Allodynia : mechanisms and treatment

Abstract

The painful perception of innocuous stimuli (allodynia) is a condition afflicting many individuals worldwide including type II diabetics, spinal cord injury victims, and cancer patients. However, a reliable treatment for allodynia specifically and hypersensitivity at large has remained unattainable largely due to the fundamental lack of understanding of the mechanisms driving allodynia. The key aim of this thesis was to understand the mechanisms which drive hypersensitivity in general and cold allodynia specifically. By understanding these mechanisms, we aim to identify new strategies to treat such conditions. In chapter two we aimed to characterise the peripheral substrate of cold allodynia through a series of human psychophysical experiments, wherein cold allodynia was observed during infusion of hypertonic saline (HS) in the tibialis anterior muscle. We demonstrated that cold allodynia does not require myelinated sensory nerve afferents, TRPV1 channels (typically associated with nociceptive or pain fibres) or TRPM8 channels (typically associated with cold sensation). Whereas cold allodynia was abolished by blocking a specific calcium channel (Cav 3.2, associated with C-tactile fibres). The results of this study showed that cold allodynia persists independently of A fibres (i.e., the fibre class classically associated with cold sensation) and nociceptive pain channels; suggesting a strong role for C tactile fibres in the mediation of allodynia. Additionally, we observed cold allodynia in clinical patients that persists following A fibre block; this allodynia was associated with the underlying muscular hypersensitivity. In chapter three, a model of persistent muscular hypersensitivity and cold allodynia was developed in healthy humans using repeated bolus HS injections into the Tibialis Anterior muscle. Moreover, this hypersensitivity extended bilaterally; mimicking the diffuse hypersensitivities observations in clinical syndromes (e.g. complex regional pain syndrome, fibromyalgia). This novel experimental model was used to test the efficacy of minocycline at alleviating the evoked hypersensitivity. Minocycline had no effect on acute pain processing, but did reliably prevent the production of hypersensitivity following repeated injections of HS. Minocycline's ability to prevent the development of hypersensitivity in humans prompted a reverse-translational study in animals in order to understand the apparent disconnect between the efficacy in animal models and limited efficacy in humans, as well as explore the mechanisms behind the actions of HS and minocycline. We hypothesised that minocycline acts by inhibiting microglial activation and proliferation caused by repeated HS injections. This rat model of repeated HS injections was associated to the development of mechanical allodynia and microglial proliferation in the dorsal horn. However, when rats were pre-treated with minocycline while the allodynia failed to develop, microglial proliferation was unchanged by minocycline. As repeated HS injections were not associated with an increase in ATF3 expression (a known marker of nerve injury) in the dorsal root ganglia, we concluded that the afferent barrage caused by repeated HS injections alone is sufficient to induce a state of hypersensitivity. Finally, we aimed to identify the relay pathway and isolate a central marker for cold allodynia or cold hyperalgesia within the dorsal horn. pERK (a molecule released centrally and implicated in central sensitisation) while increasing its expression following noxious thermal stimuli (ie 40oC), effects that were intensified following spinal nerve ligation, reaffirmed the role of pERK in heat hyperalgesia whilst providing no evidence for the role of pERK in cold allodynia or hyperalgesia.

Date of Award	2018
Original language	English