Analgesic Effects Of Nicotine And nAChRs Agonists In Different Pain Models

Perhaps the most compelling revelation to emerge from the collective preclinical studies on nicotinic receptor-mediated antinociception is the remarkable breadth of animal pain models in which nicotinic agonists exhibit efficacy (Table 5.1). Thus, at least ten, biochemically and pharmacologically distinct agents have shown anti-nociceptive as well as antihyperalgesic/antiallodynic activity in tests of mechanical, thermal, and chemical nociception. Interestingly, these agents are effective in models of both inflammatory (e.g., carrageenan) and neuropathic (e.g., Chung) pain. This is particularly significant because persistent pain of neuropathic origin in humans is often extremely difficult to treat by any means. Taken together, animal studies to date indicate that nicotinic agonists display a profile of antinociceptive activity at least as broad as or broader than that of any other known analgesic drug class. Moreover, this spectrum of action is characterized by very high potency and by efficacy equal to that of opioids in each case in which the two drug classes have been directly compared. What remains to be seen is to what extent such effects will translate to analgesia in humans, for which there is very little and conflicting data.

In addition to the synoptic generalizability of the nicotinic agonist effects mentioned previously, other attributes are worth noting. For instance, the vast majority of behavioral studies on nicotinic receptor-mediated antinociception to date (see Table 5.1) have assessed responses in models of spinal, somatic pain. Given the widespread incidence and prevalence of orofacial pain,4 it would be important to know whether nicotinic cholinergic drugs are likely to have any efficacy

TABLE 5.1

Summary of Nicotinic Agonist Effects on Nociception in Animals

Effect

Modality/Model

Chemical

Electrical

Mechanical

Thermal

Nociceptive Test

Nicotinic Drug

Antinociception'

Acetic Acid

Formalin (Acute Phase)

Para-phenylquinone

Tooth Pulp Stimulation

Gall Bladder Distension Paw Withdrawal (M) Cold Plate Hot Plate

Paw Withdrawal (T)

Skin Twitch Tail-Flick

Tail Withdrawal

ABT-594,111 EPI5 META,156 NIC156 ABT-594,157 EPI,16 META,156

NIC156

DMPP, NIC NIC

META,156 NIC ABT-594157

ABT-418, ABT-594, EPI, EPX, META156 NIC NMCC

A-85380,47 ABT-594, CYT,

META,10 NIC NIC

ABT-418, META156

NMCC, CYT, DMPP

EPI, NIC

EPI8

Antihyperalgesia/Antiallodynia2

Species

Mouse Rat Mouse Mouse

Rabbit

Cat Rat Mouse Mouse

Mouse, Rat

Mouse

Mouse, Rat

Mouse

Antihyperalgesia/Antiallodynia2

Capsaicin

Paw Withdrawal (T)

META,11 NIC

Rat

Carrageenan

Paw Withdrawal (M)

EPI, NIC

Rat

Paw Withdrawal (T)

EPI

Rat

CFA

Paw Withdrawal (M)

META,156 NIC156

Rat

Chung

Paw Withdrawal (M-vF)

ABT-594, META11

Rat

Formalin (Tonic

Nocifensive Behavior

A-85380,129 ABT-594, EPI5

Rat

Phase)

META156, NIC156

Mouse

Adapted from Flores and Hargreaves.51

Abbreviations: CFA, complete Freund's adjuvant; CYT, cytisine; DMPP, dimethylphenylpiperazin-ium; EPI, epibatidine; EPX, epiboxidine; M, mechanical (Randall-Selitto); M-vF, mehcanical (von Frey); META, metanicotine (RJR-2403); NIC, nicotine; NMCC, N-methylcarbamylcholine; T, thermal (Hargreaves).

1antinociceptive: relating to an increase in nociceptive threshold in naïve animals.

2antihyperalgesic/antiallodynic: relating to a reversal of the exaggerated responsiveness to noxious stimuli or of the reduction in nociceptive threshold, respectively, following injury.

in treating painful conditions of trigeminal origin. Recently, Gilbert et al.,5 showed that, in the orofacial adaptation of the formalin model,6 epibatidine exhibited dose-and time-dependent antinociception in both phases of the test. This is important because the effects in the acute and tonic phases were abolished by mecamylamine, indicating that epibatidine was exerting its antinociceptive and antihyperalgesic effects, respectively, via nicotinic receptors, thereby further extending the breadth of action for this drug class. In another example, Lawand et al.,7 showed that, in the kaolin/carrageenan model of knee joint inflammation, not only did spinally administered epibatidine reduce spontaneous pain-related behaviors as well as edema and hyperthermia of the joint, but also significantly blocked the secondary thermal hyperalgesia that developed in the ipsilateral paw. Moreover, epibatidine also was capable of reversing these effects when administered 4.5 hours after the induction of experimental arthritis. This latter finding is particularly relevant from the standpoint of human behavior that most commonly involves treatment with analgesic and/or anti-inflammatory drugs following rather than preceding tissue damage. It is important to note that this is one of only a relatively few rat studies811 showing any direct antinociceptive effects of nicotinic agents at the level of the spinal cord. Indeed, whereas some have shown that intrathecally administered nicotinic agonists have little or no antinociceptive effect,1214 others have suggested a pronociceptive effect.15 Conversely, antinociception following intrathecal injection of nicotinic agonists is more commonly and uniformly observed in the mouse.1618 Yet to be determined is the extent to which such discrepancies arise as a function of the particular species or pain model/test employed, or indicate an acute dependence on the precise route and/or site of drug application (e.g., direct intraspinal drug compared with intrathecal injections) or, more likely, on the drug itself.

Another promising avenue of research involves the evaluation of combinatorial antinociceptive effects produced by the coadministration of nicotine and opioids. For example, intrathecal or intracerebroventricular nicotine, at doses which had little effect by themselves, potentiated the antinociception produced by morphine.1920 Similarly, Zarrindast et al.,21 found that doses of nicotine as low as 0.0001 mg/kg, which had no antinociceptive effects alone, potentiated morphine-induced antinoci-ception in the tail-flick assay. It is interesting that whereas naloxone predictably reduced the response to morphine in the presence or absence of nicotine, atropine — but not mecamylamine — blocked the potentiating effects of nicotine. Whether such a result is idiosyncratic, indicates a complex interaction between nicotinic and muscarinic receptors or implicates the involvement of an atropine-sensitive nicotinic receptor subtype (e.g., a922) remains to be determined. Nonetheless, this line of investigation provides a rationale for the relatively attractive approach of using a nicotinic analgesic as an opioid-sparing adjunct or vice versa. Indeed, the major limitation of currently utilized analgesics agents, aside from a lack of efficacy against certain types of pain, is dose-limiting toxicity. For the opioids, in particular, such untoward effects include a potential abuse liability. This concern over chemical dependence increases as tolerance develops because of the consequent necessity to escalate the dose and frequency of administration, raising apprehensions that can result in underutilization and undertreatment.

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