The voltage-gated sodium channel, Nav 1.8, is known to play an important role in pain signalling. In this thesis, the functional properties and drug binding sites of wild type and mutant Nav 1.8 sodium channel currents were studied in mammalian sensory neuron-derived ND7/23 cells using whole-cell patch clamp. While the voltage-dependence of activation was similar for wild type human and rat Nay 1.8 channels, the voltage-dependence of steady-state inactivation was more hyperpolarised for hNav 1.8 compared to rNav 1.8. Furthermore, as a consequence of the different time course for inactivation between human and rat channels, inhibition during frequent stimulation was less pronounced for hNav 1.8 than for rNav 1.8. Thus, this would imply that the human channel is more inactivated at normal resting potentials, and can support higher firing frequencies than the rat channel. The action of tetracaine, ralfmamide, 227c89, Vl02862, and Nav1. 8-selective compound A-803467 on wild type hNav 1.8 and rNav 1.8 channels was studied. All compounds showed preferential block of inactivated channels rather than resting channels. Compound A-803467 showed greater affinity for inactivated hNav 1.8 channels than for inactivated rNav 1.8 channels. Unexpectedly, an increase in current was observed for V102862 and A-803467 during recovery from inactivation, likely due to "disinhibition" of resting block. For A-803467, rather than usedependent inhibition, this disinhibition increased the current during frequent stimulation, while for VI 02862 it led to the absence of inhibition during low frequency stimulation. Thus while both V 102862 and A-803467 are potent inhibitors ofNav 1.8, V102862, rather than A-803467 might be a more useful blocker where physiological firing frequencies are higher. Alanine mutations at residues 1381, N390, L14l0, V14l4, Il706, F1710 and Y1717 were made in the pore-lining S6 segments of the hN av 1. 8 channel, and at the corresponding positions in the rNav 1.8 channel. Many of the mutations caused shifts in voltage-dependence of activation and inactivation, and gave a faster time course of inactivation, indicating that the native residues at these positions are important for both activation and inactivation in Nav 1.8 sodium channels. The affinity of tetracaine for the resting and inactivated channels was reduced by hNav1.8 mutations 138lA, F1710A and Y1717A (only inactivated state affinity was measured for the latter), and by mutation F17l0A for A-803467. For mutation L1410A both compounds caused complete resting block at very low concentrations; this block was removed by further stimulation. While tetracaine did not show disinhibition for wild type channels during recovery from inactivation, it was seen particularly for mutants L1410 and F1710A. All mutations increased the extent of disinhibition of A-803467. These results suggest that the Nav 1.8-selective compound A-803467 acts within the pore S6 segments with a differing but partially overlapping site to that of the local anaesthetic tetracaine.

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The aim of this study is to gain a comprehensive illustration of the experience of non-serious, non-chronic, general aches and pains, and their associated risk factors in the workplace. A cross-sectional questionnaire survey was carried out in 23 different workplaces in Scotland, inviting individuals to comment on their pain prevalence, pain responses, and pain experience in relation to the Glasgow Pain Questionnaire (GPQ; Thomas et al., 1996). The GPQ provides an index of total pain experience, Pain Frequency, Pain Intensity, Ability to Cope with Pain, Pain Emotion and Pain impact. Although response rates were low (24%), 1888 workers participated in the final study, representing a variety of ten different industry groups. Results showed that the prevalence of general aches and pains was high (70%), for which workers were most likely to either present to a primary care professional (doctor or dentist), or to take a medication that they had close at hand. One third of those suffering for general aches and pains did not act on them at all. Prevalence of non-troublesome general aches and pains varied marginally in relation to risk factors, although an adjusted association was found between the likelihood of pain and some demographic groups (female sex, having a chronic condition). An association was also found between pain prevalence and higher work stress. Adjusted responses to pain differed in relation to pain site and pain cause, although demographic and work variables show little association, after adjustment, with the decision to act on or consult for pain. The more negative the pain experience, the more likely workers were to act or consult, although ‘Ability to Cope with Pain’ showed no association with either acting or consulting. After adjustment for age and gender, the experience of pain was relatively similar across pain sites, although it was more negative in long-term conditions, or where medical intervention was required.