SUMMARY1. The actions of dopamine (DA) and DA receptor specific agonists and antagonist ionophoretically applied in the spinal dorsal horn, and of focal electrical stimulation in the region of the supraspinal DA cell groups (A9 and All) were assessed on the somatosensory responses of dorsal horn neurones, in both the rat and cat. The neurones tested were multireceptive, giving reproducible responses to both noxious (using a mechanical pinch or radiant heat) and innocuous (using a motorized brush) cutaneous stimuli, as well as to ionophoretically applied DL-homocysteic acid (DLH, a direct excitant). In the cat, all neurones tested were identified as belonging to the spinocervical tract (SCT) and were located in the dorsal horn laminae III-V, whilst in the rat, spinothalamic tract (STT) and spinomesencephalic (SMT) neurones located in the region of lamina I and laminae Ill-V were tested.2. lonophoretically applied DA and RU24213, a D2 DA receptor agonist, caused a selective inhibition of the responses to noxious stimuli of SCT, STT and SMT neurones, whilst the responses to non-nociceptive stimuli, spontaneous activity and DLH-evoked activity were unaffected. This action was reversed in the presence of sulpiride, the highly selective D2 DA receptor antagonist. Neither sulpiride alone nor SKF38393, a D1 DA receptor agonist, altered evoked or spontaneous activity when ionophoretically applied.3. Focal electrical stimulation in the region of the All, but not the A9, DA cell group selectively suppressed nociceptive responses of spinal, multireceptive neurones in the rat. This stimulus-evoked effect was consistently and rapidly reversed by ionophoresis of sulpiride, in the vicinity of the dorsal horn neurone being tested. In contrast, naloxone and idazoxan (RX781094), an oc2-antagonist, were not effective.4. This study presents data supporting a selective antinociceptive role for DA at the spinal level, where it has a widespread antinociceptive influence, on cells in both the superficial and deeper dorsal horn. The Al1 DA cell group was shown to be a supraspinal site from which a selective antinociceptive action could be electrically evoked and which was mediated by DA at the level of the dorsal horn.

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.

Endometriosis is an incurable gynecological disorder characterized by debilitating pain and the establishment of innervated endometriosis lesions outside the uterus. In a preclinical mouse model of endometriosis we demonstrated overexpression of the PGE2-signaling pathway (including COX-2, EP2, EP4) in endometriosis lesions, dorsal root ganglia (DRG), spinal cord, thalamus and forebrain. TRPV1, a PGE2-regulated channel in nociceptive neurons was also increased in the DRG. These findings support the concept that an amplification process occurs along the pain neuroaxis in endometriosis. We then tested TRPV1, EP2, and EP4 receptor antagonists: The EP2 antagonist was the most efficient analgesic, reducing primary hyperalgesia by 80% and secondary hyperalgesia by 40%. In this study we demonstrate reversible peripheral and central hyperalgesia in mice with induced endometriosis.

Following the establishment of a chronic varicellazoster virus infection in the rat, behavioural allodynia and hyperalgesia were observed in the injected, but not the contralateral hind limb up to 33 days post-infection. This model may prove useful in investigating mechanisms involved in the establishment of post-herpetic neuralgia.

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