threshold on the operated side in both 1- and 2-ligation groups which began at 3 days, peaked at 2-5 week, and gradually recovered. A delayed threshold reduction was also seen on the non-operated side. Immediately post-surgery there was a significant increase (hypoalgesia) in thermal paw withdrawal latency (Hargreaves test) in 1- and 2-ligation groups on the operated (but not non-operated) side that recovered after 1 week. Significantly less weight was borne by the operated limb 1-5 weeks post-operatively in 1- and 2-ligation groups. The force of hind limb withdrawals elicited by graded noxious heat pulses (38-52 degrees C) was significantly lower 1 week post-surgery on the operated side (1-ligation group) followed by recovery. Withdrawal forces were higher 5-9 week post-surgery on the non-operated side in 1- and 2-ligation groups. We found no evidence of cold allodynia. Neither sham-operated nor suture controls showed any signs of allodynia or hyperalgesia. Following behavioral testing, rats were anesthetized with halothane for single-unit recordings from lumbar wide dynamic range-type (WDR) neurons. At 22 week post-surgery, the mean area of mechanosensitive receptive fields was significantly larger for units on the operated side in 1- and 2-ligation groups compared with those on the non-operated side or with those from sham-operated rats. Mean stimulus-response functions to graded noxious heat pulses (38-52 degrees C, 5 s) were not significantly different between operated and non-operated sides for 1- or 2-ligation groups, or compared with the 22-week sham-operated group. At 5 week post-surgery, the mean area of cutaneous receptive fields, and stimulus-response functions to graded noxious heat, were not significantly different between units recorded on operated versus non-operated sides, or compared with units from 5-week sham-operated rats. Spontaneous unit activity was significantly higher on the operated versus non-operated side in the 2-ligation (22-week) and sham (5-week) groups. Enlarged cutaneous receptive fields of dorsal horn neurons may contribute to mechanical allodynia associated with dorsal root constriction. However, the slow (>5 week) development of receptive field enlargement does not match the rapid development of allodynia. The lack of effect of dorsal root constriction on thermal sensitivity of dorsal horn units ipsilaterally corresponds to the lack of marked thermal hyperalgesia observed behaviorally.
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