Birrell, Graham James

2018-01-31T11:18:44Z

2018-01-31T11:18:44Z

1991

A novel model of unilateral, localized adjuvant-induced arthritis in the rat was assessed for its use in pharmacological studies on the pain associated with chronic joint inflammation. Levels of inflammation, changes in behaviour and joint pathology were examined. Electrophysiological recordings of afferent activity were made in anaesthetized rats in vivo and in vitro from a fine branch of the medial plantar nerve innervating the tarsal joint. The effects of various putative inflammatory mediators on the discharge of articular nociceptors both in normal and arthritic joints were also examined. Where possible, selective agonists and antagonists were used to characterize the pharmacological receptors involved in the actions of these substances.

Injection of Freunds Complete Adjuvant around the left ankle joint caused a localized swelling, nociceptive thresholds to mechanical stimuli were lowered and use of the injected joint was significantly reduced. Histological studies revealed the presence of an arthritis which was confined to the injected ankle. Electrophysiological investigations showed that in arthritic joints there were a larger number of identifiable receptive fields for articular mechanonociceptors compared to those found in normal joints. Receptors had lower activation thresholds, and often displayed a resting discharge not seen in normal joints.

Intra-arterial (i.a.) injection of 5-hydroxytryptamine (5-HT), excited articular nociceptors from normal and arthritic joints. Responses consisted of two components: (a) a fast transient burst of activity mediated by a 5-HT₃-receptor, followed by (b) a delayed, longer-lasting excitation mediated by a 5-HT₂-receptor. These responses were shown to occur both in vivo and in vitro. 5-HT also increased the mechanical responsiveness of articular mechanonociceptors via a 5-HT₃-receptor. Sensory receptors in arthritic joints were more sensitive to 5-HT than those from normal joints. Administration of the 5-HT₃- or 5-HT₂ receptor antagonists caused short-lasting reductions in background activity in arthritic joints, as well as in normal joints in which activity had increased following administration of 5-HT.

In normal joints, i.a. injection of PGE₂, PGI₂ or the selective IPreceptor agonist cicaprost, excited and caused mechanical sensitization of articular mechanonociceptors. Potentiation of the short-lived excitatory and sensitizing effects of i.a. injected bradykinin on these receptors was also shown. Examination of the effects of PGE₂, PGI₂ and cicaprost in vivo or PGE₂, cicaprost, PGD₂, and PGF₂ alpha in vitro, produced a rank order of potency of

PGI₂ - cicaprost » PGE₂ » PGD₂ - PGF₂ alpha In arthritic rats injection of cicaprost, and to a lesser extent PGE₂, was effective in increasing the mechanical responsiveness and resting discharge of articular mechanonociceptors previously depressed by i.v. lysine acetylsalicylate. These results provide evidence for the involvement of IP-receptors, and perhaps EP-receptors, in the excitatory and sensitizing actions of the prostanoids on articular nociceptors, and suggest that PGI₂ is the major endogenous prostanoid responsible for the mechanonociceptor sensitization seen in arthritic rat ankle joints.

Overall the results suggest that more than one mediator is required to produce conditions of mechanonociceptor sensitization seen in arthritic rat ankle joints. However, as modulators of the responsiveness of nociceptors to other mediators, and as potent excitants themselves, the prostanoids, and in particular PGI₂, probably play a major role in the alterations in nociceptor sensitivity seen in arthritic joints.

http://hdl.handle.net/1842/26331

The University of Edinburgh

Annexe Thesis Digitisation Project 2017 Block 15

Pharmacological studies of prostanoids and other substances on sensory nerves in arthritic rats

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy