Mechanisms underlying prolonged nociception.

The sensitivity of the formalin response to opiates was reduced if the opiates were administered shortly after the formalin injection. This is in contrast to both local anaesthetics and NMDA antagonists which are

equally potent either as a pretreatment or a post-treatment in the formalin response (Haley et al,1990; Chapman et al,1994) and in other models of central hypersensitivity, the facilitated flexion reflex (W oolf and

Thompson, 1991) and chronic constriction of the sciatic nerve (Mao et al,1992). This opioid insensitivity appears to have correlation in clinical practice - pretreatment with analgesics appears to lesson the post­

operative pain and associated demand for post operative analgesics

(McQuay, 1992). The lack of involvement of capsaicin-sensitive afferents on which opioid receptors are found (Shibata et al,1989) or SP in the second peak of the formalin response (Ohkubo et al,1990) might explain morphine's reduced potency in inhibiting the second peak once

established.

Alternatively central mechanisms post synaptic to opiate inhibition of primary afferent neurotransmitter release may become more important during a sustained nociceptive input such as the second formalin peak. Prolonged facilitation of the flexion reflex occurs after a brief electrical conditioning stimulus (Wall and Woolf, 1984) or peripheral noxious input (Woolf, 1983) which is central in origin rather than peripheral

(Woolf, 1983; Cook et al, 1986). Interestingly this model is sometimes biphasic and also less susceptible to opiate inhibition once the facilitation is established (Wall and Woolf, 1984; Woolf and Wall; 1986a). In this model it was also suggested that excitability changes were postsynaptic to the afferent terminals since no changes in presynaptic membrane

potentials were apparent during the period of facilitation (Cook et al,1986).

Peptides have been implicated in prolonged changes in central excitability; SP, CCK, somatostatin, VIP and particularly CGRP, associated with small diameter primary afferents and released by

nociceptive stimuli (see chapter 1), produce slow depolarizations of dorsal

horn neurones with a slow onset and prolonged duration (Urban and Randic,1984; Miletic and Tan,1988;Ryu et al,1988). Furthermore intrathecal administration of these peptides produced facilitations of the flexor reflex similar to the effect of a conditioning stimulus (Xu et al,1990). There is some doubt as to the involvement of SP in the second peak of the formalin response (see before) but the reduction of the second peak behaviourally by depletion of somatostatin or intrathecal

administration of a somatostatin antagonist does suggest a role for this peptide in the formalin response (Ohkubo et al,1990). The opioid insensitivity could also involve peptides known to antagonize opioid actions such as CCK (see chapter 10), CGRP (Welch et al,1989) and somatostatin (Mulder et al,1988). Another peptide shown to interact with opioids is dynorphin and increases in dorsal horn content of this peptide and predynorphin mRNA occurred during prolonged inflammation (ladorala et al,1988; Ruda et al,I988; Weihe et al,1989). However whether the increased synthesis reflects an increased release is unknown and the time-course of these changes may be too slow in onset (>2hrs) to

participate in the formalin response (Draisci and Iadomla,1989). NMDA pathways in the spinal cord are implicated in excitability changes such as windup during prolonged acute nociceptive inputs in the dorsal horn (see chapter 3) and in the second peak of the formalin

response (see earlier). We already know that windup involving activation of NMDA pathways postsynaptic to opioid receptors is relatively

insensitive to opioids (see chapter 3). Thus an NMDA component to the second peak of the formalin response may render this response less opioid-sensitive. As already mentioned NMDA agonists are equally effective as either pre- or post-treatments in the formalin response.

NMDA mechanisms are also implicated in clinical and animal models of prolonged nociception such as neuropathic pain in which peripheral and central changes lead to a pathological pain state involving allodynia and hyperalgesia (Woolf and Thompson, 1991; Mao et al,1992; Yamamoto and Y aksh,1992; Coderre et al,1993) and are less sensitive to opioid analgesia (Arner and Meyerson,1988).

Although coadministration of naloxone with DAGOL prior to

formalin prevented opioid inhibition of the response, if the administration of naloxone was delayed to allow opioid inhibition of the first peak, the second peak failed to occur despite the adequate time for naloxone antagonism of DAGOL. This might imply that the development of the second peak is dependent on changes induced by the first peak. However blockade of the first peak by local anaesthetic into the receptive field in this electrophysiological model did not prevent the second peak occurring leading to the conclusion that aninitial peripheral input is not necessary to activate mechanisms for the second peak (Haley et al,1990). This

contrasts with the findings of Coderre et al, (1990) where transient spinal anaesthesia pre but not post formalin administration substantially reduced the behavioural formalin response, also indicating the activation of central mechanisms during the first peak which influence the development of the second peak. In addition W oolf and Wall (1986b) demonstrated that

facilitation of the flexion reflex by a conditioning stimulus was blocked by pretreatment of the sciatic nerve with capsaicin. It may be a difference in timing. The local anaesthetic effect is short and input at the beginning of the second peak may be sufficient to activate amplification mechanisms in the cord to produce the second peak, whereas insufficient opioid

antagonism occurred to allow the second peak to develop. Alternatively DAGOL-mediated central inhibitions during the first peak could affect the development of the second peak. These changes are possibly not

mimicked by peripheral local anaesthetic simply inhibiting afferent input. In conclusion the formalin response appears to be a useful

electrophysiological model of a more prolonged nociceptive input. The nociceptive neuronal activity evoked by formalin is inhibited by \x and ô opioid pretreatment in a similar dose-dependent manner to acute

nociceptive inputs. The decreased opioid-insensitivity of the formalin response to opioid post-treatment may reflect the involvement of

additional mechanisms not activated with acute nociceptive inputs which are relevant in physiological pain mechanisms.

CHAPTER 8