Modelado por Competencias

T h e prostanoids are thought to sensitise nociceptors d irectly (T a iw o & Levine, 1989; Pitchford & Levine, 1991) by acting through specific recep to rs th at are coupled to the intracellular adenylyl cyclase / cA M P transduction pathway (F e rre ira & N akam ura, 1979; T a iw o et al, 1989; Cui & N icol, 1995).

In this study, both PGEj and PGD^ increased the fo rm a tio n o f intracellular

cA M P in cultured D R G neurones w hereas P G Ij and PGFja had no significant effect.

This data suggests th a t th e D P re c e p to r and EPj re c e p to r sub-type are expressed in sensory neurones as both have been shown to be positively coupled to th e adenylyl cyclase / c A M P transduction pathway (H o n d a et al, 1993; Sim on, 1980). It is surprising th a t PGI^ had no effect on intracellular cA M P as it also enhanced the sensitivity o f neurones to histamine and th e IP re c e p to r is coupled to th e adenylyl

cyclase transduction cascade (G o rm a n et al, 1977; H ashim oto et al, 19 9 0 ). T h e re is no evidence to date to suggest the existence o f IP re c e p to r sub-types, th e re fo re it

is unlikely th a t P G Ij is acting a t a d ifferen t re c e p to r sub-type to produce its sensitising effects. PGI^ is, h o w ever, unstable a t physiological pH and te m p e ra tu re

and is rapidly hydrolysed to 6 -keto -P G F ,a, th e re fo re th e lack o f effect on cA M P

production may re fle c t degradation o f P G Ij under th e exp erim en tal conditions o f

th e cA M P assay. T h e lack o f effect o f PGFja on intracellular cA M P is n o t surprising,

h o w e v e r as FP recep to rs are n o t th ought to be coupled to th e adenylyl cyclase pathway, instead they are coupled to th e PLC / IP3 intracellular pathw ay to bring

about an increase in [Ca^^],. PGFja had no effect on [Ca^^], in any o f th e D R G

neurones th e re b y suggesting that, in this preparation, the neurones do n o t express FP receptors.

Agents which elevate intracellular cAM P, such as 8 -b ro m o -c A M P and

forskolin also produced a sensitisation o f th e histamine response. This sensitisation shared sim ilar features to th a t obtained to PGEj in th a t the n u m b er o f cells responding to histamine was increased w ith no significant effect on th e profile of the [Ca^^Ji response. T h e PGEj-induced sensitisation was preven ted by inhibiting the fo rm a tio n o f cA M P in th e neurones w ith the m em brane p erm eable in h ib ito r o f adenylyl cyclase activity, T H F A . This data suggests th a t th e sensitising effects o f the prostanoids are m ediated via a cA M P -d ep en d en t mechanism and a re consistent w ith previous studies th a t d em o n strate th a t agents which e ith e r increase o r decrease intracellular cA M P m ediate o r inhibit th e sensitisation to bradykinin, respectively (Pitchford & Levine, 1991; C ui & N ico l, 1995; W a n g et al, 1996).

T h e H , antagonist, m epyram ine, produced an inhibition o f th e prostanoid-

induced sensitisation th e re fo re suggesting th a t th e sensitised [Ca^^], response was mediated by the activation o f H , recep to rs. Surprisingly, th e H2 antagonist,

histamine response. T h e mechanism by which it produced this effect is n o t clear, h o w ever, th e re are several possible explanations: I) H istam ine may be able to

enhance th e response to itself via an H ; re c e p to r-m e d ia te d rise in intracellular cAM P, h o w ever, histamine alone had no effect on cAMP; 2 ) C im etid in e may be in terferin g a t th e level o f th e prostanoid re c e p to r and its ability to activate adenylyl cyclase but cim etidine had no effect on th e prostanoid-evoked increase in cAMP; 3) T h e re is som e evidence th a t th e activation o f H j re cep to rs can evoke a rise in [Ca^^]i (C h e w , 1986; D elvalle et al, 19 9 2 ), th e re fo re , cim etidine may inhibit an H j re c e p to r-m e d ia te d rise in [Ca^^Jj. This is also unlikely as cim etidine had no effect on th e [Ca^^j response obtained to histamine alone. It is m o re likely th a t th e high co n cen tratio n o f cim etidine used had a non-selective action on o th er, as yet undefined systems which, in turn, had an inhibitory effect on th e prostanoid- induced sensitisation.