Neurokinin and NMDA antagonists (but not a kainic acid antagonist) are antinociceptive in the mouse formalin model

While much evidence implicates substance P (SP), an endogenous neurokinin (NK), as a primary sensory transmitter of acute pain in mammalian spinal cord, its role in continuous (tonic) pain is less clear. Although glutamate is co-localized with SP in dorsal root ganglion neurons, its role in nociceptive processing is uncertain. While antagonists of NKs and excitatory amino acids (EAAs) have been found to be antinociceptive in some acute assays, they have not been tested against tonic pain. We hypothesize that: 1. (1) NKs and EAAs contribute to signaling of tonic chemogenic nociception 2. (2) interaction between NK and EAA systems is important in determining the perceived intensity of a continuous noxious stimulus. We therefore evaluated two NK antagonists ([d-Pro²,d-Trp^7,9] SP (DPDT-SP, 0.26-6.6 nmoles, non-specific) and [d-Pro⁴,d-Trp^7,9,10,Phe¹¹]-SP(4-11) (DPDTP-octa, 1.6-12.3 nmoles, somewhat NK-1 selective)), as well as dl-2-amino-5-phosphonovalerate (dl-AP5, NMDA antagonist, 0.05-1 nmole) and urethane (a kainic acid (KA) antagonist at 2.5 μmoles) for antinociceptive activity in the mouse formalin model. Administered intrathecally (i.t.), dl-AP5 and both NK antagonists were significantly antinociceptive while urethane (2.5 μmoles) and naloxone (2.7 nmoles) were inactive. A₅₀ values for mean % analgesia, nmoles/mouse i.t. (95% CLs) were: DPDT-SP, 1.1 (0.79-1.6); DPDTP-octa, 3.9 (2.4-6.1); dl-AP5, 0.29 (0.16-0.71). The antinociception associated with 1.3 nmoles of DPDT-SP was not reversed by co-administering 2.7 nmoles of naloxone. Co-administration of 0.1 nmoles of dl-AP5 with either 1.3 nmoles of DPDT-SP or 3.3 nmoles of DPDTP-octa did not lead to additive antinociception. One nmole of dl-AP5 also produced significant antinociception in the mouse tail-flick test. These data support the contention that NK (probably NK-1) and NMDA (but not KA) receptors are involved in spinal processing of tonic chemical/inflammatory nociception in mice.