In animals, different types of COMT inhibitors, irrespective of their brain penetration, are pro-nociceptive in several models of acute and inflammatory
pain. Similarly, COMT knock-out mice are more sensitive to nociceptive stimuli, whereas in mice over-expressing a high activity COMT variant nociceptive sensitivity is decreased. COMT knock-out mice also show altered response to
opioids and stress-induced
analgesia. In different rat models of
neuropathic pain, the action of
nitecapone is opposite: it is antinociceptive and antiallodynic. Complex actions of low COMT activity may be caused by enhanced
adrenergic and dopaminergic activities that play different and even contrasting roles at different parts of the nociceptive system. Also compensatory changes in other
neurotransmitters may occur. Pro-nociceptive effects seem to be caused by increased activation of peripheral
adrenergic β(2)- and β(3) -receptors. Other properties of COMT inhibitors, like scavenging of
oxygen and
nitrogen radicals, may be important in antiallodynic effects found in
neuropathic pain models. Increased number of µ-
opioid receptors in certain brain areas may be responsible of enhanced
opioid effects associated with a low COMT activity. In human
pain studies, a low COMT activity is often associated with increased
pain sensitivity in experimental
pain models and with increased pre- and
postoperative pain in acute clinical situations. As a rule, a simultaneous occurrence of several SNPs within the haplotype, causing low COMT activity, is more often associated with
pain than any single SNP alone. In experimental
pain studies, all negative findings resulted from concentrating solely on SNP rs4680 (Val158Met). Virtually all studies assessing haplotypes were able to confirm an association of a low COMT and increased
pain. In chronic clinical
pain, the effect of COMT polymorphisms depends on the
pain conditions. Hence, in neuropathic and
cancer pains, COMT activity is meaningless but in some chronic
musculoskeletal pain conditions and
migraine or
headache low COMT activity appears to increase incidence and symptoms. A low COMT activity also increases availability of
opioid receptors and may enhance
opioid analgesia and adverse effects at least in
cancer pains.