This thesis tests the hypothesis that certain inflammatory mediators, including kinins
and cytokines are involved in sensitisation of peripheral nociceptors and contribute to
the hyperalgesia associated with inflammatory conditions. These studies involved the
development of a new model for recording from C- fibres innervating the rat knee joint
and determined the role of these substances and their interactions in modulating neural
discharge from articular nociceptors. Complementary behavioural studies were
carried out to assess the role of these mediators in thermal and mechanical
Recordings from C-fibres innervating the medial side of the rat knee joint revealed
that Bk induced an increase in neural discharge in normal and arthritic knee joints
which was blocked by a kinin B₂ receptor antagonist, icatibant. desArg⁹-Bk was
ineffective in normal joints, however in arthritic joints desArg⁹-Bk induced an
increase in neural discharge in C- fibres which was mediated via kinin B₁ receptors, as
it was reduced by desArg⁹leu⁸-Bk, but not icatibant.
IL-iß injected into the knee joint induced an increase in neural discharge from C-fibres which was blocked by concomitant injection of IL-lra. This was consistent
with behavioural studies where local injection of IL-1ß induced a mechanical and
thermal hyperalgesia. IL-1ß also enhanced responses mediated by Bk in C- fibres and
in mechanical hyperalgesia. In the mechanical hyperalgesia model the enhanced
responses to Bk were blocked by both desArg⁹leu⁸-Bk and icatibant. IL-1ß was also
shown to be involved in inducing a desArg9 -Bk- mediated increase in neural discharge
in C-fibres and a desArg⁹-Bk- mediated behavioural hyperalgesia (mechanical and
thermal). The desArg⁹-Bk mediated hyperalgesia was blocked by desArg⁹leu⁸-Bk, but
Pre-treatment with indomethacin blocks IL-1ß-induced increase in neural discharge
and behavioural hyperalgesia. Indomethacin also blocks IL-1ß- induced enhancement
of Bk-mediated increase in neural discharge from C-fibres and IL-1ß-induced
enhancement of Bk-mediated mechanical hyperalgesia. Although indomethacin
blocked the kinin-B₁-mediated increase in neural discharge induced by IL-1ß,
indomethacin did not reduce the kinin B₁- mediated mechanical hyperalgesia induced
by IL-1ß and only blocked the kinin B₁-mediated thermal hyperalgesia induced by IL-1ß for one hour.
These studies also considered the involvement of mediators which are increased
during inflammation in modulation of C-fibre activity and behavioural hyperalgesia.
The role of endogenous nitric oxide in modulating neural discharge of C-fibres was
studied in normal and arthritic ankle joints. L-NAME, a nitric oxide synthase
inhibitor, induced an increase in neural discharge from articular C-fibres in both
normal and arthritic ankle joints and increased Bk-mediated increase in neural
discharge in arthritic ankle joints. These effects were reduced by L-Arginine, a nitric
oxide precursor. L-Arginine itself reduced Bk-mediated increase in neural discharge
in both normal and arthritic ankle joints. The role of two `anti -inflammatory'
cytokines (IL-4 and IL-10) in modulating behavioural hyperalgesia was also studied.
IL-4 and IL-10 reduced IL-1ß-induced mechanical hyperalgesia and thermal
hyperalgesia, however the duration of action of IL-10 (less than 2h) was shorter than
IL-4 (at least 5h) in the thermal hyperalgesia model. IL-4 and IL-10 also blocked IL1ß-induced enhancement of Bk-mediated and desArg⁹-Bk-mediated mechanical and
thermal hyperalgesia, however once again, the duration of action of IL-10 (less than
2h) was shorter than IL-4 (at least 5h).
In conclusion, the results illustrate a role for both kinin B₂ and B₁ receptors in
modulating neural discharge from knee joint C-fibres and hyperalgesia in
inflammation. 1L-1ß is involved in modulating neural discharge from articular C-fibres and modulation of kinin-mediated modulation of neural discharge which
appears to involve generation of prostanoids in the case of enhancement of Bk-mediated responses. These results also highlight a role for IL-4, IL-10 and nitric oxide
as mediators which potentially limit the hyperalgesia associated with inflammation.
Overall, the present results add further to our knowledge and understanding of the
peripheral mechanisms involved in inflammatory pain.