Glutamate, substance P (SP) and neurokinin A (NKA) are all found in fine
primary afferent fibres and can be released upon noxious stimulation of the
corresponding cutaneous receptive field. The possibility of a role in nociception for
the metabotropic class of glutamate receptors (mGluRs) as well as those at which SP
and NKA preferentially act (NKj and NK2), was investigated in the present study.
Since protein kinase C (PKC) has been shown to be important in the mediation of
noxious, but not non-nociceptive inputs, the potential role of this and several other
signal transduction pathways in sensory inputs was assessed here, especially in the
context of actions via mGluRs.
(a) Extracellular recordings were made from single dorsal horn neurons
(laminae III-V) in the spinal cords of chloralose/urethane anaesthetised rats. Activity
evoked by innocuous brushing of the cutaneous receptive field was not reduced by
ionophoresis of mGluR antagonists L-l-amino-3-phosphopropionic acid (AP3),
(R,S)- or (S)-4-carboxy-3-hydroxyphenylglycine (CHPG). However, sustained
elevated firing evoked by the application of the C-fibre selective chemical irritant
mustard oil was significantly attenuated by L (but not D)-AP3 and (R,S)-CHPG.
Approximately one fifth of dorsal horn neurons could be excited by ionophoresis of
the mGluR agonist (lS,3R)-l-aminocyclopentane-l-3-dicarboxylic acid (ACPD), and
this evoked activity was similarly reduced by L (but not D)-AP3 and (R,S)-CHPG.
(b) Inhibitors of calmodulin/Ca++-dependent kinase (CamKII), phospholipase
A2 (PLA2), protein kinase A (PKA) and non-receptor tyrosine kinases were
ionophoresed during brush- and mustard oil-evoked activity. CamKII and PLA2
inhibitors were less effective in reducing innocuous rather than noxious inputs.
Inhibitors of PKA and tyrosine kinases were equally effective in reducing all evoked
activity. All of these antagonists, as well as two PKC inhibitors significantly
decreased activity elicited by the ionophoresis of (1S,3R)-ACPD.
(c) The behaviour of conscious rats in response to noxious mechanical and
thermal stimulation of one hindpaw (non-inflamed or inflamed by an intraplantar
injection of carrageenan) was monitored following an intrathecal injection of mGluR
antagonists L-AP3 and (S)-CHPG, as well as GR82334 and L659,874, antagonists at
NK] and NK2 receptors respectively. (S)-CHPG significantly increased withdrawal
responses in each model to both mechanical and thermal stimulation, whereas L-AP3
was only effective in the inflamed paw. L659,874 was antinociceptive in thermal,
but not mechanical, tests in the non-inflamed and inflamed paws. GR82334 did not
alter latencies in any tests. However, a co-injection of GR82334 or L659,874 with
each mGluR antagonist resulted in an apparent reversal of the analgesic effects
observed when the mGluR antagonists were administered alone.
This investigation demonstrates a role for spinal cord mGluRs in the
transmission of sustained nociception, possibly mediated by PKC, CamKII and
PLA2. NK2 receptors appear to have a selective role in thermal inputs to the spinal
cord, whereas this study provided no evidence for an overt role of NK] receptors in
the nociceptive models assessed. It is possible that NK] receptors play a greater role
in more prolonged or severe nociceptive inputs. The present data suggest however
that not only NK2, but also NK] receptors exhibit a functional interaction with the
influence of mGluRs on nociceptive thresholds.