Progressive tactile hypersensitivity: an inflammation-induced incremental increase in the excitability of the spinal cord

Abstract

Two established phenomena contribute to the generation of post-injury pain hypersensitivity: peripheral sensitization, an increase in transduction sensitivity of high threshold Aδ and C-fibre nociceptors, and central sensitization, an increase in excitability of neurones in the spinal cord triggered exclusively by C-fibre inputs. We now describe a novel phenomenon: progressive tactile hypersensitivity, which contributes to a cumulative allodynia during inflammation. Behavioural measurements in conscious intact animals showed that repeated light touch stimuli delivered at 5-min intervals to an inflamed paw, established 48 h earlier by an intra-plantar injection of complete Freund's adjuvant (CFA), resulted in a progressive reduction in the mechanical withdrawal threshold by more than 75%, from its already hypersensitive basal level. This hypersensitive state persisted for several hours after discontinuing the touch stimuli and did not occur in non-inflamed animals. To monitor nociceptive processing and the afferent fibres responsible, we also measured activity in posterior biceps femoris/semitendinosus flexor motor neurons. In non-inflamed decerebrate-spinal rats, the cutaneous mechanical threshold and pinch-evoked activity of these neurones are stable when tested repeatedly at 5-min intervals and are characterised by absent or small responses to low intensity mechanical stimuli or electrical activation of Aβ-fibres. In inflamed animals, the spontaneous activity, touch-, pinch- and Aβ-afferent-evoked responses of hamstring flexor motor neurones are significantly increased. The flexor reflex becomes, moreover, progressively more sensitized by repetition every 5 min, of standard mechanical stimuli (touch and pinch), that do not modify excitability in control non-inflamed animals. A cumulative increase in Aβ-afferent-evoked responses also occurs when the test stimulus only comprises stimulation of the sural nerve at Aβ strength (10 Hz, 10 sec), showing that Aβ-afferents have the capacity to produce progressive hypersensitivity. Progressive hypersensitivity, measured here as a progressive tactile allodynia after inflammation in either intact or decerebrate-spinal rats, with its gradual build-up and contribution from Aβ fibres, is very different from the central sensitization induced by C-fibre stimulation which is characterised by a peak increase in excitability soon after the conditioning input followed by a steady decrement to baseline levels. Progressive hypersensitivity is likely to be the consequence of an alteration in the function and phenotype of afferents innervating inflamed tissue and the pattern of excitation they produce in spinal neurones. The phenomenon may have an important role in the development of inflammatory pain and hypersensitivity.