Advances in the development of corticotropin-releasing-hormone (CRH) receptor agonists as candidate analgesics
SummaryIt has been estimated that 9% of the US population suffers from moderate to severe non-cancer-related pain. Acute pain resulting from conditions such as headache, muscle spasms, dental problems or following surgery, affects 90 million Americans every year and the development of analgesics represents a major pharmaceutical objective. A recent study has demonstrated the analgesic activity of corticotropin-releasing-hormone (CRH) and has shown that this activity is probably due to activity within t
It has been estimated that 9% of the population suffers from moderate to severe non-cancer-related pain. Acute pain resulting from conditions such as headache, muscle spas, dental problems or following surgery, affects 90 million Americans every year. Chronic pain affects 40-70 million Americans and the total economic cost of pain is $100 billion in the alone. The estimated worldwide market for pain and inflammation treatments has been estimated as $18.7 billion. It is therefore not surprising that the development of analgesics has represented a major pharmaceutical objective (for a comprehensive listing of pain reports click here).
One target for the development of analgesics is corticotropin-releasing-hormone (CRH). This peptide is released by the hypothalamus and stimulates the anterior pituitary cortex to release adrenocorticotropic hormone, which then activates the adrenal gland to release corticosteroids. CRH plays a pivotal effect in the stress response of an organi and it also has the potential to modulate pain tranission in part by its effect on the release of beta-endorphin from the pituitary.
In one clinical trial CRH has been shown to reduce post-operative analgesia while in a second more recent report CRH had no effect on heat pain sensitivity. CRH binds to and activates at least two receptors, CRHR1 and CRHR2. These receptors are found both centrally and peripherally and the analgesic activity of CRH been proposed to involve both systemic and central neural modulation. This level of complexity is further extended by the ability of CRH to modulate inflammation. In particular CRHR1 and CRHR2 activation has been proposed to release endorphin from macrophage/monocytes, granulocytes and lymphocytes of inflamed tissue which in turn desensitizes sensory nerve endings. Given the complexity of its mechani of action it is unsurprising that CRH has produced variable clinical efficacy.
In order to exploit the potential analgesic activity of CRH it is first necessary to more fully understand such effects. This will direct the development of CRH receptor agonists that target a particular receptor or that have an appropriate level of CNS penetrability. Likewise it will determine which of the many pain etiologies would most benefit from the use of such therapeutic agents.
A recent study by researchers from the San Ignacio Hospital in in collaboration with researchers at has investigated the efficacy of CRH in rodents with epidermal burns. These animals had increased systemic hyperalgesia quantified as a decrease in latency of tail withdrawal away from a heat source.
The administration of CRH reduced the hyperalgesia in the skin burn model. The implantation of a chamber beneath the burn site allowed the measurement of local mediator levels and it was found that the administration had no effect on local beta-endorphin or corticosterone levels. The authors therefore suggest that in this model of hyperalgesia CRH has analgesic activity that is not mediated by the release of endorphin from immune cells at the site of injury and propose instead that the analgesia of CRH may arise from CNS activity.
This study is important because not only does it confirm the analgesic activity of CRH in non-inflammatory pain but it also suggests that to exploit such properties, the development of CRH ligands with good CNS penetration may be necessary. While centrally acting CRFR1 agonists may be anxiogenic, CRFR2 agonists have recently been suggested to be anxiolytic and if such agents retain the analgesic properties of CRH, CRFR2 selectivity may be advantageous. Such a pharmacological profile may be particularly useful in treating hyperalgesia that co-exists with anxiety. For example an estimated 9-15% of all Americans avoid much needed dental care due to anxiety and fear surrounding the dental experience. This translates to some 30 - 40 million people so afraid of dental treatment that they avoid it altogether. The development of CRF2 receptor agonists for the dual treatment of anxiety and pain associated dental treatment could represent a niche market.
Featured on TherapeuticAdvances from LeadDiscovery, Sept. 2004
Adapted from Soledad Cepeda et al, Regul Pept. 2004 Apr 15;118(1-2):39-43.