Evaluation of peripheral versus central effects of GABA(B) receptor activation using a novel, positive allosteric modulator of the GABA(B) receptor ADX71943, a pharmacological tool compound with a fully peripheral activity profile.

BACKGROUND AND PURPOSE: The GABA(B) receptor agonist, baclofen, has shown promising effects in patients suffering from pain, post-traumatic stress disorder, alcoholism, overactive bladder and gastroesophageal reflux disease. However, baclofen's short duration of action and side effects limit its wider use. Here we characterized a novel, GABA(B) receptor positive allosteric modulator (PAM) ADX71943. EXPERIMENTAL APPROACH: In vitro, ADX71943 was assessed for pharmacological activity and selectivity using recombinant and native GABA(B) receptors. In vivo ADX71943 was assessed in the acetic acid-induced writhing (AAW) test in mice and formalin tests (FTs) in mice and rats. Marble burying (MB) and elevated plus maze (EPM) tests, rotarod, spontaneous locomotor activity (sLMA) and body temperature (BT) tests in mice and rats were used to investigate centrally-mediated effects. KEY RESULTS: In vitro, in the presence of GABA, ADX71943 increased the potency and efficacy of agonists and showed selectivity at the GABA(B) receptor. ADX71943 reduced pain-associated behaviours in AAW; an effect blocked by GABA(B) receptor antagonist CGP63360. ADX71943 reduced pain in the FT in mice and rats, but was inactive in the MB and EPM despite reaching high concentrations in plasma. ADX71943 had no effect on BT, rotarod and sLMA. CONCLUSIONS AND IMPLICATIONS: ADX71943 showed consistent and target-related efficacy in tests of disorders that have a significant peripheral component (acute and chronic pain), while having no effect in those associated with centrally-mediated anxiety-like reactivity and side effects. Thus, ADX71943 is a useful pharmacological tool for delineation of peripherally- versus centrally-mediated effects of GABA(B) receptor activation.

Superficial dorsal horn neuronal responses and the emergence of behavioural hyperalgesia in a rat model of cancer-induced bone pain.

Animal models of cancer-induced bone pain have revealed a unique neurochemical reorganisation of segments of dorsal horn of the spinal cord receiving nociceptive input from the affected bone, and altered spinal neuronal response patterns. The aim of this investigation was determine correlations between the behavioural hyperalgesia and allodynia observed in these animals and the dorsal horn neuronal changes. The results show that in this rat model of cancer-induced bone pain, behavioural manifestations of pain emerge in parallel with the altered superficial dorsal horn neuronal response. Thus, in this model, the alterations in neuronal responses are a viable substrate for pharmacological studies on suprathreshold stimuli. In addition the clear temporal link between behavioural hyperalgesia and altered neuronal responses may provide an opportunity to investigate changes in dorsal horn gene expression in hyperalgesia.

Alterations in dorsal horn neurones in a rat model of cancer-induced bone pain.

Cancer-induced bone pain is a major clinical problem. A rat model based on intra-tibial injection of MRMT-1 mammary tumour cells was used to mimic progressive cancer-induced bone pain. At the time of stable behavioural changes (decreased thresholds to mechanical and cold stimuli) and bone destruction, in vivo electrophysiology was used to characterize natural (mechanical, thermal, and cold) and electrical-evoked responses of superficial and deep dorsal horn neurones in halothane-anaesthetized rats. Receptive field size was significantly enlarged for superficial neurones in the MRMT-1 animals. Superficial cells were characterised as either nociceptive specific (NS) or wide dynamic range (WDR). The ratio of WDR to NS cells was substantially different between sham operated (growth media alone) (26:74%) and MRMT-1 injected rats (47:53%). NS cells showed no significant difference in their neuronal responses in MRMT-1-injected compared to sham rats. However, superficial WDR neurones in MRMT-1-injected rats had significantly increased responses to mechanical, thermal and electrical (A beta-, C fibre-, and post-discharge evoked response) stimuli. Deep WDR neurones showed less pronounced changes to the superficial dorsal horn, however, the response to thermal and electrical stimuli, but not mechanical, were significantly increased in the MRMT-1-injected rats. In conclusion, the spinal cord is significantly hyperexcitable with previously superficial NS cells becoming responsive to wide-dynamic range stimuli possibly driving this plasticity via ascending and descending facilitatory pathways. The alterations in superficial dorsal horn neurones have not been reported in neuropathy or inflammation adding to the evidence for cancer-induced bone pain reflecting a unique pain state.