Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity.

We and others have previously demonstrated that nociception in the mouse is heritable. A genetic correlation analysis of 12 common measures of nociception among a common set of inbred strains revealed three major clusters (or 'types') of nociception in this species. In the present study, we re-evaluated the major types of nociception and their interrelatedness using ten additional assays of nociception and hypersensitivity, including: three thermal assays (tail withdrawal from 47.5 degrees C water or -15 degrees C ethanol; tail flick from radiant heat), two chemical assays of spontaneous nociception (bee venom test; capsaicin test) and their subsequent thermal hypersensitivity states (including contralateral hypersensitivity in the bee venom test), a mechanical nociceptive assay (tail-clip test), and a mechanical hypersensitivity assay (intrathecal dynorphin). Confirming our earlier findings, the results demonstrate distinct thermal and chemical nociceptive types. It is now clear that mechanical hypersensitivity and thermal hypersensitivity are genetically dissociable phenomena. Furthermore, we now see at least two distinct types of thermal hypersensitivity: afferent-dependent, featuring a preceding significant period of spontaneous nociceptive behavior associated with afferent neural activity, and non-afferent-dependent. In conclusion, our latest analysis suggests that there are at least five fundamental types of nociception and hypersensitivity: (1) baseline thermal nociception; (2) spontaneous responses to noxious chemical stimuli; (3) thermal hypersensitivity; (4) mechanical hypersensitivity; and (5) afferent input-dependent hypersensitivity.

Comparison of antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse models of acute, prolonged, and chronic nociception.

Some antiepileptic drugs have been shown to be clinically effective in the treatment of neuropathic pain. This study determined whether the new antiepileptic drug tiagabine, a GABA uptake inhibitor, is efficacious in mice in a broad range of nociceptive tests (hot-plate, formalin, and dynorphin-induced chronic allodynia) and compared tiagabine's potency with two other antiepileptic drugs, gabapentin and lamotrigine. Intraperitoneally administered tiagabine, but not lamotrigine, gabapentin, or i.t. tiagabine, produced dose-dependent antinoception in the hot-plate test. A 5-min pretreatment with tiagabine (2-29 nmol i.t.) dose-dependently inhibited both the acute and late phase formalin behaviors; pretreatment with lamotrigine (4-265 nmol i.t.) inhibited only the late phase. In the formalin assay the GABA(A) antagonist bicuculline reversed the acute phase antinociception, whereas the GABA(B) antagonist saclofen reversed both the acute and late phase tiagabine-induced antinociception. Tiagabine administered i.p. but not i.t. dose-dependently reduced dynorphin-induced chronic allodynia for 120 min. Gabapentin and lamotrigine produced antinociception administered either i.t. or i.p. in a dose-dependent manner. Thus, we have shown that gabapentin and lamotrigine produced antinociception in two mouse models of pain, whereas tiagabine produced antinociception in all three mouse models of pain.