A novel conditioned nociceptive response in mice

Chronic pain tends to be intractable, regardless of whether the etiology has improved or is persistent. This intractability may be due, in part, to conditioning factors, but studies of the underlying mechanism are limited. We predicted that the body might learn pain sensation during sustained pain. In the present study, we sought to examine the prediction that nociceptive pain could be a conditioned response. After pre-exposing mice to the context box, we assessed hind-paw licking responses(s), an unconditioned nociceptive response (UCR), in the training phase for 30 min following each of two injections (24 h apart) of formalin into the hind paws. Forty-eight hours later, in the test phase, we tested for a conditioned nociceptive response (CR) from paw injections of saline, with mice placed in either the same or a different visual context box. The results showed that the CR elicited in the same context box was significantly larger than one elicited in the different box. An audiovisual context, which is used in prototypical Pavlovian conditioning, augmented the CR. The CR diminished to baseline levels during repeated extinction procedures, in which saline alone was given in the same context box. However, the CR in animals injected with saline in their home cages was unchanged. Treatment with scopolamine, which has an antimuscarinic action, and thus induces an amnestic effect, did not affect the UCR, but reduced the CR. These results indicated that repeated nociceptive stimuli were sufficient to produce a CR.

Research highlights
► A novel conditioned pain response was achieved after twice injecting mice with formalin.
► This conditioned nociceptive response was formed in the same audiovisual context.
► The amnestic drug scopolamine inhibited the formation of the conditioning.
► The conditioned nociceptive response disappeared by extinction procedure.
► The conditioned nociceptive response was unaffected with narcotic drug (to be published data).